Hemodynamic Deterioration of Trauma Patients Undergoing Interhospital Transfer.

INTRODUCTION: Organized trauma systems reduce morbidity and mortality after serious injury. Rapid transport to high-level trauma centers is ideal, but not always feasible. Thus, interhospital transfers are an important component of trauma systems. However, transferring a seriously injured patient carries the risk of worsening condition before reaching definitive care. In this study, we evaluated characteristics and outcomes of patients whose hemodynamic status worsened during the transfer process. METHODS: We conducted a retrospective cohort study using data from the Pennsylvania Trauma Outcomes Study database from 2011 to 2018. Patients were included if they had a heart rate ≤ 100 and systolic blood pressure ≥ 100 at presentation to the referring hospital and were transferred within 24 h. We defined hemodynamic deterioration (HDD) as admitting heart rate > 100 or systolic blood pressure < 100 at the receiving center. We compared demographics, mechanism of injury, injury severity, management, and outcomes between patients with and without HDD using descriptive statistics and multivariable regression analysis. RESULTS: Of 52,919 included patients, 5331 (10.1%) had HDD. HDD patients were more often moderately-severely injured (injury severity score 9-15; 40.4% versus 39.4%, P < 0.001) and injured via motor vehicle collision (23.2% versus 16.6%, P < 0.001) or gunshot wound (2.1% versus 1.3%, P < 0.001). HDD patients more often had extremity or torso injuries and after transfer were more likely to be transferred to the intensive care unit (35% versus 28.5%, P < 0.001), go directly to surgery (8.4% versus 5.9%, P < 0.001), or interventional radiology (0.8% versus 0.3%, P < 0.001). Overall mortality in the HDD group was 4.9% versus 2.1% in the group who remained stable. These results were confirmed using multivariable analysis. CONCLUSIONS: Interhospital transfers are essential in trauma, but one in 10 transferred patients deteriorated hemodynamically in that process. This high-risk component of the trauma system requires close attention to the important aspects of transfer such as patient selection, pretransfer management/stabilization, and communication between facilities.

Overriding native cell coordination enhances external programming of collective cell migration.

As collective cell migration is essential in biological processes spanning development, healing, and cancer progression, methods to externally program cell migration are of great value. However, problems can arise if the external commands compete with strong, preexisting collective behaviors in the tissue or system. We investigate this problem by applying a potent external migratory cue-electrical stimulation and electrotaxis-to primary mouse skin monolayers where we can tune cell-cell adhesion strength to modulate endogenous collectivity. Monolayers with high cell-cell adhesion showed strong natural coordination and resisted electrotactic control, with this conflict actively damaging the leading edge of the tissue. However, reducing preexisting coordination in the tissue by specifically inhibiting E-cadherin-dependent cell-cell adhesion, either by disrupting the formation of cell-cell junctions with E-cadherin-specific antibodies or rapidly dismantling E-cadherin junctions with calcium chelators, significantly improved controllability. Finally, we applied this paradigm of weakening existing coordination to improve control and demonstrate accelerated wound closure in vitro. These results are in keeping with those from diverse, noncellular systems and confirm that endogenous collectivity should be considered as a key quantitative design variable when optimizing external control of collective migration.

A time-dependent survival analysis for early prognosis of chronic wounds by monitoring wound alkalinity.

The objective is to determine whether monitoring wound alkalinity between visits may help prognosticate chronic wound healing. The alkalinity of 167 wounds during the first 3 visits was assessed using disposable DETEC® pH. Wounds grouped by frequency of alkaline results were compared by % wound size reduction during each visit and 120-day healing probability. The Cox proportional hazards model for time-dependent variables was used to generate non-healing probability curves, where variables are binary (alkaline/non-alkaline, infection/no infection), categorical (wound type), and continuous (wound area); the response is time to complete wound healing; and the event of interest is complete wound healing in 120 days. Results show that wounds with frequent alkaline results have significantly smaller % size reduction per visit. Logistic regression shows an increase in 120-day healing probability with fewer alkaline results. Survival analysis shows that the instantaneous healing rate of non-alkaline or non-alkaline transitioning wounds is 1.785, 2.925, and 5.908 times that of alkaline or alkaline-transitioning wounds for 1, 2, and 3 alkalinity measurements, respectively. Furthermore, the concordance statistic of each survival model shows that goodness of fit increases with more alkalinity measurements. Overall, frequent wound alkalinity assessments may serve as a novel way to prognosticate wound healing outcomes.

