PEBP1 Wardens Ferroptosis by Enabling Lipoxygenase Generation of Lipid Death Signals.

Ferroptosis is a form of programmed cell death that is pathogenic to several acute and chronic diseases and executed via oxygenation of polyunsaturated phosphatidylethanolamines (PE) by 15-lipoxygenases (15-LO) that normally use free polyunsaturated fatty acids as substrates. Mechanisms of the altered 15-LO substrate specificity are enigmatic. We sought a common ferroptosis regulator for 15LO. We discovered that PEBP1, a scaffold protein inhibitor of protein kinase cascades, complexes with two 15LO isoforms, 15LO1 and 15LO2, and changes their substrate competence to generate hydroperoxy-PE. Inadequate reduction of hydroperoxy-PE due to insufficiency or dysfunction of a selenoperoxidase, GPX4, leads to ferroptosis. We demonstrated the importance of PEBP1-dependent regulatory mechanisms of ferroptotic death in airway epithelial cells in asthma, kidney epithelial cells in renal failure, and cortical and hippocampal neurons in brain trauma. As master regulators of ferroptotic cell death with profound implications for human disease, PEBP1/15LO complexes represent a new target for drug discovery.

Flap Closure of Spinal Defects in High-Risk Patients: A 10-Year Institutional Experience.

BACKGROUND: Complication rates after spinal surgery are high, in part because of surgical advancements that have made procedures available to a broader range of medically complicated patients. The high rates of infection, hematoma, and dehiscence resulting in open wounds after spinal surgery often warrant plastic surgery involvement. In this study, we aim to examine the effects of preoperative and operative risk factors on complication rates, reoperation rates, and hospital length of stay after flap reconstruction of spinal defects. METHODS: A retrospective review was performed of 373 patients who required flap reconstruction for spinal wound closure at our institution between 2003 and 2013. Data regarding demographics, comorbidities, operative variables, and postreconstructive course were collected. RESULTS: Of the 373 patients, 97.3% had at least 1 comorbid condition associated with poor wound healing, 91.2% had a significant wound condition at the time of reconstruction, and 81.8% had a history of 2 or more spinal surgeries. After reconstruction, average hospital stay was 14 days, with 35% of patients developing complications and 30% requiring reoperation. Risk factors including elevated body mass index, diabetes, tobacco use, steroid use, low prealbumin level, therapeutic anticoagulation, infection, history of spine surgery, multilevel spinal reconstruction, and spinal hardware were associated with complications, reoperations, and prolonged length of stay. CONCLUSIONS: Local muscle flap coverage is an effective strategy for the reconstruction of spinal defects in medically complex patients. To reduce the inherently high risks associated with paraspinous reconstruction in this challenging population, special consideration should be given to preoperative and operative variables associated with poor outcomes. Early coordination between spine and plastic surgeons should be considered in patients at high-risk of wound complications.

Cadaveric Dissections to Determine Surface Landmarks Locating the Facial Artery for Filler Injections.

BACKGROUND: The facial artery is a high-risk structure when performing filler injections at the nasolabial fold, buccal, and mandibular regions. OBJECTIVES: This study aimed to establish reference landmarks locating the course of the facial artery and its essential branches. METHODS: Thirty-one embalmed cadavers were enrolled in this study. The course of the facial artery was observed in regard to the following reference points: masseter insertion, oral commissure, and common bony landmarks. The corner of the mouth was utilized as the landmark to measure the turning point of the facial artery. RESULTS: Seven points were established to identify the course and turning point of the facial artery. These included the anterior masseteric, lateral mental, infraorbital, medial canthal, basal alar, post-modiolar (PMP), and supra-commissural (SCP) points. The course of the facial artery deviates at least twice at the lateral mental points and at the SCP or PMP. The facial artery appeared more medially when the artery turned at the PMP and SCP. It presented through the lateral channel if the turning point was solely at the PMP. Wherever the facial artery deviates, it can be divided into 3 segments: the mandibular, buccal, and nasolabial segments. The arterial course may deviate laterally from the mouth corner towards PMP. The nasolabial segment may also deviate laterally to the basal alar point at the alar grove for 0.5 to 1 cm. CONCLUSIONS: The deviation of facial artery closely relates with mandibular, buccal, and nasolabial segments. It is essential in avoiding arterial injury for physicians and surgeons who perform procedures in these areas.

