Evaluation of urological and gynecological surgeons as force multipliers for mass casualty trauma care.

BACKGROUND: The clinical demands of mass casualty events strain even the most well-equipped trauma centers and are especially challenging in resource-limited rural, remote, or austere environments. Gynecologists and urologists care for patients with pelvic and abdominal injuries, but the extent to which they are able to serve as "force multipliers" for trauma care is unclear. This study examined the abilities of urologists and gynecologists to perform 32 trauma procedures after mentored training by expert trauma educators to inform the potential for these specialists to independently care for trauma patients. METHODS: Urological (6), gynecological surgeons (6), senior (postgraduate year 5) general surgery residents (6), and non-trauma-trained general surgeons (8) completed a rigorous trauma training program (Advanced Surgical Skills Exposure in Trauma Plus). All participants were assessed in their trauma knowledge and surgical abilities performing 32 trauma procedures before/after mentored training by expert trauma surgeons. Performance benchmarks were set for knowledge (80%) and independent accurate completion of all procedural components within a realistic time window (90%). RESULTS: General surgery participants demonstrated greater trauma knowledge than gynecologists and urologists; however, none of the specialties reached the 80% benchmark. Before training, general surgery, and urology participants outperformed gynecologists for overall procedural abilities. After training, only general surgeons met the 90% benchmark. Post hoc analysis revealed no differences between the groups performing most pelvic and abdominal procedures; however, knowledge associated with decision making and judgment in the provision of trauma care was significantly below the benchmark for gynecologists and urologists, even after training. CONCLUSION: For physiologically stable patients with traumatic injuries to the abdomen, pelvis, or retroperitoneum, these specialists might be able to provide appropriate care; however, they would best benefit trauma patients in the capacity of highly skilled assisting surgeons to trauma specialists. These specialists should not be considered for solo resuscitative surgical care. LEVEL OF EVIDENCE: Therapeutic/Care Management; Level IV.

The last days: The medical response of United States and allied military teams during the Afghanistan Exodus.

OBJECTIVES: The objective of this study is to describe the United States and allied military medical response during the withdrawal from Afghanistan. BACKGROUND: The military withdrawal from Afghanistan concluded with severe hostilities resulting in numerous civilian and military casualties. The clinical care provided by coalition forces capitalized on decades of lessons learned and enabled unprecedented accomplishments. METHODS: In this retrospective, observational analysis, casualty numbers, and operative information was collected and reported from military medical assets in Kabul, Afghanistan. The continuum of medical care and the trauma system, from the point of injury back to the United States was captured and described. RESULTS: Prior to a large suicide bombing resulting in a mass casualty event, the international medical teams managed distinct 45 trauma incidents involving nearly 200 combat and non-combat civilian and military patients over the preceding 3 months. Military medical personnel treated 63 casualties from the Kabul airport suicide attack and performed 15 trauma operations. US air transport teams evacuated 37 patients within 15 hours of the attack. CONCLUSION: Lessons learned from the last 20 years of combat casualty care were successfully implemented during the culmination of the Afghanistan conflict. Ultimately, the effort, teamwork, and system adaptability exemplify not only the attitudes and character of service members who provide modern combat casualty care but also the paramount importance of the battlefield learning health care system. A continued posture to maintain military surgical preparedness in unique environments remain crucial as the US military prepares for the future.Retrospective observational analysis. LEVEL OF EVIDENCE: Therapeutic/Care Management; Level V.

Development, refinement, and characterization of a nonhuman primate critical care environment.