Contact allergy mimicking trench foot infection: a case study.

Hard-to-heal wounds are a major cause of morbidity and/or mortality. Multiple aetiologies can be identified and wounds can be treated according to their aetiology and macroscopic appearance. However, evidence behind the wide range of locally applied treatments is weak, without clear guidelines available to treat a variety of wound aetiologies. We present the case of a 63-year-old male with hard-to-heal wounds not responding to standard topical treatment. No clear underlying aetiology could be found. Extensive contact allergies were diagnosed after multiple topical and systemic treatments had been applied. A full recovery was observed after stopping topical agents and treating the wounds with an alternative treatment based on epicutaneous test results.

Mitochondria-cytokine crosstalk following skeletal muscle injury and disuse: a mini-review.

Skeletal muscle mitochondria are highly adaptable, highly dynamic organelles that maintain the functional integrity of the muscle fiber by providing ATP for contraction and cellular homeostasis (e.g., Na+/K+ ATPase). Emerging as early modulators of inflammation, mitochondria sense and respond to cellular stress. Mitochondria communicate with the environment, in part, by release of physical signals called mitochondrial-derived damage-associated molecular patterns (mito-DAMPs) and deviation from routine function (e.g., reduced ATP production, Ca2+ overload). When skeletal muscle is compromised, mitochondria contribute to an acute inflammatory response necessary for myofibril regeneration; however, exhaustive signaling associated with altered or reduced mitochondrial function can be detrimental to muscle outcomes. Here, we describe changes in mitochondrial content, structure, and function following skeletal muscle injury and disuse and highlight the influence of mitochondria-cytokine crosstalk on muscle regeneration and recovery. Although the appropriate therapeutic modulation following muscle stressors remains unknown, retrospective gene expression analysis reveals that interleukin-6 (IL-6), interleukin-1ß (IL-1ß), chemokine C-X-C motif ligand 1 (CXCL1), and monocyte chemoattractant protein 1 (MCP-1) are significantly upregulated following three unique muscle injuries. These cytokines modulate mitochondrial function and execute bona fide pleiotropic roles that can aid functional recovery of muscle, however, when aberrant, chronically disrupt healing partly by exacerbating mitochondrial dysfunction. Multidisciplinary efforts to delineate the opposing regulatory roles of inflammatory cytokines in the muscle mitochondrial environment are required to modulate regenerative behavior following skeletal muscle injury or disuse. Future therapeutic directions to consider include quenching or limited release of mito-DAMPs and cytokines present in cytosol or circulation.

Metabolic reprogramming mediates hippocampal microglial M1 polarization in response to surgical trauma causing perioperative neurocognitive disorders.

BACKGROUND: Microglial polarization toward pro-inflammatory M1 phenotype are major contributors to the development of perioperative neurocognitive disorders (PNDs). Metabolic reprogramming plays an important role in regulating microglial polarization. We therefore hypothesized that surgical trauma can activate microglial M1 polarization by metabolic reprogramming to induce hippocampal neuroinflammation and subsequent postoperative cognitive impairment. METHODS: We used aged mice to establish a model of PNDs, and investigated whether surgical trauma induced metabolic reprograming in hippocampus using PET/CT and GC/TOF-MS based metabolomic analysis. We then determined the effect of the glycolytic inhibitor 2-deoxy-D-glucose (2-DG) on hippocampal microglial M1 polarization, neuroinflammation, and cognitive function at 3 d after surgery. RESULTS: We found that surgery group had less context-related freezing time than either control or anesthesia group (P < 0.05) without significant difference in tone-related freezing time (P > 0.05). The level of Iba-1 fluorescence intensity in hippocampus were significantly increased in surgery group than that in control group (P < 0.05) accompanied by activated morphological changes of microglia and increased expression of iNOS/CD86 (M1 marker) in enriched microglia from hippocampus (P < 0.05). PET/CT and metabolomics analysis indicated that surgical trauma provoked the metabolic reprogramming from oxidative phosphorylation to glycolysis in hippocampus. Inhibition of glycolysis by 2-DG significantly alleviated the surgical trauma induced increase of M1 (CD86+CD206-) phenotype in enriched microglia from hippocampus and up-regulation of pro-inflammatory mediators (IL-1ß and IL-6) expression in hippocampus. Furthermore, glycolytic inhibition by 2-DG ameliorated the hippocampus dependent cognitive deficit caused by surgical trauma. CONCLUSIONS: Metabolic reprogramming is crucial for regulating hippocampal microglial M1 polarization and neuroinflammation in PNDs. Manipulating microglial metabolism might provide a valuable therapeutic strategy for treating PNDs.