Bioactive Oxylipins in Infants and Children With Congenital Heart Disease Undergoing Pediatric Cardiopulmonary Bypass.

OBJECTIVES: To determine the production of 9-hydroxyoctadecadienoic acid and 13-hydroxyoctadecadienoic acid during cardiopulmonary bypass in infants and children undergoing cardiac surgery, evaluate their relationship with increase in cell-free plasma hemoglobin, provide evidence of bioactivity through markers of inflammation and vasoactivity (WBC count, milrinone use, vasoactive-inotropic score), and examine their association with overall clinical burden (ICU/hospital length of stay and mechanical ventilation duration). DESIGN: Prospective observational study. SETTING: Twelve-bed cardiac ICU in a university-affiliated children's hospital. PATIENTS: Children were prospectively enrolled during their preoperative clinic appointments with the following criteria: greater than 1 month to less than 18 years old, procedures requiring cardiopulmonary bypass INTERVENTIONS:: None. MEASUREMENTS AND MAIN RESULTS: Plasma was collected at the start and end of cardiopulmonary bypass in 34 patients. 9-hydroxyoctadecadienoic acid, 13-hydroxyoctadecadienoic acid, plasma hemoglobin, and WBC increased. 9:13-hydroxyoctadecadienoic acid at the start of cardiopulmonary bypass was associated with vasoactive-inotropic score at 2-24 hours postcardiopulmonary bypass (R = 0.25; p < 0.01), milrinone use (R = 0.17; p < 0.05), and WBC (R = 0.12; p < 0.05). 9:13-hydroxyoctadecadienoic acid at the end of cardiopulmonary bypass was associated with vasoactive-inotropic score at 2-24 hours (R = 0.17; p < 0.05), 24-48 hours postcardiopulmonary bypass (R = 0.12; p < 0.05), and milrinone use (R = 0.19; p < 0.05). 9:13-hydroxyoctadecadienoic acid at the start and end of cardiopulmonary bypass were associated with the changes in plasma hemoglobin (R = 0.21 and R = 0.23; p < 0.01). The changes in plasma hemoglobin was associated with milrinone use (R = 0.36; p < 0.001) and vasoactive-inotropic score less than 2 hours (R = 0.22; p < 0.01), 2-24 hours (R = 0.24; p < 0.01), and 24-48 hours (R = 0.48; p < 0.001) postcardiopulmonary bypass. Cardiopulmonary bypass duration, 9:13-hydroxyoctadecadienoic acid at start of cardiopulmonary bypass, and plasma hemoglobin may be risk factors for high vasoactive-inotropic score. Cardiopulmonary bypass duration, changes in plasma hemoglobin, 9:13-hydroxyoctadecadienoic acid, and vasoactive-inotropic score correlate with ICU and hospital length of stay and/mechanical ventilation days. CONCLUSIONS: In low-risk pediatric patients undergoing cardiopulmonary bypass, 9:13-hydroxyoctadecadienoic acid was associated with changes in plasma hemoglobin, vasoactive-inotropic score, and WBC count, and may be a risk factor for high vasoactive-inotropic score, indicating possible inflammatory and vasoactive effects. Further studies are warranted to delineate the role of hydroxyoctadecadienoic acids and plasma hemoglobin in cardiopulmonary bypass-related dysfunction and to explore hydroxyoctadecadienoic acid production as a potential therapeutic target.

Ferroptosis Contributes to Neuronal Death and Functional Outcome After Traumatic Brain Injury.

