Topical steroid use for suppression of hypergranulation in burns: Trends across the Atlantic.

Hypergranulated wounds from thermal injury remain a complex and debilitating problem for burn patients. Currently, there is no standard therapy to prevent or treat hypergranulation following burn injury. Many centers use topical corticosteroids; however, their use seems to be geographically dependent and controversial. The primary aim of this study was to quantify the current use of topical corticosteroids for post-burn hypergranulation in North America (NA) and Europe, while secondarily assessing for perceptions of safety and efficacy. We designed a survey that was distributed to the members of the European and American Burn Associations. Data was extracted and analyzed using SPSS software. A total of 165 respondents completed the survey (90 and 75 for the European and NA members, respectively). Seventy-one of the 90 (78.9%) European respondents reported they routinely use topical steroids for suppression of hypergranulation tissue in burns, versus 25 of the 75 (33.3%) NA respondents (p<0.001). European respondents, compared to NA respondents, were significantly more likely to consider topical steroid use safe (100% vs. 74.4%, p <0.001) and effective (98.6% vs. 66.7%, p < 0.001) for treatment of hypergranulated burn wounds. There was no significant difference in reported systemic effects seen after topical steroid use when comparing NA respondents and European respondents (6.5% vs. 6.9%, p > 0.10). The results of this study suggest that the use of steroids for hypergranulation tissue in burn care is more prevalent in Europe than NA, which may be due to discordant views on safety and efficacy despite minimal reported adverse effects.

A Review of Laser Therapies for the Treatment of Scarring and Vascular Anomalies.

Significance: Laser use has become part of the gold standard of treatment as an effective adjuvant in multimodal therapy for pathologic scarring caused by burns, trauma, acne, and surgery, as well as vascular anomalies. Understanding indications and applications for laser therapy is essential for physicians to improve patient outcomes. Recent Advances: Since the 1980s, the medical use of lasers has continuously evolved with improvements in technology. Novel lasers and fractionated technologies are currently being studied in the hopes to improve treatment efficacy, while reducing complications. Recent advancements include acne treatment with novel picosecond lasers, new hypertrophic scar therapies with simultaneous laser and intense pulsed light use, and novel systems such as lasers with intralesional optical fiber delivery devices. In addition, optimizing the timing of laser therapy and its use in multimodal treatments continue to advance the field of photothermolysis. Critical Issues: Selecting the correct laser for a given indication is the fundamental decision when choosing a laser balancing effective treatment with minimal complications. This article covers the principles of laser therapy, the preferred lasers used for the treatment of scarring and vascular anomalies, and discusses the current evidence behind these laser choices. Future Directions: To optimize laser therapy, larger randomized control trials and split scar studies are needed. Continued advancement through better randomized controlled studies will help to improve patient outcomes on a broader scale.

Provider Perception of Time During Trauma Resuscitation: A Prospective Quantitative Trauma Video Review Analysis.

INTRODUCTION: Delays in transition to the next phase of care result in increased mortality. Prehospital literature suggests emergency medical service technicians underestimate transport times by as much as 20%. What remains unknown is clinician perception of time during the trauma resuscitation. We sought to determine if clinicians have an altered perception of time. We hypothesized that clinicians underestimate time, resulting in delay of care. METHODS: Clinicians at a large level 1 trauma center completed a post-trauma activation survey on the perceived elapsed time to complete three specific resuscitation endpoints. The primary study endpoint was the time to the next phase of care, defined as leaving the trauma bay to go to the operating room, interventional radiology, computerized tomography or time of death. The data from the surveys were linked and compared with recorded videos of the resuscitations. The difference in perceived versus actual time, along with confounding variables, was used to assess the impact of perception of time on the time to the next phase of care using a stepwise multivariate linear model. RESULTS: There were 284 complete surveys and videos, culminating in 543 time points. The median perceived versus actual time (minutes [interquartile range]) to the next phase of care was 20 [10-25] versus 26 [19-40] (P < 0.001). Overall, clinicians underestimated time by 28%, such that if the resuscitation lasted 20 min, the clinician's perception was that 14.4 min elapsed. Differences in the perceived versus actual time in the procedure group impacted time to the next phase of care (P = 0.01). CONCLUSIONS: Clinicians have significant gaps in the perception of time during trauma resuscitations. This misperception occurs during procedures and correlates with an increase in the length of time to the next phase of care.