The multifaceted role of fibrinogen in tissue injury and inflammation.

The canonical role of the hemostatic and fibrinolytic systems is to maintain vascular integrity. Perturbations in either system can prompt primary pathological end points of hemorrhage or thrombosis with vessel occlusion. However, fibrin(ogen) and proteases controlling its deposition and clearance, including (pro)thrombin and plasmin(ogen), have powerful roles in driving acute and reparative inflammatory pathways that affect the spectrum of tissue injury, remodeling, and repair. Indeed, fibrin(ogen) deposits are a near-universal feature of tissue injury, regardless of the nature of the inciting event, including injuries driven by mechanical insult, infection, or immunological derangements. Fibrin can modify multiple aspects of inflammatory cell function by engaging leukocytes through a variety of cellular receptors and mechanisms. Studies on the role of coagulation system activation and fibrin(ogen) deposition in models of inflammatory disease and tissue injury have revealed points of commonality, as well as context-dependent contributions of coagulation and fibrinolytic factors. However, there remains a critical need to define the precise temporal and spatial mechanisms by which fibrinogen-directed inflammatory events may dictate the severity of tissue injury and coordinate the remodeling and repair events essential to restore normal organ function. Current research trends suggest that future studies will give way to the identification of novel hemostatic factor-targeted therapies for a range of tissue injuries and disease.

The majority of major amputations after resuscitative endovascular balloon occlusion of the aorta are associated with preadmission trauma.

OBJECTIVE: Resuscitative endovascular balloon occlusion of the aorta (REBOA) is a potentially life-saving intervention. However, recent reports of associations with limb loss and mortality have called its safety into question. We aimed to evaluate patient and hospital characteristics associated with major amputation and in-hospital mortality among patients undergoing REBOA for trauma. METHODS: The National Trauma Data Bank (2015-2017) was queried for patients presenting to trauma centers and treated with REBOA. We included REBOA performed on hospital day 1 in patients who survived 6 or more hours from presentation. Univariable and multivariable analyses evaluated associations with major amputation and in-hospital mortality. RESULTS: A total of 316 patients underwent REBOA and survived in the acute period after presentation. Overall, mean age was 45 ± 20 years and the majority were male (73%) and White (56%). Most patients presented to level I trauma centers (72%) after blunt injuries (79%) with an average Injury Severity Score (ISS) of 31 ± 15, indicating major trauma. In 15 patients (5%), there were 18 major amputations-7 above knee and 11 below knee. A subgroup of 11 amputations were either traumatic amputations (73%) or mangled limbs requiring amputation within 24 hours (27%). Of the remaining amputations, 71% were associated with ipsilateral vascular or orthopedic lower extremity injuries of serious to severe Abbreviated Injury Scale severity. Comparing patients with amputations with those without amputations, there were no significant differences in patient demographics, comorbidities, or hospital characteristics. During hospitalization, patients requiring amputation more frequently received open peripheral vascular interventions (40% vs 10%; P = .002), underwent similar numbers of endovascular interventions (6.7% vs 4.7%; P = .5), and more often developed compartment syndrome (13% vs 2%; P = .04). Overall, there were 110 deaths (35%). The major amputation prevalence was similar between patients who died vs those who survived (3.6% vs 5.3%; P = .5). In multivariable analysis, prehospital cardiac arrest (odds ratio [OR], 8.47; 95% confidence interval [CI], 1.47-48.66; P = .02), penetrating vs blunt trauma (OR, 5.5; 95% CI, 1.05-28.82; P = .04), decreased Glasgow Coma Scale score (OR, 1.18; 95% CI, 1.05-1.32; P = .01), older age (OR, 1.06; 95% CI, 1.03-1.10; P < .001), and increased Injury Severity Score (OR, 1.05; 95% CI, 1.0-1.1; P = .03) were associated with higher mortality. CONCLUSIONS: The majority of major amputations in patients undergoing REBOA were secondary to the initial traumatic mechanism. Injury type and severity, as well as initial hemodynamic derangements, are associated with mortality after REBOA. Despite concerns about prohibitive limb complications of REBOA, baseline injuries seem to be the primary cause of limb loss, but further prospective analysis is needed.