OBJECTIVES: Traumatic brain injury triggers multiple cell death pathways, possibly including ferroptosis-a recently described cell death pathway that results from accumulation of 15-lipoxygenase-mediated lipid oxidation products, specifically oxidized phosphatidylethanolamine containing arachidonic or adrenic acid. This study aimed to investigate whether ferroptosis contributed to the pathogenesis of in vitro and in vivo traumatic brain injury, and whether inhibition of 15-lipoxygenase provided neuroprotection. DESIGN: Cell culture study and randomized controlled animal study. SETTING: University research laboratory. SUBJECTS: HT22 neuronal cell line and adult male C57BL/6 mice. INTERVENTIONS: HT22 cells were subjected to pharmacologic induction of ferroptosis or mechanical stretch injury with and without administration of inhibitors of ferroptosis. Mice were subjected to sham or controlled cortical impact injury. Injured mice were randomized to receive vehicle or baicalein (12/15-lipoxygenase inhibitor) at 10-15 minutes postinjury. MEASUREMENTS AND MAIN RESULTS: Pharmacologic inducers of ferroptosis and mechanical stretch injury resulted in cell death that was rescued by prototypical antiferroptotic agents including baicalein. Liquid chromatography tandem-mass spectrometry revealed the abundance of arachidonic/adrenic-phosphatidylethanolamine compared with other arachidonic/adrenic acid-containing phospholipids in the brain. Controlled cortical impact resulted in accumulation of oxidized phosphatidylethanolamine, increased expression of 15-lipoxygenase and acyl-CoA synthetase long-chain family member 4 (enzyme that generates substrate for the esterification of arachidonic/adrenic acid into phosphatidylethanolamine), and depletion of glutathione in the ipsilateral cortex. Postinjury administration of baicalein attenuated oxidation of arachidonic/adrenic acid-containing-phosphatidylethanolamine, decreased the number of terminal deoxynucleotidyl transferase dUTP nick-end labeling positive cells in the hippocampus, and improved spatial memory acquisition versus vehicle. CONCLUSIONS: Biomarkers of ferroptotic death were increased after traumatic brain injury. Baicalein decreased ferroptotic phosphatidylethanolamine oxidation and improved outcome after controlled cortical impact, suggesting that 15-lipoxygenase pathway might be a valuable therapeutic target after traumatic brain injury.

Lipidomics Detection of Brain Cardiolipins in Plasma Is Associated With Outcome After Cardiac Arrest.

OBJECTIVES: Brain mitochondrial dysfunction limits neurologic recovery after cardiac arrest. Brain polyunsaturated cardiolipins, mitochondria-unique and functionally essential phospholipids, have unprecedented diversification. Since brain cardiolipins are not present in plasma normally, we hypothesized their appearance would correlate with brain injury severity early after cardiac arrest and return of spontaneous circulation. DESIGN: Observational case-control study. SETTING: Two medical centers within one city. PARTICIPANTS (SUBJECTS): We enrolled 41 adult cardiac arrest patients in whom blood could be obtained within 6 hours of resuscitation. Two subjects were excluded following outlier analysis. Ten healthy subjects were controls. Sprague-Dawley rats were used in asphyxial cardiac arrest studies. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: We developed a high-resolution liquid chromatography/mass spectrometry method and determined cardiolipins speciation in human brain, heart, and plasma within 6 hours of (return of spontaneous circulation) from 39 patients with cardiac arrest, 5 with myocardial infarction, and 10 healthy controls. Cerebral score was derived from brain-specific cardiolipins identified in plasma of patients with varying neurologic injury and outcome. Using a rat model of cardiac arrest, cardiolipins were quantified in plasma, brain, and heart. Human brain exhibited a highly diverse cardiolipinome compared with heart that allowed the identification of brain-specific cardiolipins. Nine of 26 brain-specific cardiolipins were detected in plasma and correlated with brain injury. The cerebral score correlated with early neurologic injury and predicted discharge neurologic/functional outcome. Cardiolipin (70:5) emerged as a potential point-of-care marker predicting injury severity and outcome. In rat cardiac arrest, a significant reduction in hippocampal cardiolipins corresponded to their release from the brain into systemic circulation. Cerebral score was significantly increased in 10 minutes versus 5 minutes no-flow cardiac arrest and naïve controls. CONCLUSIONS: Brain-specific cardiolipins accumulate in plasma early after return of spontaneous circulation and proportional to neurologic injury representing a promising novel biomarker.

Empowerment of 15-Lipoxygenase Catalytic Competence in Selective Oxidation of Membrane ETE-PE to Ferroptotic Death Signals, HpETE-PE.

sn2-15-Hydroperoxy-eicasotetraenoyl-phosphatidylethanolamines ( sn2-15-HpETE-PE) generated by mammalian 15-lipoxygenase/phosphatidylethanolamine binding protein-1 (15-LO/PEBP1) complex is a death signal in a recently identified type of programmed cell demise, ferroptosis. How the enzymatic complex selects sn2-ETE-PE as the substrate among 1 of ∼100 total oxidizable membrane PUFA phospholipids is a central, yet unresolved question. To unearth the highly selective and specific mechanisms of catalytic competence, we used a combination of redox lipidomics, mutational and computational structural analysis to show they stem from (i) reactivity toward readily accessible hexagonally organized membrane sn2-ETE-PEs, (ii) relative preponderance of sn2-ETE-PE species vs other sn2-ETE-PLs, and (iii) allosteric modification of the enzyme in the complex with PEBP1. This emphasizes the role of enzymatic vs random stochastic free radical reactions in ferroptotic death signaling.