BACKGROUND: Systemic inflammatory response remains a poorly understood cause of morbidity and mortality after traumatic injury. Recent nonhuman primate (NHP) trauma models have been used to characterize the systemic response to trauma, but none have incorporated a critical care phase without the use of general anesthesia. We describe the development of a prolonged critical care environment with sedation and ventilation support, and also report corresponding NHP biologic and inflammatory markers. METHODS: Eight adult male rhesus macaques underwent ventilation with sedation for 48-96 hours in a critical care setting. Three of these NHPs underwent "sham" procedures as part of trauma control model development. Blood counts, chemistries, coagulation studies, and cytokines/chemokines were collected throughout the study, and histopathologic analysis was conducted at necropsy. RESULTS: Eight NHPs were intentionally survived and extubated. Three NHPs were euthanized at 72-96 hours without extubation. Transaminitis occurred over the duration of ventilation, but renal function, acid-base status, and hematologic profile remained stable. Chemokine and cytokine analysis were notable for baseline fold-change for Il-6 and Il-1ra (9.7 and 42.7, respectively) that subsequently downtrended throughout the experiment unless clinical respiratory compromise was observed. CONCLUSIONS: A NHP critical care environment with ventilation support is feasible but requires robust resources. The inflammatory profile of NHPs is not profoundly altered by sedation and mechanical ventilation. NHPs are susceptible to the pulmonary effects of short-term ventilation and demonstrate a similar bioprofile response to ventilator-induced pulmonary pathology. This work has implications for further development of a prolonged care NHP model.

Cellular microRNAs correlate with clinical parameters in multiple injury patients.

INTRODUCTION: The pathophysiology of the inflammatory response after major trauma is complex, and the magnitude correlates with severity of tissue injury and outcomes. Study of infection-mediated immune pathways has demonstrated that cellular microRNAs may modulate the inflammatory response. The authors hypothesize that the expression of microRNAs would correlate to complicated recoveries in polytrauma patients (PtPs). METHODS: Polytrauma patients enrolled in the prospective observational Tissue and Data Acquisition Protocol with Injury Severity Score of >15 were selected for this study. Polytrauma patients were divided into complicated recoveries and uncomplicated recovery groups. Polytrauma patients' blood samples were obtained at the time of admission (T0). Established biomarkers of systemic inflammation, including cytokines and chemokines, were measured using multiplexed Luminex-based methods, and novel microRNAs were measured in plasma samples using multiplex RNA hybridization. RESULTS: Polytrauma patients (n = 180) had high Injury Severity Score (26 [20-34]) and complicated recovery rate of 33%. MicroRNAs were lower in PtPs at T0 compared with healthy controls, and bivariate analysis demonstrated that variations of microRNAs correlated with age, race, comorbidities, venous thromboembolism, pulmonary complications, complicated recovery, and mortality. Positive correlations were noted between microRNAs and interleukin 10, vascular endothelial growth factor, Acute Physiology and Chronic Health Evaluation, and Sequential Organ Failure Assessment scores. Multivariable Lasso regression analysis of predictors of complicated recovery based on microRNAs, cytokines, and chemokines revealed that miR-21-3p and monocyte chemoattractant protein-1 were predictive of complicated recovery with an area under the curve of 0.78. CONCLUSION: Systemic microRNAs were associated with poor outcomes in PtPs, and results are consistent with previously described trends in critically ill patients. These early biomarkers of inflammation might provide predictive utility in early complicated recovery diagnosis and prognosis. Because of their potential to regulate immune responses, microRNAs may provide therapeutic targets for immunomodulation. LEVEL OF EVIDENCE: Diagnostic Tests/Criteria; Level II.

Risk Factors for Urgent or Emergent Cholecystectomy Mid-workup for Symptomatic Cholelithiasis.

BACKGROUND: Patients who undergo cholecystectomy often do so for diagnoses related to the sequelae of gallstones. Many patients present acutely, requiring urgent removal due to complications of cholelithiasis. This study aims to characterize the patient population likely to present acutely during ongoing workup for cholelithiasis to better identify those who may benefit from expedited care. METHODS: Medical records of all adult patients who underwent cholecystectomy for indications related to cholelithiasis between 2015 and 2016 were reviewed retrospectively. Qualitative data was analyzed using Chi square test and quantitative data was analyzed using independent t-tests. RESULTS: One hundred and seventy-four cholecystectomies were performed. Overall, 74.2% of the procedures were done electively while 25.8% were done urgently. And 42.2% of patients who underwent acute surgical intervention had evidence of prior workup. Patients requiring urgent intervention during ongoing diagnostic evaluation were more likely to have initially presented to an emergency department (ED) than another provider (68.4% vs 31.3%, P < .001) and had an odds ratio of 4.7 for undergoing acute intervention if they initially presented to the ED. They also tended to be more temporally remote from their initial diagnosis (119 ± 142 vs 74.6 ± 68.2 days, P < .19) relative to those who underwent elective operations. DISCUSSION: Patients who require urgent intervention during ongoing workup for cholelithiasis have prolonged courses of care and present to the ED more often for initial evaluation when compared to those who undergo elective intervention. These findings suggest that an emphasis on expedited workup of cholelithiasis and early surgical referral may be warranted, especially for those who initially present in the ED.