The cGAS-STING pathway connects mitochondrial damage to inflammation in burn-induced acute lung injury in rat.

OBJECTIVE: Damage associated molecular patterns (DAMPs) are pathological mediators linking local tissue damage to systemic inflammation in various diseases. Some DAMPs, such as mitochondrial DNA (mtDNA), can be recognized by the cytoplasmic cGAS protein to trigger the activation of the stimulator of interferon genes (STING)-dependent innate immune pathway responsible for infection or sterile inflammation. The objective of our study was to evaluate the association between circulating mtDNA and cGAS-STING pathway activation in mediating inflammation following burn injury. METHODS: 48 adult Sprague-Dawley male rats were divided into eight groups (Sham, 2, 4, 8, 12, 24, 48, 72 h after burn injury). The animals underwent 40% total body surface area scald injury to produce a full-thickness burn. Plasma samples were collected via cardiac puncture under deep anesthesia. Tissues were harvested and placed in formalin, followed by paraffin embedment. Total plasma DNA was isolated followed by measurement of mtDNA using quantitative polymerase chain reaction. Haemotoxylin-Eosin stain and Western blot was used for lung histology and protein assays, respectively. Statistical analyses were performed using ANOVA and student's t-test and represented as mean ± s.d. RESULTS: Plasma mtDNA trended upward at early time-points following burn injury with peak levels at 8 h after burn when compared to the control group (345 ± 83.4 copies/µl vs. 239 ± 43.1 copies/µl, p = 0.07) and followed a bell-shaped distribution. Lung slices from burned rats showed acute injury marked by increased inflammatory infiltrate, with the maximum changes seen at 24 h, accompanied with significant upregulation of neutrophil elastase (p = 0.04). Compared with sham animals, cGAS and STING protein levels in lung tissue were up-regulated at 4 and 8 h after burn (p = 0.03 and p < 0.001, respectively). CONCLUSION: Activation of the cGAS-STING pathway by increased plasma mtDNA is an important pathway driving neutrophil infiltration in burn-induced acute lung injury in rats. A further understanding of the STING-mediated immunopathology in lung and other susceptible organs may be important for the development of novel therapies for burn injury.

Inflammasome-Dependent Coagulation Activation in Sepsis.

Sepsis is a potentially life-threatening, pathological condition caused by a dysregulated host response to infection. Pathologically, systemic inflammation can initiate coagulation activation, leading to organ dysfunction, and ultimately to multiple organ failure and septic death. The inflammasomes are cytosolic multiprotein signaling complexes that control the host response to diverse pathogen-associated molecular patterns (PAMPs) from microorganisms as well as damage-associated molecular patterns (DAMPs) from dead or dying host cells. Recent studies highlight that the activation of canonical and non-canonical inflammasomes not only mediate the maturation and secretion of interleukin-1 (IL1) family cytokines, but also trigger the release of coagulation factor III, tissue factor (F3, best known as TF) in activated macrophages and monocytes. These emerging functions of inflammasomes in immunocoagulation are further positively regulated by stimulator of interferon response cGAMP interactor 1 (STING1, also known as STING or TMEM173, a hub of the innate immune signaling network) and high mobility group box 1 (HMGB1, a nuclear DAMP). This mini-review will discuss the regulation and function of inflammasome-dependent coagulation activation in sepsis.

Adoption of rescue colloid during burn resuscitation decreases fluid administered and restores end-organ perfusion.