Primary Closure of Wide Fasciotomy and Surgical Wounds Using Rubber Band-Assisted External Tissue Expansion: A Simple, Safe, and Cost-effective Technique.

BACKGROUND: Although decompressive fasciotomy is a limb-saving procedure in the setting of acute compartment syndrome, it leaves a large wound defect with tissue edema and skin retraction that can preclude primary closure. Numerous techniques have been described to address the challenge of closing fasciotomy wounds. This study reports our experience with fasciotomy closure using rubber bands (RBs) for external tissue expansion. METHODS: Patients were informed about RB closure and split-thickness skin graft options. Only patients who opted for RB closure and had wounds that could not be approximated using the pinch test underwent the procedure. Starting from the apex and progressively advancing, the RBs were applied to the skin edges at 3 to 4 mm intervals using staples. The RBs were advanced by twisting back-and-forth to create a criss-cross pattern. One week after application, fasciotomy wounds were closed primarily or underwent further RB application, based on clinical assessment of adequacy of skin advancement, compartment tension, and perfusion. Review of a prospectively maintained database was performed, including demographics, comorbidities, etiology, wound and operative details, hospital stay, and complications. RESULTS: Seventeen consecutive patients with 25 wounds (22 fasciotomy and 3 other surgical wounds) were treated using the RB technique. Average wound length and width measured 15.7 cm (range, 5-32 cm) and 5.2 cm (range, 1-12 cm), respectively. Locations of wounds included forearm (n = 12, 48.0%), leg (n = 7, 28.0%), hand (n = 4, 16.0%), elbow (n = 1, 4.0%), and hip (n = 1, 4.0%). Eighteen of 25 wounds (72.0%) were closed primarily after 1 RB application. Additional RB application was required for 5 wounds to achieve primary closure. Between stages, patients were discharged home if they did not have other conditions requiring in-hospital stay. No complications were observed, and no revision surgeries were required. Patient satisfaction was 100%, and all indicated that they would choose the RB technique over skin grafting. CONCLUSIONS: The modified RB technique is a simple, safe, and cost-effective alternative for treating fasciotomy and other surgical defects resulting in high patient satisfaction and good cosmetic outcome, without the need for split-thickness skin graft or flap coverage.

Global assessment of oxidized free fatty acids in brain reveals an enzymatic predominance to oxidative signaling after trauma.

Traumatic brain injury (TBI) is a major health problem associated with significant morbidity and mortality. The pathophysiology of TBI is complex involving signaling through multiple cascades, including lipid peroxidation. Oxidized free fatty acids, a prominent product of lipid peroxidation, are potent cellular mediators involved in induction and resolution of inflammation and modulation of vasomotor tone. While previous studies have assessed lipid peroxidation after TBI, to our knowledge no studies have used a systematic approach to quantify the global oxidative changes in free fatty acids. In this study, we identified and quantified 244 free fatty acid oxidation products using a newly developed global liquid chromatography tandem-mass spectrometry (LC-MS/MS) method. This methodology was used to follow the time course of these lipid species in the contusional cortex of our pediatric rat model of TBI. We show that oxidation peaked at 1h after controlled cortical impact and was progressively attenuated at 4 and 24h time points. While enzymatic and non-enzymatic pathways were activated at 1h post-TBI, enzymatic lipid peroxidation was the predominant mechanism with 15-lipoxygenase (LOX) contributing to the majority of total oxidized fatty acid content. Pro-inflammatory lipid mediators were significantly increased at 1 and 4h after TBI with return to basal levels by 24h. Anti-inflammatory lipid mediators remained significantly increased across all three time points, indicating an elevated and sustained anti-inflammatory response following TBI.

Heterogeneity in Body Contouring Outcomes Based Research: The Pittsburgh Body Contouring Complication Reporting System.

