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The emergence and spread of antibiotic resistance in bacterial pathogens are serious and ongoing threats to public health. Since chromosome replication is essential to cell growth and pathogenesis, the essential DNA polymerases in bacteria have long been targets of antimicrobial development, although none have yet advanced to the market. Here, we use transient-state kinetic methods to characterize the inhibition of the PolC replicative DNA polymerase from Staphylococcus aureus by 2-methoxyethyl-6-(3'-ethyl-4'-methylanilino)uracil (ME-EMAU), a member of the 6-anilinouracil compounds that specifically target PolC enzymes, which are found in low-GC content Gram-positive bacteria. We find that ME-EMAU binds to S. aureus PolC with a dissociation constant of 14 nM, more than 200-fold tighter than the previously reported inhibition constant, which was determined using steady-state kinetic methods. This tight binding is driven by a very slow off rate of 0.006 s -1 . We also characterized the kinetics of nucleotide incorporation by PolC containing a mutation of phenylalanine 1261 to leucine (F1261L). The F1261L mutation decreases ME-EMAU binding affinity by at least 3,500-fold but also decreases the maximal rate of nucleotide incorporation by 11.5-fold. This suggests that bacteria acquiring this mutation would be likely to replicate slowly and be unable to out-compete wild-type strains in the absence of inhibitors, reducing the likelihood of the resistant bacteria propagating and spreading resistance., Competing Interests: The authors declare no conflict of interest.

Purpose: The purpose of this study was to determine whether a single-use negative pressure wound therapy (NPWT) system achieves individualized goals of therapy when used to treat patients with a variety of wound types., Design: Multiple case series., Subjects and Setting: The same comprised 25 participants; their mean age was 51.2 years (SD: 18.2; range: 19-79 years); 14 were male (56%) and 11 were female (44%). Seven study participants withdrew from study participation. Wound etiologies vary; 4 had diabetic foot ulcers; 1 had a full-thickness pressure injury; 7 were treated for management of an abscess or cyst; 4 had necrotizing fasciitis, 5 had nonhealing postsurgical wounds, and 4 had wounds of other etiologies. Data were collected at 2 ambulatory wound care clinics located in the Southeastern United States (Augusta and Austell, Georgia)., Methods: A single-outcome measure was selected for each participant by his or her attending physician at a baseline visit. Selected end points were (1) decrease in wound volume, (2) decrease in size of the tunneling area, (3) decrease in size of the undermining, (4) decrease in the amount of slough, (5) increase in granulation tissue formation, (6) decrease in periwound swelling, and (7) wound bed progression toward transition to another treatment modality (such as standard dressing, surgical closure, flap, or graft). Progress toward the individualized goal was monitored until the goal was achieved (study end point) or a maximum of 4 weeks following initiation of treatment., Results: The most common primary treatment goal was to achieve a decrease in wound volume (22 of 25 study participants), and the goal to increase granulation tissue was chosen for the remaining 3 study participants. A majority of participants (18 of 23, 78.3%) reached their individualized treatment outcome. The remaining 5 participants (21.7%) were withdrawn during the study (for reasons not related to the therapy). The median (interquartile range [IQR]) duration of NPWT therapy was 19 days (IQR: 14-21 days). Between baseline and the final assessment, median reductions in wound area and volume were 42.7% (IQR: 25.7-71.5) and 87.5% (IQR: 30.7-94.6)., Conclusions: The single-use NPWT system achieved multiple individualized treatment objectives in a variety of wound types. Individually selected goals of therapy were met by all study participants who completed the study., Competing Interests: Funding for writing of the manuscript and performance of this clinical study was provided by Medela AG. Rey Paglinawan and Karin Lussi are employees of Medela AG (Switzerland). For the remaining authors, no conflicts of interest were declared., (Copyright © 2023 The Authors. Published by Wolters Kluwer Health, Inc. on behalf of the Wound, Ostomy, and Continence Nurses Society.)

Bacterial replication is a fast and accurate process, with the bulk of genome duplication being catalyzed by the α subunit of DNA polymerase III within the bacterial replisome. Structural and biochemical studies have elucidated the overall properties of these polymerases, including how they interact with other components of the replisome, but have only begun to define the enzymatic mechanism of nucleotide incorporation. Using transient-state methods, we have determined the kinetic mechanism of accurate replication by PolC, the replicative polymerase from the Gram-positive pathogen Staphylococcus aureus. Remarkably, PolC can recognize the presence of the next correct nucleotide prior to completing the addition of the current nucleotide. By modulating the rate of pyrophosphate byproduct release, PolC can tune the speed of DNA synthesis in response to the concentration of the next incoming nucleotide. The kinetic mechanism described here would allow PolC to perform high fidelity replication in response to diverse cellular environments., (© The Author(s) 2021. Published by Oxford University Press on behalf of Nucleic Acids Research.)

The effects of supplementing lambs with Co, either alone or in combination with vitamin B and Se, were evaluated over the period from weaning to selection for slaughter. Two hundred and five recently weaned (at 14 wk [SD 0.44] of age), spring-born lambs of various crossbred genotypes were stratified, within genotype, by BW and gender and allocated to 3 groups, which were then allocated at random to one of the following treatments: no supplement (Control), a supplement containing Co only (Co-only), or a supplement containing Co, vitamin B, and Se (VitMin). The concentration of Co in the Co-only supplement was 2.1 mg/mL (as cobalt sulfate); the VitMin supplement contained Co (10 mg/mL, as cobalt acetate), vitamin B (200 μg/mL), and Se (0.25 mg/mL, as sodium selenite). Lambs on the Co-only and VitMin treatments received, every 14 d, 10 and 2.1 mL, respectively, of oral drench. Lambs were managed in a rotational-grazing system from 12 July (swards predominantly ) and selected for slaughter, on the basis of BW, after 45, 73, or 115 d; all remaining lambs were slaughtered on d 157. Supplementation, with Co-only or VitMin, increased BW at slaughter ( < 0.01), ADG ( < 0.001), carcass weight ( < 0.001), dressing percentage ( < 0.001), carcass fat score ( < 0.05), and the proportion selected for slaughter by d 73 ( < 0.05) and 115 ( < 0.01). Relative to the Control, the benefit to ADG from supplementation increased as the season advanced. Therefore, supplementation did not alter ( = 0.82) ADG between d 1 and 45 but increased ADG over the intervals d 45 to 73 ( < 0.01), d 73 to 115 ( < 0.001), and d 115 to 157 ( < 0.001). There was no difference ( > 0.05) between the Co-only and the VitMin treatments for ADG, carcass weight, fat score, or dressing percentage. Supplementation with Co increased liver Co concentration ( < 0.001), and lambs supplemented with VitMin had greater liver Co concentration than lambs supplemented with Co-only ( < 0.05); the concentrations were 0.18, 0.85, and 1.18 μmol/L for the Control, Co-only, and VitMin treatments, respectively. Treatment had no effect ( = 0.65) on the concentration of Se in kidney tissue. It is concluded that supplementation with Co increased lamb performance after weaning, that response to supplementation increased as the grazing season progressed, and that no extra benefit in performance resulted from augmenting supplementary Co with B and Se.