INTRODUCTION: Traditionally, lactated Ringer's solution (LR) has been utilized for the resuscitation of thermally injured patients via the Parkland or Brooke formulas. Both of these formulas include colloid supplementation after 24 h of resuscitation. Recently, the addition of albumin within the initial resuscitation has been reported to decrease fluid creep and hourly fluids given. Our institution has previously advocated for a crystalloid-driven resuscitation. Given reports of improved outcomes with albumin, we pragmatically adjusted these practices and present our findings for doing so. METHODS: Our burn registry, consisting of prospectively collected patient data, was queried for those at least 18 years of age who, between July 2017 and December 2018, sustained a thermal injury and completed a formal resuscitation (24 h). At the attending physician's discretion, rescue colloid was administered using 25% albumin for those failing to respond to traditional resuscitation (patients with sustained urine output of <0.5 mL/kg over 2-3 h, or unstable vital signs and ongoing fluid administration). We compared the total volume of the crystalloid-only and rescue colloid resuscitation fluids given to patients. We also examined the in/out fluid balances during resuscitation. Statistical analysis was performed using Stata software. RESULTS: A total of 91 patients with thermal injuries were included: the median age was 40 (IQR 31-57), 73% were male, and 30 patients received rescue albumin. The percentage of total body surface area burned (%TBSA) was greater in those who received rescue albumin (40.3% vs. 34%; p = 0.047). Despite a higher %TBSA in the albumin group, the total LR given during resuscitation was not significantly different between groups (15,914.43 mL vs. 11,828.71 mL; p = 0.129) even when normalized for TBSA and weight (ml LR/kg/%TBSA: 4.31 vs. 3.66; p = 0.129. The average in/out fluid ratio for the rescue group was higher than for the crystalloid group (0.83 ± 0.05 vs. 0.59 ± 0.11; p = 0.06) and returned to normal after colloid administration. CONCLUSION: Rescue albumin administration decreases the amount of fluid administered per %TBSA during resuscitation, and also increases end organ function as evidenced by increased urinary output. These effects occurred in patients who sustained larger burns and failed to respond to traditional crystalloid resuscitation. Our findings led us to modify our current protocol and a related prospective study of clinical outcomes.

Pharmacological Modulation of BET Family in Sepsis.

The Third International Consensus Definitions for Sepsis and Septic Shock (Sepsis 3.0) recommended defining sepsis as a life-threatening organ dysfunction caused by the host's uncontrolled response to infection. The bromodomain and extra-terminal (BET) protein family (such as BRD2, BRD3, and BRD4), an epigenetic regulator of gene transcription, has recently been recognized as a significant septic regulator of inflammation and immune response, including cytokine and chemokine production. Mechanistically, the two N-terminal conserved tandem bromodomains (namely the first bromodomain [BD1] and the second bromodomain [BD2]) favor the binding of BETs to acetylated histones or transcription factors, thereby initiating gene transcription machinery after CycT1 and CDK9 (also known as P-TEFb) are recruited to gene promoters to phosphorylate RNA pol II. Notably, BD1 and BD2 are not functionally redundant because they have different target genes in innate immune cells. Small-molecule BET inhibitors (BETis) for different BDs, such as I-BET, JQ1, I-BET151, apabetalone, RVX-297, and dBET1 have shown promising therapeutic effects in experimental sepsis models. This mini-review summarizes the emerging roles of BETs and the applications of BETis in sepsis, discusses the existing shortcomings of BETis, and introduces possible future research directions in this area.

Characteristics and Biomarkers of Ferroptosis.

The induction and consequences of regulated cell death (RCD) are accompanied by changes in gene and protein expression, biochemical pathways, as well as cell morphology and size. Such RCDs have a significant impact on development, tissue homeostasis, and the occurrence and progression of disease. Among different forms of RCD, ferroptosis appears to be the main cause of tissue damage driven by iron overload and lipid peroxidation. In fact, the dysfunctional ferroptotic response is implicated in a variety of pathological conditions and diseases, such as neurodegenerative diseases, tissue ischemia-reperfusion injury, tumorigenesis, infections, and immune diseases. Ferroptotic response can be fine-tuned through various oxidative stress and antioxidant defense pathways, coupling with metabolism, gene transcription, and protein degradation machinery. Accordingly, a series of ferroptosis inducers or inhibitors targeting redox- or iron metabolism-related proteins or signal transduction have been developed. Although this kind of RCD has recently attracted great interest in basic and clinical research, detecting and monitoring a ferroptotic response still faces challenges. In this mini-review, we not only summarize the latest knowledge about the characteristics of ferroptosis in vitro and in vivo, but also discuss the specificity and limitations of current biomarkers of ferroptosis.

Fast track pathway provides safe, value based care on busy acute care surgery service.