Cold atmospheric plasma improves cutaneous microcirculation in standardized acute wounds: Results of a controlled, prospective cohort study.

BACKGROUND: Given the high prevalence of wounds and their challenging treatment, the research of therapies to improve wound healing is of great clinical interest. In addition, the general consequences of developing chronic wounds constitute a large health economic aspect, which underscores the interest in the development of efficient treatment strategies. Direct cold atmospheric plasma (di_CAP) has been shown to have beneficial effects on microcirculation of human tissue (Kisch et al., 2016a). It also affects microbial settlements, which may have supportive effects on wound healing processes (Balzer et al., 2015). To treat these adequately, in our view, the positive effects on wound healing should be objectified by application on standardized wounds. However, wound healing is a complex process, depending on nutrient and oxygen supply by cutaneous blood circulation. In spite of microcirculation has been shown to improve in healthy skin by CAP, a quantification of the effect in a standardized wound model has never been evaluated (Kisch et al., 2016a). Based on this, we hypothesize that CAP also influences the microcirculation in standardized acute wounds in a prospective cohort study. METHODS: Microcirculatory data of 20 healthy subjects (14 males, 6 females; mean age 40.85 ± 15.84 years; BMI 26.83 ± 7.27 kg/m2) were recorded continuously at a standardized acute wound after skin transplantation (donor site) at the thigh. Under standardized conditions, microcirculatory measurements were performed using a combined laser Doppler and photospectrometry system. After baseline measurement, CAP was applied by a dielectric barrier discharge (DBD) plasma device for 90 s to the acute wound area. Immediately after the application, cutaneous microcirculation was assessed for 30 min (min) at the same site. RESULTS: After CAP application, tissue oxygen saturation immediately increased by 5% (92,66 ± 4,76% vs. Baseline 88,21 ± 6,52%, p < 0,01) in the first 60 s and remained significantly elevated for 4 min. Capillary blood flow increased by 19.3% within the first minute of CAP therapy (220.14 ± 65.91 AU vs. Baseline 184.52 ± 56.77 AU, p < 0.001). The statistically highly significant increase in blood flow continued over the entire measurement time. A maximum value was shown in the blood flow in the 15th minute (232.15 ± 58.90 AU, p < 0.001) according to CAP application. With regard to the output measurement, it represents a percentage increase of 25.8%. The measurement of post-capillary venous filling pressure at a tissue depth of 6-8 mm was 59.39 ± AU 12.94 at baseline measurement. After application, there were no significant changes. CONCLUSION: CAP increases cutaneous tissue oxygen saturation and capillary blood flow at the standardized acute wound healing model. These results support recently published data on wound healing after CAP treatment. However, further studies are needed to determine if this treatment can improve the reduced microcirculation in chronic wounds. Moreover, repetitive application protocols have to be compared with a single session treatment approach.

Compensatory reserve detects subclinical shock with more expeditious prediction for need of life-saving interventions compared to systolic blood pressure and blood lactate.