Telemedicine has been successfully used in many areas of medicine, including triage and evaluation of the acute burn patient. The utility of telemedicine during the rehabilitative phase of burn care has yet to be evaluated; therefore, we expanded our telemedicine program to link our burn center with a rehabilitation facility. The goal of this project was to demonstrate cost-effective improvements in the transition and quality of care. A retrospective review was performed on all patients enrolled in our telemedicine/rehabilitation program between March 2013 and March 2014. Data collected included total number of encounters, visits, type of visit, physician time, and readmissions. Transportation costs were based on local ambulance rates between the two facilities. The impact of telemedicine was evaluated with respect to the time saved for the physician, burn center, and burn clinic, as well as rehabilitative days saved. A patient satisfaction survey was also administered. A total of 29 patients participated in 73 virtual visits through the telemedicine project. Virtual visits included new consults, preoperative evaluations, and postoperative follow-ups. A total of 146 ambulance transports were averted during the study period, totaling $101,110. Virtual visits saved 6.8 outpatient burn clinic days, or 73 clinic appointments of 30-min duration. The ability to perform more outpatient surgery resulted in 80 inpatient bed days saved at the burn hospital. The rehabilitation hospital saved an average of 2 to 3 patient days secondary to unnecessary travel. Satisfaction surveys demonstrated patient satisfaction with the encounters, primarily related to time saved. The decrease in travel time for the patient from the rehabilitation hospital to outpatient burn clinic improved adherence to the rehabilitation care plan and resulted in increased throughput at the rehabilitation facility. Videoconferencing between a burn center and rehabilitation hospital streamlined patient care and reduced health care costs, while maintaining quality of care and patient satisfaction. This program has improved inpatient burn rehabilitation by maximizing time spent in therapy and avoiding unnecessary patient travel to offsite appointments.

Long-term follow-up care of survivors after burn injuries can potentially be improved by the application of patient-reported outcome measures (PROMs). PROMs can inform clinical decision-making and foster communication between the patient and provider. There are no previous reports using real-time, burn-specific PROMs in clinical practice to track and benchmark burn recovery over time. This study examines the feasibility of a computerized, burn-specific PROM, the Young Adult Burn Outcome Questionnaire (YABOQ), with real-time benchmarking feedback in a burn outpatient practice. The YABOQ was redesigned for formatting and presentation purposes using images and transcribed to a computerized format. The redesigned questionnaire was administered to young adult burn survivors (ages 19-30 years, 1-24 months from injury) via an ipad platform in the office before outpatient visits. A report including recovery curves benchmarked to a nonburned relatively healthy age-matched population and to patients with similar injuries was produced for the domains of physical function and social function limited by appearance. A copy of the domain reports as well as a complete copy of the patient's responses to all domain questions was provided for use during the clinical visit. Patients and clinicians completed satisfaction surveys at the conclusion of the visit. Free-text responses, included in the satisfaction surveys, were treated as qualitative data adding contextual information about the assessment of feasibility. Eleven patients and their providers completed the study for 12 clinical visits. All patients found the ipad survey and report "easy" or "very easy" to use. In nine instances, patients "agreed" or "strongly agreed" that it helped them communicate their situation to their doctor/nurse practitioner. Patients "agreed" or "strongly agreed" that the report helped them understand their course of recovery in 10 visits. In 11 visits, the patients "agreed" or "strongly agreed" that they would recommend this feedback to others. Qualitative comments included: "it helped organize my thoughts of recovery," "it opened lines of communication with the doctor," "it showed me how far I have come, and how far I need to go," and "it raised questions I would not have thought of." Only four of 12 provider surveys agreed that it helped them understand a patient's condition; however, in two visits, the providers stated that it helped identify a pertinent clinical issue. During two visits, providers stated that a treatment plan was discussed or recommended based on the survey results. Separately, qualitative comments from the providers included "survey was not sensitive enough to identify that this patient needed surgery for their scars." This is the first report describing clinical use of a burn-specific patient reported outcome measure. Real-time feedback using the ipad YABOQ was well received for the most part by the clinicians and burn survivors in the outpatient clinic setting. The information provided by the reports can be tested in a future randomized controlled clinical study evaluating impacts on physician decisions.

One of the fundamental aspects of initial burn care is the ability to accurately measure the TBSA of injured tissue. Discrepancies between initial estimates of burn size and actual TBSA (determined at the burn unit) have long been reported. These inconsistencies have the potential for unnecessary patient transfer and inappropriate fluid administration which may result in morbidity. In an effort to study these inconsistencies and their impact on initial care, we evaluated the differences between initial TBSA estimates and its impact on fluid resuscitation at an American Burn Association-verified pediatric burn center. A prospective observational study of 50 consecutive burn patients admitted to Shriner's Hospital for Children in Boston, Massachusetts, between October 2011 and April 2012 was performed. Data collected included age, mechanism of burn injury, type of referral center, referring hospital TBSA, and volume of fluid administration as well as admission TBSA and volume of fluid administration. Determination of over or under resuscitation was based on comparing the amount of fluids received at the referral center to that received at the pediatric burn center. A total of 50 patients were admitted during the 7-month study period. The average age was 4.1 years old (25 days-16 years) and the average TBSA was 2.5% (0.25-55%). There were significant differences in the TBSA calculations between referring centers and the pediatric burn center. Overestimation of scald and contact burn size (P < .05) was noted with no difference in flame burn size estimation. Community referrals were more likely than tertiary centers to overestimate TBSA (P < .05 vs P = .29). Overall, 59% of study patients were administered more fluid at the referring hospital than would have been expected by the burn size calculated at our facility. Inconsistencies with the estimation of TBSA burn between referring hospitals and tertiary referral centers remains a problem in pediatric patients and may lead to inappropriate resuscitation. This study highlights the continued need for educational outreach programs and for the provision of novel resources to initial burn providers. Additional support through online resources (eg, Lund-Browder diagram) and remotely assisting providers during their TBSA measurements are potential options which may help to improve the initial care of burn patients.