BACKGROUND: Fast track (FT) pathways have been adopted across a multitude of elective surgeries but have been slow to be adopted into the acute care surgery realm. We hypothesized that an FT pathway for acute cholecystitis patients would decrease patient length of stay and resource utilization. METHODS: All patients at two hospitals, one with an FT pathway and one with a traditional pathway, who underwent an urgent laparoscopic cholecystectomy for acute cholecystitis between May 1, 2019, and October 31, 2019, were queried using CPT codes. Exclusion criteria were conversion to open or partial cholecystectomy. Retrospective chart review was used to gather demographics, operative, hospital course, and outcomes. Time to operating room, hospital length of stay, and resource utilization were the primary outcomes. RESULTS: There was a total of 479 urgent laparoscopic cholecystectomies performed, 430 (89.8%) were performed under the FT pathway. The median (interquartile range [IQR]) time to the operating room was not different: 14.1 hours (IQR, 8.3-29.0 hours) for FT and 18.5 hours (IQR, 11.9-25.9 hours) for traditional (p = 0.316). However, the median length of stay was shorter by 15.9 hours in the FT cohort (22.6 hours; IQR, 14.2-40.4 hours vs. 38.5 hours; IQR, 28.3-56.3 hours; p < 0.001). Under the FT pathway, 33.0% of patients were admitted to the hospital and 75.6% were discharged from the postanesthesia care unit, compared with 91.8% and 12.2% on the traditional pathway (both p < 0.001). There were 59.6% of the FT patients that received a phone call follow up, as opposed to 100% of the traditional patients having clinic follow up (p < 0.001). The emergency department bounce back rate, readmission rates, and complication rates were similar (p > 0.2 for all). On multivariate analysis, having a FT pathway was an independent predictor of discharge within 24 hours of surgical consultation (odds ratio, 7.65; 95% confidence interval< 2.90-20.15; p < 0.001). CONCLUSION: Use of a FT program for patients with acute cholecystitis has a significant positive impact on resource utilization without compromise of clinical outcomes. LEVEL OF EVIDENCE: Therapeutic/care management, level IV.

Damage-Associated Molecular Patterns and the Systemic Immune Consequences of Severe Thermal Injury.

Thermal injury is often associated with a proinflammatory state resulting in serious complications. After a burn, the innate immune system is activated with subsequent immune cell infiltration and cytokine production. Although the innate immune response is typically beneficial, an excessive activation leads to cytokine storms, multiple organ failure, and even death. This overwhelming immune response is regulated by damage-associated molecular patterns (DAMPs). DAMPs are endogenous molecules that are actively secreted by immune cells or passively released by dead or dying cells that can bind to pathogen recognition receptors in immune and nonimmune cells. Recent studies involving animal models along with human studies have drawn great attention to the possible pathological role of DAMPs as an immune consequence of thermal injury. In this review, we outline DAMPs and their function in thermal injury, shedding light on the mechanism of sterile inflammation during tissue injury and identifying new immune targets for treating thermal injury.

The hallmarks of COVID-19 disease.

Severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) is a novel coronavirus that has caused a worldwide pandemic of the human respiratory illness COVID-19, resulting in a severe threat to public health and safety. Analysis of the genetic tree suggests that SARS-CoV-2 belongs to the same Betacoronavirus group as severe acute respiratory syndrome coronavirus (SARS-CoV) and Middle East respiratory syndrome coronavirus (MERS-CoV). Although the route for viral transmission remains a mystery, SARS-CoV-2 may have originated in an animal reservoir, likely that of bat. The clinical features of COVID-19, such as fever, cough, shortness of breath, and fatigue, are similar to those of many acute respiratory infections. There is currently no specific treatment for COVID-19, but antiviral therapy combined with supportive care is the main strategy. Here, we summarize recent progress in understanding the epidemiological, virological, and clinical characteristics of COVID-19 and discuss potential targets with existing drugs for the treatment of this emerging zoonotic disease.

Transcription factors in ferroptotic cell death.