Upper-Extremity Vascular Exposures for Trauma: Comparative Performance Outcomes for General Surgeons and Orthopedic Surgeons.

INTRODUCTION: As combat-related trauma decreases, there remains an increasing need to maintain the ability to care for trauma victims from other casualty events around the world (e.g., terrorism, natural disasters, and infrastructure failures). During these events, military surgeons often work closely with their civilian counterparts, often in austere and expeditionary contexts. In these environments, the primary aim of the surgical team is to implement damage control principles to avert blood loss, optimize oxygenation, and improve survival. Upper-extremity vascular injuries are associated with high rates of morbidity and mortality resulting from exsanguination and ischemic complications; however, fatalities may be avoided if hemorrhage is rapidly controlled. In austere contexts, deployed surgical teams typically include one general surgeon and one orthopedic surgeon, neither of which have acquired the expertise to manage these vascular injuries. The purpose of this study was to examine the baseline capabilities of general surgeons and orthopedic surgeons to surgically expose and control axillary and brachial arteries and to determine if the abilities of both groups could be increased through a focused cadaver-based training intervention. METHODS: This study received IRB approval at our institution. Study methods included the use of cadavers for baseline assessment of procedural capabilities to expose and control axillary and brachial vessels, followed by 1:1 procedural training and posttraining re-assessment of procedural capabilities. Inferential analyses included ANOVA/MANOVA for within- and between-group effects (P < .05). Effect sizes were calculated using Cohen's d. RESULTS: Study outcomes demonstrated significant differences between the baseline performance abilities of the two groups, with general surgeons outperforming orthopedic surgeons. Before training, neither group reached performance benchmarks for overall or critical procedural abilities in exposing axillary and brachial vessels. Training led to increased abilities for both groups. There were statistically significant gains for overall procedural abilities, as well as for critical procedural elements that are directly associated with morbidity and mortality. These outcomes were consistent for both general and orthopedic surgeons. Effect sizes ranged between medium (general surgeons) and very large (orthopedic surgeons). CONCLUSION: There was a baseline capability gap for both general surgeons and orthopedic surgeons to surgically expose and control the axillary and brachial vessels. Outcomes from the course suggest that the methodology facilitates the acquisition of accurate and independent vascular procedural capabilities in the management of upper-extremity trauma injuries. The impact of this training for surgeons situated in expeditionary or remote contexts has direct relevance for caring for victims of extremity trauma. These outcomes underscore the need to train all surgeons serving in rural, remote, expeditionary, combat, or global health contexts to be able to competently manage extremity trauma and concurrent vascular injuries to increase the quality of care in those settings.

Anastomotic Outcomes in Military Exploratory Laparotomies in the Modern Combat Era.