The loss of an extremity is a disastrous injury with tremendous impact on a patient's life. Current mechanical prostheses are technically highly sophisticated, but only partially replace physiologic function and aesthetic appearance. As a biologic alternative, approximately 70 patients have undergone allogeneic hand transplantation to date worldwide. While outcomes are favorable, risks and side effects of transplantation and long-term immunosuppression pose a significant ethical dilemma. An autologous, bio-artificial graft based on native extracellular matrix and patient derived cells could be produced on demand and would not require immunosuppression after transplantation. To create such a graft, we decellularized rat and primate forearms by detergent perfusion and yielded acellular scaffolds with preserved composite architecture. We then repopulated muscle and vasculature with cells of appropriate phenotypes, and matured the composite tissue in a perfusion bioreactor under electrical stimulation in vitro. After confirmation of composite tissue formation, we transplanted the resulting bio-composite grafts to confirm perfusion in vivo., (Copyright © 2015 Elsevier Ltd. All rights reserved.)

Diagnosis and management of infectious endocarditis are particularly challenging in patients with severe burns. Cases requiring operative intervention are likely to have higher complication rates as a result of poor wound healing, recurrent bacteremia secondary to burn wound manipulation, and sequelae of anticoagulation in patients who require repeated reconstructive and cosmetic procedures. Few case reports exist describing mitral valve replacement for infectious endocarditis in burn patients. In this article, we review the literature to describe and address these challenges, and present what we believe to be the first case of mitral valve repair for infectious endocarditis in a thermally injured patient., (Copyright © 2015 Elsevier Ltd and ISBI. All rights reserved.)

This article presents a small case series demonstrating clinical success with thrombolytic agents for severe frostbite injury to the lower extremities. The authors report three patients with severe frostbite injuries to their distal lower extremities who were managed with urgent interventional radiology and intra-arterial tissue plasminogen activator infusion according to a prespecified protocol. Limbs and digits were successfully salvaged and patients returned to normal activity within 2 weeks. Although further studies are needed, results of this study support a new approach in the management of frostbite: from conservative management and observation to urgent interventional radiology and possible tissue plasminogen activator infusion. A protocol for the management of such injuries is presented.

Finely tuned to respond quickly to infections, neutrophils have amazing abilities to migrate fast and efficiently towards sites of infection and inflammation. Although neutrophils ability to migrate is perturbed in patients after major burns, no correlations have yet been demonstrated between altered migration and higher rate of infections and sepsis in these patients when compared to healthy individuals. To probe if such correlations exist, we designed microfluidic devices to quantify the neutrophil migration phenotype with high precision. Inside these devices, moving neutrophils are confined in channels smaller than the neutrophils and forced to make directional decisions at bifurcations and around posts. We employed these devices to quantify neutrophil migration across 18 independent parameters in 74 blood samples from 13 patients with major burns and 3 healthy subjects. Blinded, retrospective analysis of clinical data and neutrophil migration parameters revealed that neutrophils isolated from blood samples collected during sepsis migrate spontaneously inside the microfluidic channels. The spontaneous neutrophil migration is a unique phenotype, typical for patients with major burns during sepsis and often observed one or two days before the diagnosis of sepsis is confirmed. The spontaneous neutrophil migration phenotype is rare in patients with major burns in the absence of sepsis, and is not encountered in healthy individuals. Our findings warrant further studies of neutrophils and their utility for early diagnosing and monitoring sepsis in patients after major burns.

This report describes a case of burn injury following exposure to sulfur mustard, a chemical agent used in war. A review of the diagnostic characteristics, clinical manifestations, and therapeutic measures used to treat this uncommon, yet extremely toxic, entity is presented. The aim of this report is to highlight the importance of considering this diagnosis in any war victim, especially during these unfortunate times of rising terrorist activities.

As a result of continuous development in the treatment of burns, the LD50 (the burn size lethal to 50% of the population) for thermal injuries has risen from 42% total body surface area (TBSA) during the 1940s and 1950s to more than 90% TBSA for young thermally injured patients. This vast improvement in survival is due to simultaneous developments in critical care, advancements in resuscitation, control of infection through early excision, and pharmacologic support of the hypermetabolic response to burns. This article reviews these recent advances and how they influence modern intensive care of burns., (Copyright © 2014 Elsevier Inc. All rights reserved.)

Objective: To determine and compare outcomes with accepted benchmarks in burn care at 6 academic burn centers., Background: Since the 1960s, US morbidity and mortality rates have declined tremendously for burn patients, likely related to improvements in surgical and critical care treatment. We describe the baseline patient characteristics and well-defined outcomes for major burn injuries., Methods: We followed 300 adults and 241 children from 2003 to 2009 through hospitalization, using standard operating procedures developed at study onset. We created an extensive database on patient and injury characteristics, anatomic and physiological derangement, clinical treatment, and outcomes. These data were compared with existing benchmarks in burn care., Results: Study patients were critically injured, as demonstrated by mean % total body surface area (TBSA) (41.2 ± 18.3 for adults and 57.8 ± 18.2 for children) and presence of inhalation injury in 38% of the adults and 54.8% of the children. Mortality in adults was 14.1% for those younger than 55 years and 38.5% for those aged 55 years and older. Mortality in patients younger than 17 years was 7.9%. Overall, the multiple organ failure rate was 27%. When controlling for age and % TBSA, presence of inhalation injury continues to be significant., Conclusions: This study provides the current benchmark for major burn patients. Mortality rates, notwithstanding significant % TBSA and presence of inhalation injury, have significantly declined compared with previous benchmarks. Modern day surgical and medically intensive management has markedly improved to the point where we can expect patients younger than 55 years with severe burn injuries and inhalation injury to survive these devastating conditions.