INTRODUCTION: We conducted a prospective observational study on 205 trauma patients at a level I trauma facility to test the hypothesis that a compensatory reserve measurement (CRM) would identify higher risk for progression to shock and/or need a life-saving interventions (LSIs) earlier than systolic blood pressure (SBP) and blood lactate (LAC). METHODS: A composite outcome metric included blood transfusion, procedural LSI, and mortality. Discrete measures assessed as abnormal (ab) were SBP <90 mmHg, CRM <60%, and LAC >2.0. A graded categorization of shock was defined as: no shock (normal [n] SBP [n-SBP], n-CRM, n-LAC); sub-clinical shock (ab-CRM, n-SBP, n-LAC); occult shock (n-SBP, ab-CRM, ab-LAC); or overt shock (ab-SBP, ab-CRM, ab-LAC). RESULTS: Three patients displayed overt shock, 53 displayed sub-clinical shock, and 149 displayed no shock. After incorporating lactate into the analysis, 86 patients demonstrated no shock, 25 were classified as sub-clinical shock, 91 were classified as occult shock, and 3 were characterized as overt shock. Each shock subcategory revealed a graded increase requiring LSI and transfusion. Initial CRM was associated with progression to shock (odds ratio = 0.97; p < .001) at an earlier time than SBP or LAC. CONCLUSIONS: Initial CRM uncovers a clinically relevant subset of patients who are not detected by SBP and LAC. Our results suggest CRM could be used to more expeditiously identify injured patients likely to deteriorate to shock, with requirements for blood transfusion or procedural LSI.

Efficacy of the compensatory reserve measurement in an emergency department trauma population.

BACKGROUND: The Compensatory Reserve Measurement (CRM) is a novel method used to provide early assessment of shock based on arterial wave form morphology changes. We hypothesized that (1) CRM would be significantly lower in those trauma patients who received life-saving interventions compared with those not receiving interventions, and (2) CRM in patients who received interventions would recover after the intervention was performed. STUDY DESIGN AND METHODS: We captured vital signs along with analog arterial waveform data from trauma patients meeting major activation criteria using a prospective study design. Study team members tracked interventions throughout their emergency department stay. RESULTS: Ninety subjects met inclusion with 13 receiving a blood product and 10 a major airway intervention. Most trauma was blunt (69%) with motor vehicle collisions making up the largest proportion (37%) of injury mechanism. Patients receiving blood products had lower CRM values just prior to administration versus those who did not (50% versus 58%, p = .045), and lower systolic pressure (SBP; 95 versus 123 mmHg, p = .005), diastolic (DBP; 62 versus 79, p = .007), and mean arterial pressure (MAP; 75 versus 95, p = .006), and a higher pulse rate (HR; 101 versus 89 bpm, p = .039). Patients receiving an airway intervention had lower CRM values just prior to administration versus those who did not (48% versus 58%, p = .062); however, SBP, DBP, MAP, and HR were not statistically distinguishable (p ≥ .645). CONCLUSIONS: Our results support our hypotheses that the CRM distinguished those patients who received blood or an airway intervention from those who did not, and increased appropriately after interventions were performed.

Urinary metabolites predict mortality or need for renal replacement therapy after combat injury.

BACKGROUND: Traditionally, patient risk scoring is done by evaluating vital signs and clinical severity scores with clinical intuition. Urinary biomarkers can add objectivity to these models to make risk prediction more accurate. We used metabolomics to identify prognostic urinary biomarkers of mortality or need for renal replacement therapy (RRT). Additionally, we assessed acute kidney injury (AKI) diagnosis, injury severity score (ISS), and AKI stage. METHODS: Urine samples (n = 82) from a previous study of combat casualties were evaluated using proton nuclear magnetic resonance (1H-NMR) spectroscopy. Chenomx software was used to identify and quantify urinary metabolites. Metabolite concentrations were normalized by urine output, autoscaled, and log-transformed. Partial least squares discriminant analysis (PLS-DA) and statistical analysis were performed. Receiver operating characteristic (ROC) curves were used to assess prognostic utility of biomarkers for mortality and RRT. RESULTS: Eighty-four (84) metabolites were identified and quantified in each urine sample. Of these, 11 were identified as drugs or drug metabolites and excluded. The PLS-DA models for ISS and AKI diagnosis did not have acceptable model statistics. Therefore, only mortality/RRT and AKI stage were analyzed further. Of 73 analyzed metabolites, 9 were significantly associated with mortality/RRT (p < 0.05) and 11 were significantly associated with AKI stage (p < 0.05). 1-Methylnicotinamide was the only metabolite to be significantly associated (p < 0.05) with all outcomes and was significantly higher (p < 0.05) in patients with adverse outcomes. Elevated lactate and 1-methylnicotinamide levels were associated with higher AKI stage and mortality and RRT, whereas elevated glycine levels were associated with patients who survived and did not require RRT, or had less severe AKI. ROC curves for each of these metabolites and the combined panel had good predictive value (lactate AUC = 0.901, 1-methylnicotinamide AUC = 0.864, glycine AUC = 0.735, panel AUC = 0.858). CONCLUSIONS: We identified urinary metabolites associated with AKI stage and the primary outcome of mortality or need for RRT. Lactate, 1-methylnicotinamide, and glycine may be used as a panel of predictive biomarkers for mortality and RRT. 1-Methylnicotinamide is a novel biomarker associated with adverse outcomes. Additional studies are necessary to determine how these metabolites can be utilized in clinically-relevant risk prediction models.