BACKGROUND: Intestinal anastomoses in military settings are performed in severely injured patients who often undergo damage control laparotomy in austere environments. We describe anastomotic outcomes of patients from recent wars. METHODS: Military personnel with combat-related intra-abdominal injuries (June 2009-December 2014) requiring laparotomy with resection and anastomosis were analyzed. Patients were evacuated from Iraq or Afghanistan to Landstuhl Regional Medical Center (Germany) before being transferred to participating U.S. military hospitals. RESULTS: Among 341 patients who underwent 1053 laparotomies, 87 (25.5%) required ≥1 anastomosis. Stapled anastomosis only was performed in 57.5% of patients, while hand-sewn only was performed in 14.9%, and 9.2% had both stapled and hand-sewn techniques (type unknown for 18.4%). Anastomotic failure occurred in 15% of patients. Those with anastomotic failure required more anastomoses (median 2 anastomoses, interquartile range [IQR] 1-3 vs. 1 anastomosis, IQR 1-2, P = .03) and more total laparotomies (median 5 laparotomies, IQR 3-12 vs. 3, IQR 2-4, P = .01). There were no leaks in patients that had only hand-sewn anastomoses, though a significant difference was not seen with those who had stapled anastomoses. While there was an increasing trend regarding surgical site infections (SSIs) with anastomotic failure after excluding superficial SSIs, it was not significant. There was no difference in mortality. DISCUSSION: Military trauma patients have a similar anastomotic failure rate to civilian trauma patients. Patients with anastomotic failure were more likely to have had more anastomoses and more total laparotomies. No definitive conclusions can be drawn about anastomotic outcome differences between hand-sewn and stapled techniques.

Viral Micro-RNAs Are Detected in the Early Systemic Response to Injury and Are Associated With Outcomes in Polytrauma Patients.

OBJECTIVES: To evaluate early activation of latent viruses in polytrauma patients and consider prognostic value of viral micro-RNAs in these patients. DESIGN: This was a subset analysis from a prospectively collected multicenter trauma database. Blood samples were obtained upon admission to the trauma bay (T0), and trauma metrics and recovery data were collected. SETTING: Two civilian Level 1 Trauma Centers and one Military Treatment Facility. PATIENTS: Adult polytrauma patients with Injury Severity Scores greater than or equal to 16 and available T0 plasma samples were included in this study. Patients with ICU admission greater than 14 days, mechanical ventilation greater than 7 days, or mortality within 28 days were considered to have a complicated recovery. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: Polytrauma patients (n = 180) were identified, and complicated recovery was noted in 33%. Plasma samples from T0 underwent reverse transcriptase-quantitative polymerase chain reaction analysis for Kaposi's sarcoma-associated herpesvirus micro-RNAs (miR-K12_10b and miRK-12-12) and Epstein-Barr virus-associated micro-RNA (miR-BHRF-1), as well as Luminex multiplex array analysis for established mediators of inflammation. Ninety-eight percent of polytrauma patients were found to have detectable Kaposi's sarcoma-associated herpesvirus and Epstein-Barr virus micro-RNAs at T0, whereas healthy controls demonstrated 0% and 100% detection rate for Kaposi's sarcoma-associated herpesvirus and Epstein-Barr virus, respectively. Univariate analysis revealed associations between viral micro-RNAs and polytrauma patients' age, race, and postinjury complications. Multivariate least absolute shrinkage and selection operator analysis of clinical variables and systemic biomarkers at T0 revealed that interleukin-10 was the strongest predictor of all viral micro-RNAs. Multivariate least absolute shrinkage and selection operator analysis of systemic biomarkers as predictors of complicated recovery at T0 demonstrated that miR-BHRF-1, miR-K12-12, monocyte chemoattractant protein-1, and hepatocyte growth factor were independent predictors of complicated recovery with a model complicated recovery prediction area under the curve of 0.81. CONCLUSIONS: Viral micro-RNAs were detected within hours of injury and correlated with poor outcomes in polytrauma patients. Our findings suggest that transcription of viral micro-RNAs occurs early in the response to trauma and may be associated with the biological processes involved in polytrauma-induced complicated recovery.

Primary Lung Hernia After Blunt Chest Trauma: Chest Wall Repair Strategies.

Lung herniation is a rare pathology seen after trauma. A case of acquired lung hernia is presented after blunt thoracic trauma that was repaired primarily. Surgical management and decision-making for this process are discussed.

Risk factors for abdominal surgical site infection after exploratory laparotomy among combat casualties.