BACKGROUND: Body contouring complications after massive weight loss (MWL) vary significantly in frequency and type. Currently, no standardized recommendations exist regarding which complications are most important to report. OBJECTIVES: We aim to provide a guideline for complication reporting in the body contouring literature. The Pittsburgh Body Contouring Complication Reporting System (PBCCRS) will aid in risk stratification of body contouring procedures and will decrease under-, over-, and nonreporting of complications. METHODS: The authors reviewed the literature for the terms "body contouring," "MWL," and "complications." Elimination criteria included: non-English language, case report, meta-analysis, outpatient, non-MWL, unclear demographics, N <30 and lack of numeric results. Data were analyzed in 2 groups: truncal contouring and extremity contouring. RESULTS: Eighty-nine papers were reviewed and 21 met inclusion criteria. The weighted mean rates as percentages for complications in the extremity group were: dehiscence (29.0), seroma (18.6), scarring (14.9), infection (8.8), lymphedema (7.8), hematoma (3.5), necrosis (1.9), deep venous thrombosis (DVT) or pulmonary embolism (PE) (0), and death (0). In the truncal group, weighted mean complication rates as percentages were: dehiscence (15.4), seroma (13.1), scarring (2.9), infection (9.4), lymphedema (1.3), hematoma (6.4), necrosis (7.2), DVT/PE (1.5), and death (0.6). Lymphedema was seldom reported, and suture extrusion was not reported in any selected papers. Weighted mean rates of DVT/PE in the extremity vs truncal contouring groups were significantly different. Differences in rates of scarring, lymphedema, and hematoma rates neared significance. CONCLUSIONS: Heterogeneity amongst selected studies is explained by variability in how complications are defined. The Pittsburgh Body Contouring Complication Reporting System provides suggested recommendations on complication reporting in massive weight loss body contouring surgery.

Mechanistic characterization of nitrite-mediated neuroprotection after experimental cardiac arrest.

Nitrite acts as an ischemic reservoir of nitric oxide (NO) and a potent S-nitrosating agent which reduced histologic brain injury after rat asphyxial cardiac arrest (ACA). The mechanism(s) of nitrite-mediated neuroprotection remain to be defined. We hypothesized that nitrite-mediated brain mitochondrial S-nitrosation accounts for neuroprotection by reducing reperfusion reactive oxygen species (ROS) generation. Nitrite (4 µmol) or placebo was infused IV after normothermic (37°C) ACA in randomized, blinded fashion with evaluation of neurologic function, survival, brain mitochondrial function, and ROS. Blood and CSF nitrite were quantified using reductive chemiluminescence and S-nitrosation by biotin switch. Direct neuroprotection was verified in vitro after 1 and 4 h neuronal oxygen glucose deprivation measuring neuronal death with inhibition studies to examine mechanism. Mitochondrial ROS generation was quantified by live neuronal imaging using mitoSOX. Nitrite significantly reduced neurologic disability after ACA. ROS generation was reduced in brain mitochondria from nitrite- versus placebo-treated rats after ACA with congruent preservation of brain ascorbate and reduction of ROS in brain sections using immuno-spin trapping. ATP generation was maintained with nitrite up to 24 h after ACA. Nitrite rapidly entered CSF and increased brain mitochondrial S-nitrosation. Nitrite reduced in vitro mitochondrial superoxide generation and improved survival of neurons after oxygen glucose deprivation. Protection was maintained with inhibition of soluble guanylate cyclase but lost with NO scavenging and ultraviolet irradiation. Nitrite therapy results in direct neuroprotection from ACA mediated by reductions in brain mitochondrial ROS in association with protein S-nitrosation. Neuroprotection is dependent on NO and S-nitrosothiol generation, not soluble guanylate cyclase.

Effects of inhalation of low-dose nitrite or carbon monoxide on post-reperfusion mitochondrial function and tissue injury in hemorrhagic shock swine.