Vasopressors in Trauma: A Never Event?

Vasopressor use in severely injured trauma patients is discouraged due to concerns that vasoconstriction will worsen organ perfusion and result in increased mortality and organ failure in hypotensive trauma patients. Hypotensive resuscitation is advocated based on limited data that lower systolic blood pressure and mean arterial pressure will result in improved mortality. It is classically taught that hypotension and hypovolemia in trauma are associated with peripheral vasoconstriction. However, the pathophysiology of traumatic shock is complex and involves multiple neurohormonal interactions that are ultimately manifested by an initial sympathoexcitatory phase that attempts to compensate for acute blood loss and is characterized by vasoconstriction, tachycardia, and preserved mean arterial blood pressure. The subsequent hypotension observed in hemorrhagic shock reflects a sympathoinhibitory vasodilation phase. The objectives of hemodynamic resuscitation in hypotensive trauma patients are restoring adequate intravascular volume with a balanced ratio of blood products, correcting pathologic coagulopathy, and maintaining organ perfusion. Persistent hypotension and hypoperfusion are associated with worse coagulopathy and organ function. The practice of hypotensive resuscitation would appear counterintuitive to the goals of traumatic shock resuscitation and is not supported by consistent clinical data. In addition, excessive volume resuscitation is associated with adverse clinical outcomes. Therefore, in the resuscitation of traumatic shock, it is necessary to target an appropriate balance with intravascular volume and vascular tone. It would appear logical that vasopressors may be useful in traumatic shock resuscitation to counteract vasodilation in hemorrhage as well as other clinical conditions such as traumatic brain injury, spinal cord injury, multiple organ dysfunction syndrome, and vasodilation of general anesthetics. The purpose of this article is to discuss the controversy of vasopressors in hypotensive trauma patients and advocate for a nuanced approach to vasopressor administration in the resuscitation of traumatic shock.

Evaluation of the Effects of Developmental Trauma on Neurotransmitter Systems Using Functional Molecular Imaging.

Early life stress (ELS) is strongly associated with psychiatric disorders such as anxiety, depression, and schizophrenia in adulthood. To date, biological, behavioral, and structural aspects of ELS have been studied extensively, but their functional effects remain unclear. Here, we examined NeuroPET studies of dopaminergic, glutamatergic, and serotonergic systems in ELS animal models. Maternal separation and restraint stress were used to generate single or complex developmental trauma. Body weights of animals exposed to single trauma were similar to those of control animals; however, animals exposed to complex trauma exhibited loss of body weight when compared to controls. In behavioral tests, the complex developmental trauma group exhibited a decrease in time spent in the open arm of the elevated plus-maze and an increase in immobility time in the forced swim test when compared to control animals. In NeuroPET studies, the complex trauma group displayed a reduction in brain uptake values when compared to single trauma and control groups. Of neurotransmitter systems analyzed, the rate of decrease in brain uptake was the highest in the serotonergic group. Collectively, our results indicate that developmental trauma events induce behavioral deficits, including anxiety- and depressive-like phenotypes and dysfunction in neurotransmitter systems.