BACKGROUND: Surgical site infections (SSIs) are well-recognized complications after exploratory laparotomy for abdominal trauma; however, little is known about SSI development after exploration for battlefield abdominal trauma. We examined SSI risk factors after exploratory laparotomy among combat casualties. METHODS: Military personnel with combat injuries sustained in Iraq and Afghanistan (June 2009 to May 2014) who underwent laparotomy and were evacuated to participating US military hospitals were included. Log-binominal regression was used to identify SSI risk factors. RESULTS: Of 4,304 combat casualties, 341 patients underwent a total of 1,053 laparotomies. Abdominal SSIs were diagnosed in 49 patients (14.4%): 8% with organ space SSI, 4% with deep incisional SSI, and 4% with superficial SSIs (4 patients had multiple SSIs). Patients with SSIs had more colorectal (p < 0.001), small bowel (p = 0.010), duodenum (p = 0.006), pancreas (p = 0.032), and abdominal vascular injuries (p = 0.040), as well as prolonged open abdomen (p = 0.004) and more infections diagnosed before the SSI (or final exploratory laparotomy) versus non-SSI patients (p < 0.001). Sustaining colorectal injuries (risk ratio [RR], 3.20; 95% confidence interval [CI], 1.58-6.45), duodenum injuries (RR, 6.71; 95% CI, 1.73-25.58), and being diagnosed with prior infections (RR, 10.34; 95% CI, 5.05-21.10) were independently associated with any SSI development. For either organ space or deep incisional SSIs, non-intra-abdominal infections, fecal diversion, and duodenum injuries were independently associated, while being injured via an improvised explosive device was associated with reduced likelihood compared with penetrating nonblast (e.g., gunshot wounds) injuries. Non-intra-abdominal infections and hypotension were independently associated with organ space SSIs development alone, while sustaining blast injuries were associated with reduced likelihood. CONCLUSION: Despite severity of injuries and the battlefield environment, the combat casualty laparotomy SSI rate is relatively low at 14%, with similar risk factors and rates reported following severe civilian trauma. LEVEL OF EVIDENCE: Epidemiological, level III.

The Isolated Surgeon: A Scoping Review.

BACKGROUND: Surgeons in resource-limited environments often provide care outside the expected scope of current general surgery training. Geographically isolated patients may be unwilling or unable to travel for specialty care. These same patients also present with life-threatening emergencies beyond the typical breadth of a general surgeon's practice, in hospitals with limited professional and material support. This review characterizes the unique role of isolated surgeons, so individual surgeons and health care organizations may focus professional development resources more efficiently, with the ultimate goal of improved patient care. METHODS: We performed a scoping review of the isolated surgeon, reviewing 25 years of literature regarding isolated US civilian and military surgeons. We examined emerging themes regarding the definition of an isolated surgeon, the scope of surgical practice beyond current training norms, and training gaps identified by surgeons in an isolated role. RESULTS: From 904 articles identified, we included 91 for final review. No prior definition exists for the isolated surgeon, although multiple definitions describe rural surgeons, patients, or hospitals; we propose an initial definition from consistent themes in the literature. Isolated surgeons across varied practice settings consistently performed relatively large volumes of cases of, and identified training gaps in, orthopedic, obstetric and gynecologic, urologic, and vascular surgery subspecialties. Life-threatening, "rare-but-real" cases in the above and neurosurgical disciplines are uncommon, but consistent across practice settings. CONCLUSIONS: This review represents the largest examination of the isolated surgeon in the current literature. Clarifying the identity, practice components, and training gaps of the isolated surgeon represent the first step in formalizing support for this small but critical group of surgeons and their patients.

Comparison of Outcomes Between the National Surgical Quality Improvement Program and an Emergency General Surgery Registry.