INTRODUCTION: Tissue reperfusion following hemorrhagic shock may paradoxically cause tissue injury and organ dysfunction by mitochondrial free radical expression. Both nitrite and carbon monoxide (CO) may protect from this reperfusion injury by limiting mitochondrial free radial production. We explored the effects of very small doses of inhaled nitrite and CO on tissue injury in a porcine model of hemorrhagic shock. METHODS: Twenty pigs (mean wt. 30.6 kg, range 27.2 to 36.4 kg) had microdialysis catheters inserted in muscle, peritoneum, and liver to measure lactate, pyruvate, glucose, glycerol, and nitrite. Nineteen of the pigs were bled at a rate of 20 ml/min to a mean arterial pressure of 30 mmHg and kept between 30 and 40 mmHg for 90 minutes and then resuscitated. One pig was instrumented but not bled (sham). Hemorrhaged animals were randomized to inhale nothing (control, n = 7), 11 mg nitrite (nitrite, n = 7) or 250 ppm CO (CO, n = 5) over 30 minutes before fluid resuscitation. Mitochondrial respiratory control ratio was measured in muscle biopsies. Repeated measures from microdialysis catheters were analyzed in a random effects mixed model. RESULTS: Neither nitrite nor CO had any effects on the measured hemodynamic variables. Following inhalation of nitrite, plasma, but not tissue, nitrite increased. Following reperfusion, plasma nitrite only increased in the control and CO groups. Thereafter, nitrite decreased only in the nitrite group. Inhalation of nitrite was associated with decreases in blood lactate, whereas both nitrite and CO were associated with decreases in glycerol release into peritoneal fluid. Following resuscitation, the muscular mitochondrial respiratory control ratio was reduced in the control group but preserved in the nitrite and CO groups. CONCLUSIONS: We conclude that small doses of nebulized sodium nitrite or inhaled CO may be associated with intestinal protection during resuscitation from severe hemorrhagic shock.

Skin Substitutes and Autograft Techniques: Temporary and Permanent Coverage Solutions.

Coverage of burn wounds is crucial to prevent sequalae including dehydration, wound infection, sepsis, shock, scarring, and contracture. To this end, numerous temporary and permanent options for coverage of burn wounds have been described. Temporary options for burn coverage include synthetic dressings, allografts, and xenografts. Permanent burn coverage can be achieved through skin substitutes, cultured epithelial autograft, ReCell, amnion, and autografting. Here, we aim to summarize the available options for burn coverage, as well as important considerations that must be made when choosing the best reconstructive option for a particular patient.

An Investigation Into What Factors Influence Patterns of Clinical Presentation in Adult-Onset Celiac Disease.

Introduction Anxiety and depression are common in patients with celiac disease (CD), and many psychosocial explanations have been considered. However, as the gut-brain axis is becoming increasingly understood, biological mechanisms have been proposed, including vitamin or mineral deficiencies and gut inflammation. Aim To investigate associations between anxiety/depression and symptom severity, vitamin status, and gut inflammation in untreated adult patients presenting with a serologic indication of celiac disease. Methods The Hospital Anxiety and Depression Scale (HADS), Celiac Symptom Index (CSI), and Perceived Stress Scale (PSS) questionnaires were administered to 17 patients over a 14-month period. Duodenal biopsies were obtained to determine histological Marsh scores. Iron, B12, folate, vitamin D, and thyroid function tests were reviewed. Results HADS-Anxiety (HADS-A) scores correlated with symptom severity (rs = 0.62, P = 0.008), but not with any hematological investigations or degree of intestinal inflammation. No patients scored highly for depression. Iron deficiency was the most common deficiency observed (n = 6). Greater symptomatology was associated with female sex (females versus males: average CSI scores, 32.1 versus 23.6; t17 = 2.1, P < 0.05), younger age at presentation (rs = -0.55, P = 0.02), and lower Marsh score (Marsh 0 versus Marsh 3C: mean scores, 36 versus 24.5; t5 = 6.2, P = 0.009). Conclusions The anxiety experienced by patients with CD at presentation is likely a reactive form due to gastrointestinal symptoms rather than a biological process specific to CD. Older patients tend to present less symptomatically, highlighting the need for screening of at-risk individuals. The degree of villous atrophy does not correlate well with clinical presentation. Highly symptomatic patients should be screened for anxiety at presentation.

Fat Grafting in Radiation-Induced Soft-Tissue Injury: A Narrative Review of the Clinical Evidence and Implications for Future Studies.