Following severe burns and trauma injuries, the changes of neutrophil migratory phenotype are a double-edged sword. Activated neutrophils migrate into injured tissues and help contain microbial infections, but they can also enter normal tissues and damage vital organs. Depleting the neutrophils from circulation protects vital organs against neutrophil-induced damage but leaves the body exposed to infectious complications. Here we show that restoring normal neutrophil migratory phenotype in rats with burn injuries correlates with improved survival in a classical double-injury model of sequential burn and septic insults. We uncovered that the directionality of neutrophils from burned rats can be restored both in vitro by 1 nM resolvin D2 (RvD2) and in vivo by RvD2 for 7 d, 25 ng/kg body mass (8-10 ng/rat). Restoring neutrophil directionality dramatically increases survival after a second septic insult at d 9 postburn. Survival of RvD2-treated animals increases from 0 to 100% after lipopolysaccharide injection and is extended by 1 wk after cecal ligation. Survival does not significantly increase when the restoration of neutrophil directionality is incomplete, following shorter regimens of RvD2. We conclude that restoring neutrophil directionality using RvD2 could have prophylactic value and delay lethal complications after burn injuries.

Acute kidney injury (AKI), although rare, is a major complication of burn injury that commonly leads to mortality. It results from a complex interplay of various cellular and neuro-humoral changes affecting burn patients. Guidelines for the treatment of this entity are still not well defined; therefore, prevention and early diagnosis are key to avoid the unfavorable prognosis of AKI. These entail a comprehensive understanding of the global physiologic changes underlying the condition of burn patients and a judicious interpretation of their continuous homeostatic alterations. The aim of this review is to present the salient features in burn patient physiology that contribute to AKI. Strategies for identifying early AKI are presented. Finally, the different treatment modalities are revisited.

Burn injuries are known to occur from magnetic resonance imaging. Prevention efforts focus on avoiding internal and external metallic objects from contacting the patient's tissue during image acquisition. Despite rigorous screening, however, there is a subset of thermal injuries that can occur through the formation of closed loops of current within the patient. This case report describes an example of this uncommon type of injury as well as a successful, nonoperative management approach. Given the frequent use of magnetic resonance imaging, we report this rare case to raise awareness of this mechanism of injury and its treatment.

Objective: Although enteral nutrition is the ideal mode of nutritional support following burn injury, it is often interrupted during episodes of severe sepsis and hemodynamic instability, leading to significant energy and protein deficits. Parenteral nutrition is not commonly used in burn centers due to concerns that it will lead to hyperglycemia, infection, and increased mortality. However, parenteral nutrition is often utilized in our burn unit when goal rate enteral nutrition is not feasible.To determine the safety and efficacy of a standardized protein-sparing parenteral nutrition protocol in which glucose infusion is limited to 5-7 mg/kg/hour., Design: Retrospective observational study., Setting: Pediatric burn hospital., Patients: A retrospective medical record review of all children admitted to our hospital with burns ≥ 30% total body surface area was conducted. Only patients admitted within one week of injury and who survived > 24 hours after admission were included in this study., Interventions: None., Measurements and Main Results: Of the 105 patients who met the inclusion criteria, 96 (91%) received parenteral nutrition or a combination of parenteral nutrition and enteral nutrition at some point during their care. Nine patients received only enteral nutrition. Demographic data were similar between groups. Protein intake was significantly higher in the parenteral nutrition group. Incidence of catheter-related blood infections did not differ between groups. Use of parenteral nutrition was not associated with blood or respiratory infections. Overall mortality rate was low (4%), as most patients (96%) achieved wound closure and were discharged home., Conclusions: Judicious use of parenteral nutrition is a safe and effective means of nutritional support when goal enteral nutrition cannot be achieved. A hypocaloric, high-nitrogen parenteral nutrition solution can reduce energy and protein deficits while minimizing complications commonly associated with parenteral nutrition usage.

Burn-specific guidelines for optimal catheter rotation, catheter type, insertion methods, and catheter site care do not exist, and practices vary widely from one burn unit to another. The purpose of this study was to define current practices and identify areas of practice variation for future clinical investigation. An online survey was sent to the directors of 123 U.S. burn centers. The survey consisted of 23 questions related to specific practices in placement and maintenance of central venous catheters (CVCs), arterial catheters, and peripherally inserted central catheters (PICCs). The overall response rate was 36%; response rate from verified centers was 52%. Geographic representation was wide. CVC and arterial catheter replacement varied from every 3 days (24% of sites) to only for overt infection (24% of sites); 23% of sites did not use the femoral position for CVC placement. Nearly 60% of units used some kind of antiseptic catheter. Physicians inserted the majority of catheters, and 22% of sites used nonphysicians for at least some insertions. Ultrasound was routinely used by less than 50% of units. A wide variety of post-insertion dressing protocols were followed. PICCs were used in some critically injured patients in 37% of units; the majority of these users did not rotate PICCs. Thus, it can be surmised that wide practice variation exists among burn centers with regard to insertion and maintenance of invasive catheters. Areas with particular variability that would be appropriate targets of clinical investigation are line rotation protocols, catheter site care protocols, and use of PICCs in acute burns.

It has been demonstrated that restoration of function to compromised tissue can be accomplished by transplantation of bone marrow stem cells and/or embryonic stem cells (ESCs). One limitation to this approach has been the lack of noninvasive techniques to longitudinally monitor stem cell attachment and proliferation. Recently, murine ESC lines that express green fluorescent protein (GFP), luciferase (LV), and herpes simplex thymidine kinase (HVTK) were developed for detection of actively growing cells in vivo by imaging. In this study, the authors investigated the use of these ESC lines in a burned mouse model using Integra® as a delivery scaffolding/matrix. Two different cell lines were used: one expressing GFP and LV and the other expressing GFP, LV, and HVTK. Burn wounds were produced by application of a brass block (2 × 2 cm kept in boiling water before application) to the dorsal surface of SV129 mice for 10 seconds. Twenty-four hours after injury, Integra® with adherent stem cells was engrafted onto a burn wound immediately after excision of eschar. The stem cells were monitored in vivo by measuring bioluminescence with a charge-coupled device camera and immunocytochemistry of excised tissue. Bioluminescence progressively increased in intensity over the time course of the study, and GFP-positive cells growing into the Integra® were detected. These studies demonstrate the feasibility of using Integra® as a scaffolding, or matrix, for the delivery of stem cells to burn wounds as well as the utility of bioluminescence for monitoring in vivo cellular tracking of stably transfected ESC cells.