BACKGROUND: The National Surgical Quality Improvement Program (NSQIP) has become a prevalent tool for quality improvement. At our tertiary military hospital, NSQIP collects 20% of eligible cases. We implemented an emergency general surgery (EGS) registry to prospectively review all EGS cases. We compared our EGS registry with NSQIP, hypothesizing that NSQIP sampling under-represents EGS outcomes. METHODS: A formal EGS Process Improvement Program was implemented in 2016. From 2016 to 2018, the four most common operations were laparoscopic appendectomy, laparoscopic cholecystectomy, surgery for small bowel obstruction, and nonelective hernia repair. Outcomes were compared between the EGS registry and NSQIP abstracted cases. RESULTS: In 2016, the EGS registry identified 11/112 (9.8%) patients with a complication. National Surgical Quality Improvement Program abstracted 16% of EGS cases with 16.7% (3/18) of patients having a complication. In 2017, the EGS registry identified 10/87 (11.5%) cases with complications. National Surgical Quality Improvement Program abstracted 23% of EGS with zero complications. In 2018, the EGS registry identified 9.5% of 74 cases with complications. National Surgical Quality Improvement Program abstracted 15% of EGS cases with zero complications. CONCLUSIONS: National Surgical Quality Improvement Program did not capture many important EGS outcomes. In 2 of 3 years, NSQIP did not identify a single complication for EGS. National Surgical Quality Improvement Program alone may be insufficient to target EGS improvements.

Outcomes of Exploratory Laparotomy and Abdominal Infections Among Combat Casualties.

BACKGROUND: Abdominal injuries historically account for 13% of battlefield surgical procedures. We examined the occurrence of exploratory laparotomies and subsequent abdominal surgical site infections (SSIs) among combat casualties. METHODS: Military personnel injured during deployment (2009-2014) were included if they required a laparotomy for combat-related trauma and were evacuated to Landstuhl Regional Medical Center, Germany, before being transferred to participating US military hospitals. RESULTS: Of 4304 combat casualties, 341 (7.9%) underwent laparotomy. Including re-explorations, 1053 laparotomies (median, 2; interquartile range, 1-3; range, 1-28) were performed with 58% occurring within the combat zone. Forty-nine (14.4%) patients had abdominal SSIs (four with multiple SSIs): 27 (7.9%) with deep space SSIs, 14 (4.1%) with a deep incisional SSI, and 12 (3.5%) a superficial incisional SSI. Patients with abdominal SSIs had larger volume of blood transfusions (median, 24 versus 14 units), more laparotomies (median, 4 versus 2), and more hollow viscus injuries (74% versus 45%) than patients without abdominal SSIs. Abdominal closure occurred after 10 d for 12% of the patients with SSI versus 2% of patients without SSI. Mesh adjuncts were used to achieve fascial closure in 20.4% and 2.1% of patients with and without SSI, respectively. Survival was 98% and 96% in patients with and without SSIs, respectively. CONCLUSIONS: Less than 10% of combat casualties in the modern era required abdominal exploration and most were severely injured with hollow viscus injuries and required massive transfusions. Despite the extensive contamination from battlefield injuries, the SSI proportion is consistent with civilian rates and survival was high.

BMP Ligand Trap ALK3-Fc Attenuates Osteogenesis and Heterotopic Ossification in Blast-Related Lower Extremity Trauma.

Traumatic heterotopic ossification (tHO) commonly develops in wounded service members who sustain high-energy and blast-related traumatic amputations. Currently, no safe and effective preventive measures have been identified for this patient population. Bone morphogenetic protein (BMP) signaling blockade has previously been shown to reduce ectopic bone formation in genetic models of HO. In this study, we demonstrate the efficacy of small-molecule inhibition with LDN193189 (ALK2/ALK3 inhibition), LDN212854 (ALK2-biased inhibition), and BMP ligand trap ALK3-Fc at inhibiting early and late osteogenic differentiation of tissue-resident mesenchymal progenitor cells (MPCs) harvested from mice subjected to burn/tenotomy, a well-characterized trauma-induced model of HO. Using an established rat tHO model of blast-related extremity trauma and methicillin-resistant Staphylococcus aureus infection, a significant decrease in ectopic bone volume was observed by micro-computed tomography imaging following treatment with LDN193189, LDN212854, and ALK3-Fc. The efficacy of LDN193189 and LDN212854 in this model was associated with weight loss (17%-19%) within the first two postoperative weeks, and in the case of LDN193189, delayed wound healing and metastatic infection was observed, while ALK3-Fc was well tolerated. At day 14 following injury, RNA-Seq and quantitative reverse transcriptase-polymerase chain reaction analysis revealed that ALK3-Fc enhanced the expression of skeletal muscle structural genes and myogenic transcriptional factors while inhibiting the expression of inflammatory genes. Tissue-resident MPCs harvested from rats treated with ALK3-Fc exhibited reduced osteogenic differentiation, proliferation, and self-renewal capacity and diminished expression of genes associated with endochondral ossification and SMAD-dependent signaling pathways. Together, these results confirm the contribution of BMP signaling in osteogenic differentiation and ectopic bone formation and that a selective ligand-trap approach such as ALK3-Fc may be an effective and tolerable prophylactic strategy for tHO.