SUMMARY: Radiation-induced changes in skin and soft tissue result in significant cosmetic and functional impairment with subsequent decrease in quality of life. Fat grafting has emerged as a therapy for radiation-induced soft-tissue injury, and this narrative review aims to evaluate the current clinical evidence regarding its efficacy. A review was conducted to examine the current clinical evidence of fat grafting as a therapy for radiation-induced injury to the skin and soft tissue and to outline the clinical outcomes that can be used to more consistently quantify chronic radiation-induced injury in future clinical studies. The current clinical evidence regarding the efficacy of fat grafting to treat radiation-induced injury of the skin and soft tissue suggests that fat grafting increases skin softness and pliability, induces volume restoration, improves hair growth in areas of alopecia, reduces pain, and improves cosmetic and functional outcomes. However, literature in this field is far from robust and mired by the retrospective nature of the studies, lack of adequate controls, and inherent limitations of small case series and cohorts. A series of actions have been identified to strengthen future clinical data, including the need for physical examination using a validated scale, appropriate imaging, skin biomechanics and microcirculation testing, and histologic analysis. In conclusion, radiation-induced soft-tissue injury is a significant health burden that can lead to severe functional and aesthetic sequelae. Although still in a preliminary research phase, there is promising clinical evidence demonstrating the benefits of fat grafting to treat chronic changes after radiation therapy. Future clinical studies will require larger cohorts, adequate controls, and consistent use of objective measurements.

A Nomogram for the Rapid Prediction of Hematocrit Following Blood Loss and Fluid Shifts in Neonates, Infants, and Adults.

Introduction There is often a need for a simple means of predicting hematocrit (Hct) following blood loss, administration of intravenous fluids, or fluid shifts. The aim of this study is to introduce a nomogram for the rapid prediction of blood volume and packed red cell volume appropriate for a given patient's body weight and Hct in both the pediatric and adult populations. Methods A nomogram for prediction of Hct was created using the following variables: 1) blood volume determined from bodyweight, 2) estimated blood loss, and 3) initial Hct. Results Hct was calculated after blood loss, administration of intravenous fluids, or fluid shifts using the pediatric and adult nomograms. Alternatively, the nomograms can be used to back-calculate blood or fluid loss if Hct is known. The nomogram allows for adjustment for measured and insensible fluid losses and fluid administration. Conclusions  The nomogram helps to predict the Hct and fluid requirements in neonates, children, and adults with blood loss, fluid administration, and rehydration following dehydration. It allows for the calculation of Hct after fluid shifts in a simple, fast, and portable manner. We believe it can be a useful adjunct to monitor the fluid balance in all patients, especially in resource-limited settings where laboratory equipment may not be available.

Reduction Mammaplasty in Adolescents: A Comparison of Wise and Vertical Incision Patterns.

BACKGROUND: Reduction mammaplasty was shown to ameliorate physical and psychological problems in adolescents suffering from macromastia. However, benefits of the Wise compared to the vertical incision pattern have not yet been established in this population. The aim of this study is to compare the outcomes of these 2 techniques in adolescents undergoing reduction mammaplasty. METHODS: A retrospective study of adolescents undergoing breast reduction by a single surgeon between 2011 and 2017 was conducted. Wise and vertical reduction techniques were compared based on demographics, surgical outcomes, patient satisfaction, and aesthetic outcomes. Patient satisfaction was determined using the validated BREAST-Q survey, and aesthetic outcomes using the validated ABNSW system. RESULTS: A total of 60 adolescents underwent reduction mammaplasty (Wise/inferior pedicle = 80.0%, Wise/superior medial pedicle = 1.7%, vertical/superior medial pedicle = 18.3%). Patients who reported preoperative pain (Wise = 95.9%, vertical = 72.7%, P = 0.039) were more likely to undergo Wise reduction. Patients with Wise reductions also were more likely to undergo bilateral reduction (Wise = 93.9%; vertical = 63.6%, P = 0.017). The major and minor complication rates were 1.7% (Wise = 2.0%, vertical = 0%, P = NS) and 23.3% (Wise = 20.4%, vertical = 36.4%, P = NS), respectively. Adolescents undergoing Wise incision demonstrated statistically significant improvement in NAC contour (Wise = 61%, vertical = 47%, P = 0.028) and overall aesthetic outcome (Wise = 25%, vertical = 17%, P = 0.008) with scarring not being a negative factor (Wise = -16%; vertical = -35%, P = 0.004). Patient satisfaction was comparable in both groups. CONCLUSIONS: Reduction mammaplasty is a safe, effective treatment for adolescent macromastia. The similarity in complication and satisfaction rates between Wise and vertical patterns suggests that both techniques can be safely performed in the adolescent population and allow for overall improvements in aesthetic outcomes.

Aiming for the target: Mitochondrial drug delivery in traumatic brain injury.