Infection is the most common and most serious complication of a major burn related to burn size. Recent studies have demonstrated that statin treatment can decrease mortality in murine or human sepsis. In the current study mice were anesthetized and subjected to a dorsal 30% TBSA scald burn. Simvastatin or placebo were administered by intraperitoneal injection once daily or every 12h. On post burn day 7 cecal ligation and puncture with a 21-gauge needle (CLP) was performed under ketamine/xylazine anesthesia, the two different dosing schedules were continued and survival was monitored. In other groups of mice, interleukin-6 (IL-6) levels in blood were measured in mice at 7 days after injury. A simvastatin dependent improvement in survival was observed in the burn sepsis model. This protection was found to be dose and time dependent. In addition, statin treatment reduced the elevation in IL-6 levels of mice burned 7 days previously. However, IL-6 levels in burned mice with or without statin treatment were elevated by CLP to the same degree. The results of these studies suggest that statin treatment reduces mortality in mice with burns and CLP and that this effect may not be mediated via IL-6 levels., (Copyright © 2010 Elsevier Ltd and ISBI. All rights reserved.)

Severe burns result in T lymphocyte specific immunologic changes. In addition to decreased levels of circulating lymphocytes, changes in cytokine secretion and receptor expression also take place. Our finer understanding of the inflammatory response has led to the development of immune-targeted therapeutics, requiring specialized gene-expression monitoring. The emerging field of bio-micro-electromechanical systems can be used to isolate highly pure T lymphocytes in a clinically relevant and timely manner for downstream genomic analysis. Blood samples from healthy volunteers and burn-injured patients were introduced into microfluidic devices developed in our laboratory. Utilizing cell-affinity chromatography for positive selection of T lymphocytes, the devices served as a platform for RNA extraction and downstream cytokine analysis via quantitative real-time polymerase chain reaction (PCR). From a 0.5-mL whole blood sample, the microfluidic devices captured highly pure T lymphocytes from healthy volunteers and burn-injured patients. Cell capture was of sufficient quantity, and extracted RNA was of sufficient quality, for evaluating the gene expression of cytokines: interferon-gamma, interleukin-2, interleukin-4, and interleukin-10. Microfluidics is a useful tool in processing blood from burn-injured patients. Though in its very early stages of development, cell-specific information obtained by this platform/technology will likely be an important component of near-patient molecular diagnostics and personalized medicine., (© 2011 Wiley Periodicals, Inc.)

Introduction: Monitoring of hemodynamic and volumetric parameters after severe burns is of critical importance. Pulmonary artery catheters, however, have been associated with many risks. Our aim was to show the feasibility of continuous monitoring with minimally invasive transpulmonary thermodilution (TPTD) in severely burned pediatric patients., Methods: This prospective cohort study was conducted in patients with severe burns over 40% of the total body surface area (TBSA) who were admitted to the hospital within 96 hours after sustaining the injury. TPTD measurements were performed using the PiCCO system (Pulsion Medical Systems, Munich, Germany). Cardiac Index (CI), Intrathoracic Blood Volume Index (ITBVI) (Stewart-Hamilton equation), Extravascular Lung Water Index (EVLWI) and Systemic Vascular Resistance Index (SVRI) measurements were recorded twice daily. Statistical analysis was performed using one-way repeated measures analysis of variance with the post hoc Bonferroni test for intra- and intergroup comparisons., Results: Seventy-nine patients with a mean age (±SD) of 9 ± 5 years and a mean TBSA burn (±SD) of 64% ± 20% were studied. CI significantly increased compared to level at admission and was highest 3 weeks postburn. ITBVI increased significantly starting at 8 days postburn. SVRI continuously decreased early in the perioperative burn period. EVLWI increased significantly starting at 9 days postburn. Young children (0 to 5 years old) had a significantly increased EVLWI and decreased ITBVI compared to older children (12 to 18 years old). EVLWI was significantly higher in patients who did not survive burn injury., Conclusions: Continuous PiCCO measurements were performed for the first time in a large cohort of severely burned pediatric patients. The results suggest that hyperdynamic circulation begins within the first week after burn injury and continues throughout the entire intensive care unit stay.

Early definitive burn treatment is assumed to improve prognosis, in part because open wounds rapidly stimulate muscle catabolism and systemic inflammation. This study describes the incidence and management of injury associated malnutrition among pediatric burn patients transferred for definitive care 21-166 days following burn injury. Medical records of patients admitted to our hospital between January 2003 and January 2009, at least 3 weeks after burn injury, were retrospectively reviewed. Only children with an initial total body surface area (TBSA) burn of ≥20% were included in this study (n=36). Patients were classified as acutely well nourished or malnourished by the medical team. All patients were admitted with chronic open wounds (31±16% TBSA). Sixty-one percent (n=22) of patients were diagnosed with malnutrition. These patients had a significantly longer delay to transfer (26-166 days) than well nourished patients who transferred at 21-138 days (p<0.05). Average protein (2.8±0.18g/kg), and kilocalorie (1.6±0.1% basal metabolic rate) provision did not differ between groups. Incidence of infection was not different between well nourished and malnourished patients. Malnutrition occurs frequently among pediatric burn patients with delayed admissions. Adequate surgical care, infection control, and nutrition are required for wound healing., (Copyright © 2010 Elsevier Ltd and ISBI. All rights reserved.)