Ferroptosis, a form of regulated cell death, is characterized by an excessive degree of iron accumulation and lipid peroxidation. Although it was originally identified only in cells expressing a mutant RAS oncogene, ferroptosis has also been found in normal cells following treatment by small molecules (e.g., erastin and RSL3) or drugs (e.g., sulfasalazine, sorafenib, and artesunate), which target antioxidant enzyme systems, especially the amino acid antiporter system xc- and the glutathione peroxidase GPX4. Dysfunctional ferroptosis is implicated in various physiological and pathological processes (e.g., metabolism, differentiation, and immunity). Targeting the ferroptotic network appears to a new treatment option for diseases or pathological conditions (e.g., cancer, neurodegeneration, and ischemia reperfusion injury). While the molecular machinery of ferroptosis remains largely unknown, several transcription factors (e.g., TP53, NFE2L2/NRF2, ATF3, ATF4, YAP1, TAZ, TFAP2C, SP1, HIF1A, EPAS1/HIF2A, BACH1, TFEB, JUN, HIC1, and HNF4A) play multiple roles in shaping ferroptosis sensitivity through either transcription-dependent or transcription-independent mechanisms. In this review, we summarize recent progress in understanding the transcriptional regulation underlying ferroptotic cell death, and discuss how it has provided new insights into cancer therapy.

Fetal cyclophosphamide exposure induces testicular cancer and reduced spermatogenesis and ovarian follicle numbers in mice.

Exposure to radiation during fetal development induces testicular germ cell tumors (TGCT) and reduces spermatogenesis in mice. However, whether DNA damaging chemotherapeutic agents elicit these effects in mice remains unclear. Among such agents, cyclophosphamide (CP) is currently used to treat breast cancer in pregnant women, and the effects of fetal exposure to this drug manifested in the offspring must be better understood to offer such patients suitable counseling. The present study was designed to determine whether fetal exposure to CP induces testicular cancer and/or gonadal toxicity in 129 and in 129.MOLF congenic (L1) mice. Exposure to CP on embryonic days 10.5 and 11.5 dramatically increased TGCT incidence to 28% in offspring of 129 mice (control value, 2%) and to 80% in the male offspring of L1 (control value 33%). These increases are similar to those observed in both lines of mice by radiation. In utero exposure to CP also significantly reduced testis weights at 4 weeks of age to ∼ 70% of control and induced atrophic seminiferous tubules in ∼ 30% of the testes. When the in utero CP-exposed 129 mice reached adulthood, there were significant reductions in testicular and epididymal sperm counts to 62% and 70%, respectively, of controls. In female offspring, CP caused the loss of 77% of primordial follicles and increased follicle growth activation. The results indicate that i) DNA damage is a common mechanism leading to induction of testicular cancer, ii) increased induction of testis cancer by external agents is proportional to the spontaneous incidence due to inherent genetic susceptibility, and iii) children exposed to radiation or DNA damaging chemotherapeutic agents in utero may have increased risks of developing testis cancer and having reduced spermatogenic potential or diminished reproductive lifespan.

Fetal radiation exposure induces testicular cancer in genetically susceptible mice.

The prevalence of testicular germ cell tumors (TGCT), a common solid tissue malignancy in young men, has been annually increasing at an alarming rate of 3%. Since the majority of testicular cancers are derived from germ cells at the stage of transformation of primordial germ cell (PGC) into gonocytes, the increase has been attributed to maternal/fetal exposures to environmental factors. We examined the effects of an estrogen (diethylstilbestrol, DES), an antiandrogen (flutamide), or radiation on the incidence of testicular germ cell tumors in genetically predisposed 129.MOLF-L1 (L1) congenic mice by exposing them to these agents on days 10.5 and 11.5 of pregnancy. Neither flutamide nor DES produced noticeable increases in testis cancer incidence at 4 weeks of age. In contrast, two doses of 0.8-Gy radiation increased the incidence of TGCT from 45% to 100% in the offspring. The percentage of mice with bilateral tumors, weights of testes with TGCT, and the percentage of tumors that were clearly teratomas were higher in the irradiated mice than in controls, indicating that irradiation induced more aggressive tumors and/or more foci of initiation sites in each testis. This radiation dose did not disrupt spermatogenesis, which was qualitatively normal in tumor-free testes although they were reduced in size. This is the first proof of induction of testicular cancer by an environmental agent and suggests that the male fetus of women exposed to radiation at about 5-6 weeks of pregnancy might have an increased risk of developing testicular cancer. Furthermore, it provides a novel tool for studying the molecular and cellular events of testicular cancer pathogenesis.