Mitochondria are a keystone of neuronal function, serving a dual role as sustainer of life and harbinger of death. While mitochondria are indispensable for energy production, a dysregulated mitochondrial network can spell doom for both neurons and the functions they provide. Traumatic brain injury (TBI) is a complex and biphasic injury, often affecting children and young adults. The primary pathological mechanism of TBI is mechanical, too rapid to be mitigated by anything but prevention. However, the secondary injury of TBI evolves over hours and days after the initial insult providing a window of opportunity for intervention. As a nexus point of both survival and death during this second phase, targeting mitochondrial pathology in TBI has long been an attractive strategy. Often these attempts are mired by efficacy-limiting unintended off-target effects. Specific delivery to and enrichment of therapeutics at their submitochondrial site of action can reduce deleterious effects and increase potency. Mitochondrial drug localization is accomplished using (1) the mitochondrial membrane potential, (2) affinity of a carrier to mitochondria-specific components (e.g. lipids), (3) piggybacking on the cells own mitochondria trafficking systems, or (4) nanoparticle-based approaches. In this review, we briefly consider the mitochondrial delivery strategies and drug targets that illustrate the promise of these mitochondria-specific approaches in the design of TBI pharmacotherapy. This article is part of the Special Issue entitled "Novel Treatments for Traumatic Brain Injury".

Change Is Happening: An Evaluation of Gender Disparities in Academic Plastic Surgery.

BACKGROUND: Gender disparities in academic plastic surgery are known; however, recently, professional societies have endorsed a culture of gender diversification. This study aims to evaluate the effects of these changes at faculty and leadership positions. METHODS: A cross-sectional study was conducted in June of 2018 to evaluate gender representation among U.S. academic plastic surgery faculty, and compare career qualifications, years of experience, and faculty positions. RESULTS: A total of 938 academic plastic surgeons were identified, of which only 19.8 percent were women. Female surgeons graduated more recently than men (2009 versus 2004; p < 0.0001) and predominantly from integrated residency programs (OR, 2.72; 95 percent CI, 1.87 to 3.96), were more likely to be an assistant professor (OR, 2.19; 95 percent CI, 1.58 to 3.05), and were less likely to be a full professor (OR, 0.20; 95 percent CI, 0.11 to 0.35) or program chair (OR, 0.32; 95 percent CI, 0.16 to 0.65). After adjustment for differences in years of postresidency experience, only disparities at the full professor position remained significant (OR, 0.34; 95 percent CI, 0.16 to 0.17), indicating that experience-independent gender inequality is prominent at the full professor level and that current differences in cohort experience are a significant contributor to many of the observed positional disparities. Lastly, programs led by a female chair employed significantly more female faculty (32.5 percent versus 18.2 percent; p = 0.016). CONCLUSIONS: Gender diversity in academic plastic surgery remains a significant issue, but may see improvement as the disproportionately high number of junior female academics advance in their careers. However, leadership and promotion disparities between men and women still exist and must be addressed.

A Qualitative Survey Study of United States Burn Units: Pathways to a Career in Burn Surgery.

With current changes in training requirements, it is important to understand the venues in the United States for a general surgery (GS) and plastic surgery (PS) resident interested in pursuing a burn surgery career. The study aims to evaluate the pathways to a career in burn surgery and the current state of leadership. A cross-sectional study was conducted between August and September 2017. A 12-question survey was sent to all burn unit directors in the United States, asking about their background, who manages various aspects of burn care and the hiring requirements. Responses were received from 55 burn unit directors (47% response rate). Burn units are lead most commonly by physicians who received GS training (69%), but the majority either did not undergo fellowship training (31%) or completed a burn surgery fellowship (29%). While surgical care (GS = 51%, PS = 42%) and wound care (GS = 51%, PS = 42%) were predominantly managed by GS- or PS-trained burn teams, management of other aspects of burn care varied depending on the institution, demonstrating that a shift in burn care management. The desired hiring characteristics, including GS (67%) or PS residency (44%) and a burn surgery (55%), trauma surgery (15%), or critical care (44%) fellowship. Directors' training significantly influenced their preferences for hiring requirements. While leadership in burn surgery is dominated by GS-trained physicians, the surgical and wound care responsibilities are shared among PS and GS. Although one third of current directors did not undergo fellowship training, aspiring surgeons are advised to obtain a burn surgery and/or critical care fellowship.