Despite significant advances in burn resuscitation and wound care over the past 30 years, morbidity and mortality from thermal injury remain high. Limited donor skin in severely burned patients hinders effective wound excision and closure, leading to infectious complications and prolonged hospitalizations. Even with large-volume fluid resuscitation, the systemic inflammatory response syndrome compromises end-organ perfusion in burn patients, with resultant multiorgan failure. Stem cells, which enhance wound healing and counteract systemic inflammation, now offer potential therapies for these challenges. Through a review of the literature, this article seeks to illustrate applications of stem cell therapy to burn care and to highlight promising areas of research.

Neutrophils have key roles in modulating the immune response. We present a robust methodology for rapidly isolating neutrophils directly from whole blood with 'on-chip' processing for mRNA and protein isolation for genomics and proteomics. We validate this device with an ex vivo stimulation experiment and by comparison with standard bulk isolation methodologies. Last, we implement this tool as part of a near-patient blood processing system within a multi-center clinical study of the immune response to severe trauma and burn injury. The preliminary results from a small cohort of subjects in our study and healthy controls show a unique time-dependent gene expression pattern clearly demonstrating the ability of this tool to discriminate temporal transcriptional events of neutrophils within a clinical setting.

Background: Cirrhotic patients with sternoclavicular joint (SCJ) infection pose a unique challenge for which there are no management guidelines. We reviewed our experience with this unusual infection in this high-risk patient population., Methods: We performed a retrospective analysis of all patients with cirrhosis (n = 5) treated surgically for SCJ infection from January 1998 to July 2006., Results: All infections were locally advanced with bone necrosis, complex abscess formation, or mediastinal involvement. En bloc SCJ resection was performed in 3 patients. A more conservative approach of incision and drainage with debridement was performed in 2 patients. Sepsis and/or pulmonary compromise occurred in all patients postoperatively and the surgical mortality rate was 40%. All deaths occurred after en bloc SCJ resection., Conclusions: Sternoclavicular joint infections in cirrhotic patients tend to be extensive in nature and pose a high surgical risk. Adequate surgical drainage and debridement may be better tolerated than a radical en block resection.

Background: Transcription factor pancreatic duodenal homeobox-1 (PDX-1) is critical for beta-cell differentiation and insulin gene expression. In this study, we investigated the role of PDX-1 in ductal-to-islet cell transdifferentiation, islet cell apoptosis, and proliferation in addition to other regulators associated with these processes in two developing beta-cell models., Materials and Methods: CAPAN-1 cells were cultured with the GLP-1 analogue Exendin-4 (Ex-4) to induce transdifferentiation to an insulin-producing phenotype. Expression patterns of PDX-1, somatostatin receptors (SSTR) 1, 2, and 5, p27, and p38 were analyzed. To model pancreatic regeneration in vivo, subtotal pancreatectomies were performed in rats and remnant pancreata were compared to sham laparotomy controls to determine islet size, morphology, apoptosis, and PDX-1 expression., Results: In Ex-4-treated cells, PDX-1 expression increased 67% above basal levels within 24 h and was followed by a 10-fold decline in expression by the end of the study. Expression of cell-cycle inhibitor p27 was down-regulated by 81% at 24 h, while levels of the pro-apoptotic modulator p38 significantly increased 4-fold. When compared to controls, SSTR1 expression declined, while SSTR2 and SSTR5 expression were significantly up-regulated in treated cells. Immunofluorescence of pancreatic remnants following subtotal pancreatectomy revealed increased PDX-1 staining at 24 h followed by a significant decline at 72 h post-pancreatectomy., Conclusion: GLP-1 analogue Ex-4 resulted in up-regulation of PDX-1 in CAPAN-1 cells and PDX-1 was up-regulated in proliferating islets following subtotal pancreatectomy in rats. The increase was seen in the first 24 h. These findings suggest a possible relationship between PDX-1 and the state of islet proliferation, islet-to-ductal transdifferentiation, apoptosis, and the expression of SSTRs.

Background: The anal epithelium is subject to dysplastic change in patients with human immunodeficiency virus (HIV). We sought to determine if the duration of HIV disease or the patient's immune status were associated with the development of anal carcinoma., Methods: HIV-positive patients diagnosed with anal neoplasms were reviewed. Statistical analysis was performed via an unpaired Student t test and the Fisher exact test., Results: Fourteen patients were identified, 7 with anal intraepithelial neoplasms (group 1) and 7 with anal carcinoma (group 2). Human papillomavirus was detected in 100% of patients in group 1 and in 67% of patients in group 2. There was no significant difference in the level of immunosuppression as assessed by the CD4 counts (266.9 +/- 48.5 vs. 274.7 +/- 92.0 cell/c microl; P = .94) and viral loads (19,243 +/- 18,034 vs. 67,140 +/- 39,570 RNA/mL; P = .29) between groups 1 and 2, respectively. Group 2 had been HIV positive for a significantly longer period of time (12.6 +/- 2.3 y) compared with group 1 (5.9 +/- 2.0 y, P = .05)., Conclusions: The most significant factor for the development of invasive anal carcinoma in patients with HIV is duration of disease. As a result of improved long-term survival secondary to new HIV therapy, anal invasive carcinoma will become an increasing problem.

Background: In the operating room (OR), poor communication among the surgeons, anesthesiologists, and nurses may lead to adverse events that can compromise patient safety. A survey performed at our institution showed low communication ratings from surgeons, anesthesiologists, and OR nursing staff. Our objective was to determine if communication in the operating room could be improved through medical team training (MTT)., Methods: A dedicated training session (didactic instruction, interactive participation, role-play, training films, and clinical vignettes) was offered to the entire surgical service using crew resource management principles. Attendees also were instructed in the principles of change management. A change team was formed to drive the implementation of the principles reviewed through a preoperative briefing conducted among the surgeon, anesthesiologist, and OR nurse. A validated Likert scale survey with questions specific to effective communication was administered to the nurses, anesthesiologists, and surgeons 2 months after the MTT to determine the impact on communication. Data are presented as mean +/- SEM., Results: There was a significant increase in the anesthesiologist and surgeon communication composite score after medical team training (anesthesia pre-MTT = 2.0 +/- .3, anesthesia post-MTT = 4.5 +/- .6, P <.0008; surgeons pre-MTT = 5.2 +/- .2, surgeons post-MTT = 6.6+/-.3, P <.0004; nurses pre-MTT = 4.3 +/- .3, nurses post-MTT = 4.2 +/- .4, P = .7)., Conclusions: Medical team training using crew resource management principles can improve communication in the OR, ensuring a safer environment that leads to decreased adverse events.