The Role of Mitochondria in Immune-Cell-Mediated Tissue Regeneration and Ageing.

During tissue injury events, the innate immune system responds immediately to alarms sent from the injured cells, and the adaptive immune system subsequently joins in the inflammatory reaction. The control mechanism of each immune reaction relies on the orchestration of different types of T cells and the activators, antigen-presenting cells, co-stimulatory molecules, and cytokines. Mitochondria are an intracellular signaling organelle and energy plant, which supply the energy requirement of the immune system and maintain the system activation with the production of reactive oxygen species (ROS). Extracellular mitochondria can elicit regenerative effects or serve as an activator of the immune cells to eliminate the damaged cells. Recent clarification of the cytosolic escape of mitochondrial DNA triggering innate immunity underscores the pivotal role of mitochondria in inflammation-related diseases. Human mesenchymal stem cells could transfer mitochondria through nanotubular structures to defective mitochondrial DNA cells. In recent years, mitochondrial therapy has shown promise in treating heart ischemic events, Parkinson's disease, and fulminating hepatitis. Taken together, these results emphasize the emerging role of mitochondria in immune-cell-mediated tissue regeneration and ageing.

A review of animal models from 2015 to 2020 for preclinical chronic wounds relevant to human health.

SIGNIFICANCE: Chronic wounds fail to heal in a timely manner and exhibit sustained inflammation with slow tissue repair and remodelling. They decrease mobility and quality of life, and remain a major clinical challenge in the long-term care of many patients, affecting 6.5 million individuals annually in the U.S., decreasing mobility and quality of life. Treatment costs are a major burden on the U.S. healthcare system, totalling between $25 and $100 billion annually. Chronic wound severity depends upon several factors such as comorbidities, severity of tissue damage, infection and presence of necrosis and vary greatly in their healing mechanisms. In vivo animal models are critical for studying healing pathways of chronic wounds and seek to replicate clinical factors for trials of topical, systemic, and device-based therapeutics. This comprehensive review discusses murine, rat, lapine, canine, feline and porcine models of chronic wounds. RECENT ADVANCES: Foundational chronic wound models for several species are discussed together with refinements and advances in the time period between 2015 and 2020 which have the potential for broad utility in investigating biological and device-based wound treatment therapies for human health. CRITICAL ISSUES: Chronic wounds fail to heal in a timely manner and have differing aetiologies, rendering no single in vivo animal model universally applicable. FUTURE DIRECTIONS: Further studies are required to develop clinically relevant chronic wound animal model which reflect the clinical reality of the various influences of age, disease, comorbidities and gender on delayed healing and enhance understanding of the biological processes of human wound healing.

Wound fluid under occlusive dressings from diabetic patients show an increased angiogenic response and fibroblast migration.

INTRODUCTION: Metabolic diseases like diabetes mellitus often show prolonged healing and chronic wounds. Occlusive wound dressings are known to support wound closure by creating a moist environment which supports collagen synthesis, epithelialization and angiogenesis. We aimed to assess the effect of occlusion on diabetic wound fluid on the cellular level regarding fibroblast activity and angiogenetic response. MATERIAL AND METHODS: 22 split skin donor sites from 22 patients (11 patients with diabetes mellitus) were treated with occlusive dressings intraoperatively. On day 3, fluid and blood serum samples were harvested while changing the dressings. The influence of wound fluid on fibroblasts was assessed by measuring metabolic activity (Alamar Blue assay, Casey Counter), cell stress/death (LDH assay) and migration (in vitro wound healing assay) of fibroblasts. Angiogenesis of endothelial cells (HUVEC) was analyzed with the tube formation assay. Furthermore, a Magnetic Luminex Assay for multi-cytokines detection was performed focusing on inflammatory and pro-angiogenetic cytokines. RESULTS: The influence of wound fluid under occlusive dressings from diabetic patients showed a significantly increased angiogenic response and fibroblast migration compared to the non-diabetic patient group. Additionally, cell stress was increased in the diabetic group. Cytokine analysis showed an increase in VEGF-A in the diabetic group. CONCLUSION: Occlusive dressings may stimulate regenerative effects in diabetic wounds. Our in-vitro study shows the influence of wound fluid under occlusive dressings from diabetic patients on angiogenesis, migration and proliferation of fibroblasts, which are essential modulators of wound healing and scar modulation.