Background: Although studies have ascertained that ten percent of soldiers killed in battle bleed to death from extremity wounds, little data exists on exsanguination and mortality from extremity injuries in civilian trauma. This study examined the treatment course and outcomes of civilian patients who appear to have exsanguinated from isolated penetrating extremity injuries., Methods: Five and 1/2 years' data (Aug 1994 to Dec 1999) were reviewed from two Level I trauma centers that receive 95% of trauma patients in metropolitan Houston, TX. Records (hospital trauma registries, emergency medical system (EMS) and medical examiner data) were reviewed on all patients with isolated extremity injuries who arrived dead at the trauma center or underwent cardiopulmonary resuscitation (CPR) or emergency center thoracotomy (ECT)., Results: Fourteen patients meeting inclusion criteria were identified from over 75,000 trauma emergency center (EC) visits. Average age was 31 years and 93% were males. Gunshot wounds accounted for 50% of the injuries. The exsanguinating wound was in the lower extremity in 10/14 (71%) patients and proximal to the elbow or knee in 12/14 (86%). Ten (71%) had both a major artery and vein injured; one had only a venous injury. Prehospital hemorrhage control was primarily by gauze dressings. Twelve (86%) had "signs of life" in the field, but none had a discernable blood pressure or pulse upon arrival at the EC. Prehospital intravenous access was not obtained in 10 patients (71%). Nine patients underwent ECT, and nine were initially resuscitated (eight with ECT and one with CPR). Those undergoing operative repair received an average of 26 +/- 14 units of packed red blood cells. All patients died, 93% succumbing within 12 hours., Conclusion: Although rare, death from isolated extremity injuries does occur in the civilian population. The majority of injuries that lead to immediate death are proximal injuries of the lower extremities. The cause of death in this series appears to have been exsanguination, although definitive etiology cannot be discerned. Intravenous access was not obtainable in the majority of patients. Eight patients (57%) had bleeding from a site that anatomically might have been amenable to tourniquet control. Patients presenting to the EC without any detectable blood pressure and who received either CPR or EC thoracotomy all died.

The PROLENE Hernia System (PHS), consisting of an onlay and an underlay patch with a connector, has recently been introduced as an option for tension-free open repair of inguinal hernias and is touted for the repair of both direct and indirect hernias. In theory, the underlay is placed either through the internal ring or through the transversalis fascia and is seated in the preperitoneal space. To date, there have been no views of how this underlay is seated after open repair. Our objective was to determine the position and orientation of the underlay patch after open repair. After informed consent, two patients requiring both umbilical and inguinal hernia repairs had their inguinal hernias repaired using the open technique with the PHS. In the first patient, after open inguinal repair, the umbilical hernia was reduced, a 30 degrees laparoscope was placed intraperitoneally, and the underlay patch placed in the retroperitoneal space was visualized through the translucent peritoneum. In the second patient, the umbilical hernia was initially reduced, and the laparoscope was introduced to visualize the creation of the preperitoneal space and placement of the underlay during open repair of the inguinal hernia. As per our hypothesis, we show that the preperitoneal space is successfully created during open repair with the PHS with minimal trauma. More importantly, the underlay is deployed open and contours to the shape of the abdominal wall from the native intra-abdominal pressure, covering regions at risk for future herniation.

The repair of a simple inguinal hernia or a complicated incisional hernia no longer involves just the sewing together of a defect in the musculature. Present-day hernia operations require that the surgeon more fully understand the functional anatomy and pathophysiology of the abdominal wall and groin. Hernia surgeons must be familiar with a myriad of surgical techniques, ranging from the traditional tissue repairs with suture to the mesh-based "tension-free" open and laparoscopic techniques. Furthermore, the surgeon must comprehend outcome analysis in evaluating differing therapies. Several approaches have been used for repair of groin hernias and have included tissue repairs (later termed "tension" repairs), as well as mesh or tension-free repairs and laparoscopy. Although each of these repairs boasts its successes, there are advantages and disadvantages to each approach. This article highlights each of these repairs through review of the literature.

Over the past century, there has been a significant increase in the understanding of abdominal wall anatomy as it relates to inguinal and ventral hernia repairs. Since the initial reports of successful primary inguinal herniorrhaphy, recurrence rates have dramatically decreased because of the improved understanding of the pathologic defect. This article will review the important nomenclature of the groin region, briefly review the bony and tissue anatomy of the groin, and describe the anatomic hole from which the pathologic hole (hernia) originates.

Background: Factors previously identified by multivariate logistic regression that were predictive for gangrenous cholecystitis (GC) were used to develop a predictive equation. Our objective was to evaluate the sensitivity, specificity, and positive (PPV) and negative (NPV) predictive values of this equation for detecting GC in patients with acute cholecystitis (AC)., Methods: Medical records of patients who presented to a tertiary care hospital with AC were reviewed. Twenty-one patient and clinical variables were recorded. We prospectively tested the results of the following equation against pathologic diagnosis: P=e((0.7116+0.9944.DM+1.7157.WBC-1.0319.ALT.2.0518.ALP+2.7078.PCF))/(1+e([-0.7116+0.9944.DM+1.7157.WBC-1.0319.ALT-2.0518.ALP+2.7078.PCF])), where P = predicted value; DM = diabetes mellitus; WBC = white blood cell count; ALT = alanine aminotransferase; AST = aspartate aminotransferase; and PCF = pericholecystic fluid., Results: Ninety-eight patients presented with AC and 18% had GC (18 of 98). Using a cutoff of P = 0.724, our equation had a specificity of 93%, sensitivity of 83%, PPV of 71%, and NPV of 96%, P <0.001 for the detection of GC., Conclusions: Our study demonstrates the equation may be useful in detecting the subset of AC patients who have GC.

Background: Cirrhotic patients who present for elective and emergent surgery pose a formidable challenge for the surgeon because of the high reported morbidity and mortality. The Child-Turcotte-Pugh (CTP) score previously has been used to evaluate preoperative severity of liver dysfunction and to predict postoperative outcome. Recently, a more objective scoring classification, the model for end-stage liver disease (MELD), has been shown to predict accurately the 3-month mortality for cirrhotic patients awaiting transplantation. We sought to compare the CTP and MELD scores in predicting outcomes in cirrhotic patients undergoing surgical procedures requiring general anesthesia., Methods: During the study period, 40 patients with a history of cirrhosis who required elective (E) or emergent (EM) surgical procedures under general anesthesia were reviewed (E = 24, EM = 16). The preoperative CTP and MELD scores were calculated and patient short- (30-day) and long-term (3-month) outcomes were recorded., Results: There was a significant difference in the 1-month and 3-month mortality rates between the emergent and elective groups (EM group: 1 mo = 19%, 3 mo = 44%; E group: 1 mo = 17%, 3 mo = 21%, P <0.05). There was good correlation between the CP and MELD scores, which was greater in the emergent groups as compared with the elective group (EM: r = 0.81; E: r = 0.65)., Conclusions: Our study shows that cirrhotic patients who undergo surgery under general anesthesia have an extremely high 1- and 3-month mortality rate that progressively increases with severity of preoperative liver dysfunction. Additionally, the MELD score correlates well with the CTP score, providing a more objective predictor of postoperative mortality in cirrhotic patients undergoing surgery.

Background: Today's complex health care environment coupled with the 80-hour workweek mandate has required that surgical resident team interactions evolve from a military command-and-control style to a collaborative leadership style., Methods: A novel educational curriculum was implemented with objectives of training the residents to have the capacity/ability to create and manage powerful teams through alignment, communication, and integrity integral tools to practicing a collaborative leadership style while working 80 hours per week. Specific strategies were as follows: (1) to focus on quality of patient care and service while receiving a high education-to-service ratio, and (2) to maximize efficiency through time management., Results: This article shows that leadership training as part of a resident curriculum can significantly increase a resident's view of leadership in the areas of alignment, communication, and integrity; tools previously shown in business models to be vital for effective and efficient teams., Conclusion: This curriculum, over the course of the surgical residency, can provide residents with the necessary tools to deliver efficient quality of care while working within the 80-hour workweek mandate in a more collaborative style environment.

Background: Serum response factor (SRF) is a transcription factor that plays an important role in cellular differentiation and cell cycle regulation. SRF function is regulated in part by alternative splicing. Little is known about the expression or role of these alternatively spliced isoforms during tumorigenesis. We hypothesized that there is a change in the splice variants during intestinal tumorigenesis and that this change promotes the tumor phenotype., Materials and Methods: SRF expression was determined by Western blotting of benign intestinal cells and human colon cancer cell lines. To determine the effect of alternative splicing of SRF on intestinal growth and proliferation, the predominant alternatively spliced isoform of SRF that we identified in colon cancer cells, SRFDelta5, was transfected into IEC-6 cells. IEC-6 and IEC-6SRFDelta5 cells were plated and cell numbers were determined at four time points., Results: Western blotting demonstrates that full-length SRF is the predominant form of SRF in rat IEC-6 cells, normal human colonic mucosa, and HT-29 cells, derived from a well-differentiated human colonic adenocarcinoma. In the colon cancer cell lines derived from poorly differentiated tumors (WiDr, HCT 116, LoVo, and SW480), SRFDelta5 is the predominant isoform expressed. There was a significant increase in cell survival in IEC-6 cells transfected with SRFDelta5 compared to parental cells., Conclusion: Our data demonstrate that an alternatively spliced isoform of SRF, SRFDelta5, is expressed in human colon cancer cell lines. Additionally, these data demonstrate that expression of SRFDelta5 may contribute to the tumor phenotype by affecting cell survival. This is the first study to document a change in expression of the alternatively spliced isoform of SRF in human malignancy.

Background: Lumbar hernia is a clinical entity that has been increasingly more common since the advent of iliac bone harvest for bone grafting procedures. These can be very technically difficult to repair and have a high recurrence rate., Methods: Using a corkscrew anchor suture device, we have developed a novel and simple way to repair these hernias with no recurrence. Here we present our experience with the corkscrew suture anchor device., Results: This technique has been performed in 2 patients at our institution, and in both cases, the hernia was successfully repaired. Our 1-year follow-up on this technique demonstrates intact repairs with no sign of recurrence., Conclusions: The placement of corkscrew suture anchors along the iliac crest remnant is a simple technique requiring minimal bony exposure. The anchors facilitate the long-term fixation of mesh despite the lack of fascia in this area. We conclude that this is a simple and effective approach for repair of these challenging hernias.

Background: Although the utility of lymphatic mapping (LM) and sentinel lymph node (SLN) biopsy in patients with melanoma and breast carcinoma has been well documented, this same is not true for patients with colon carcinoma. The authors previously reported a high false-negative rate for SLN biopsy in patients with colon carcinoma using isosulfan blue dye alone. The objective of the current study was to determine whether radiocolloid would increase the sensitivity of LM/SLN biopsy in patients with colon carcinoma., Methods: The authors performed LM on 57 patients with colon carcinoma using both isosulfan blue dye and radiocolloid. The SLN(s) were identified by either their blue color or by increased radioactivity. The SLNs then underwent both routine histologic sectioning and immunohistochemical (IHC) staining for cytokeratins., Results: An SLN was identified in 56 patients (98%). Radiocolloid was able to identify only 1 additional positive SLN (9%). Overall, it was found that the disease had metastasized to the lymph nodes in 22 patients, even though there was no evidence of disease in the SLN(s) in 11 of those 22 patients on routine histologic sectioning (false-negative rate, 50%; sensitivity, 50%). In five patients, IHC of the SLN was the only indicator of metastatic disease. The inclusion of IHC-positive SLNs in these calculations would decrease the false-negative rate to 17% and would increase the sensitivity of SLN biopsy to 83%., Conclusions: In the current study, the addition of radiocolloid did not increase the sensitivity of detection of positive SLN(s) compared with the use of isosulfan blue dye alone. IHC of the SLN potentially may increase the sensitivity of LM and reduce the false-negative rate. However, the long-term prognostic significance of IHC in patients with colon carcinoma remains controversial., (Copyright 2004 American Cancer Society.)