Factors Associated With Long-term Outcomes After Injury: Results of the Functional Outcomes and Recovery After Trauma Emergencies (FORTE) Multicenter Cohort Study.

OBJECTIVE: The aim of this study was to determine factors associated with patient-reported outcomes, 6 to 12 months after moderate to severe injury. SUMMARY OF BACKGROUND DATA: Due to limitations of trauma registries, we have an incomplete understanding of factors that impact long-term patient-reported outcomes after injury. As 96% of patients survive their injuries, several entities including the National Academies of Science, Engineering and Medicine have called for a mechanism to routinely follow trauma patients and determine factors associated with survival, patient-reported outcomes, and reintegration into society after trauma. METHODS: Over 30 months, major trauma patients [Injury Severity Score (ISS) ≥9] admitted to 3 Level-I trauma centers in Boston were assessed via telephone between 6 and 12 months after injury. Outcome measures evaluated long-term functional, physical, and mental-health outcomes. Multiple regression models were utilized to identify patient and injury factors associated with outcomes. RESULTS: We successfully followed 1736 patients (65% of patients contacted). More than half (62%) reported current physical limitations, 37% needed help for at least 1 activity of daily living, 20% screened positive for posttraumatic stress disorder (PTSD), all SF-12 physical health subdomain scores were significantly below US norms, and 41% of patients who were working previously were unable to return to work. Age, sex, and education were associated with long-term outcomes, while almost none of the traditional measures of injury severity were. CONCLUSION: The long-term sequelae of trauma are more significant than previously expected. Collection of postdischarge outcomes identified patient factors, such as female sex and low education, associated with worse recovery. This suggests that social support systems are potentially at the core of recovery rather than traditional measures of injury severity.

Trends in tissue repair and regeneration.

The 6th EMBO conference on the Molecular and Cellular Basis of Regeneration and Tissue Repair took place in Paestum (Italy) on the 17th-21st September, 2016. The 160 scientists who attended discussed the importance of cellular and tissue plasticity, biophysical aspects of regeneration, the diverse roles of injury-induced immune responses, strategies to reactivate regeneration in mammals, links between regeneration and ageing, and the impact of non-mammalian models on regenerative medicine.

Traumatic-Induced Coagulopathy as a Systems Failure: A New Window into Hemostasis.

Traumatic-induced coagulopathy (TIC) is often associated with significant bleeding, transfusion requirements, inflammation, morbidity, and mortality. This review considers TIC as a systems failure, not as a single-event manifestation of trauma. After briefly reviewing the meaning of TIC and the bewildering array of fibrinolysis phenotypes, we will discuss the role of platelets and fibrinogen in coagulopathy. Next, we will review the different TIC hypotheses and drill down to a single mechanistic domain comprising (1) thrombin's differential binding to thrombomodulin, (2) the expression of annexin II-S100A10 complex, and (3) the functional integrity of the endothelial glycocalyx. This triad forms the basis of the "switch" hypothesis of TIC. We will next address the potential limitations of current practice in treating a coagulation or fibrinolytic defect, and the next defect, and so on down the line, which often leads to what U.S. surgeon William C. Shoemaker considered "an uncoordinated and sometimes contradictory therapeutic outcome." The treat-as-you-go approach using sequential, single-target treatments appears to be a by-product of decades of highly reductionist thinking and research. Lastly, we will present a unified systems hypothesis of TIC involving three pillars of physiology: the central nervous system (CNS)-cardiovascular system, the endothelial glycocalyx, and mitochondrial integrity. If CNS control of ventriculoarterial coupling is maintained close to unity following trauma, we hypothesize that the endothelium will be protected, mitochondrial energetics will be maintained, and TIC (and inflammation) will be minimized. The Systems Hypothesis of Trauma (SHOT) also helps to answer why certain groups of severely bleeding trauma patients are still dying despite receiving the best care. Currently, no drug therapy exists that targets the whole system.