Characterization of the cortisol response to traumatic hemorrhage and intra-abdominal contamination models in Cynomologus Macaques.

INTRODUCTION: Trauma, hemorrhage, and peritonitis have widely varying impacts on endocrine response in the injured patient. We sought to examine cortisol response in established non-human primate models of traumatic hemorrhage and intra-abdominal contamination. METHODS: Cynomologus Macaques were separated into two experimental groups, the polytrauma and hemorrhage model, involving a laparoscopic liver resection with uncontrolled hemorrhage, cecal perforation, and soft tissue excision; and the traumatic hemorrhage model, involving only liver resection and uncontrolled hemorrhage. Cortisol levels were measured pre-operatively, at the time of injury, and at regular intervals until post-operative day 1. RESULTS: Cortisol levels increased 600% from the pre-operative value in the polytrauma and hemorrhage model, with minimal changes (20%) in the hemorrhage only model. CONCLUSION: Cortisol levels increase dramatically in response to polytrauma and intra-abdominal contamination as compared to hemorrhage only. The lack of response in the hemorrhage only group may be due to relative adrenal insufficiency caused by the shock state or lack of enticing stimuli from fecal peritonitis.

Small molecule inhibition of non-canonical (TAK1-mediated) BMP signaling results in reduced chondrogenic ossification and heterotopic ossification in a rat model of blast-associated combat-related lower limb trauma.

Heterotopic ossification (HO) is defined as ectopic bone formation around joints and in soft tissues following trauma, particularly blast-related extremity injuries, thermal injuries, central nerve injuries, or orthopaedic surgeries, leading to increased pain and diminished quality of life. Current treatment options include pharmacotherapy with non-steroidal anti-inflammatory drugs, radiotherapy, and surgical excision, but these treatments have limited efficacy and have associated complication profiles. In contrast, small molecule inhibitors have been shown to have higher specificity and less systemic cytotoxicity. Previous studies have shown that bone morphogenetic protein (BMP) signaling and downstream non-canonical (SMAD-independent) BMP signaling mediated induction of TGF-ß activated kinase-1 (TAK1) contributes to HO. In the current study, small molecule inhibition of TAK1, NG-25, was evaluated for its efficacy in limiting ectopic bone formation following a rat blast-associated lower limb trauma and a murine burn tenotomy injury model. A significant decrease in total HO volume in the rat blast injury model was observed by microCT imaging with no systemic complications following NG-25 therapy. Furthermore, tissue-resident mesenchymal progenitor cells (MPCs) harvested from rats treated with NG-25 demonstrated decreased proliferation, limited osteogenic differentiation capacity, and reduced gene expression of Tac1, Col10a1, Ibsp, Smad3, and Sox2 (P < 0.05). Single cell RNA-sequencing of murine cells harvested from the injury site in a burn tenotomy injury model showed increased expression of these genes in MPCs during stages of chondrogenic differentiation. Additional in vitro cell cultures of murine tissue-resident MPCs and osteochondrogenic progenitors (OCPs) treated with NG-25 demonstrated reduced chondrogenic differentiation by 10.2-fold (P < 0.001) and 133.3-fold (P < 0.001), respectively, as well as associated reduction in chondrogenic gene expression. Induction of HO in Tak1 knockout mice demonstrated a 7.1-fold (P < 0.001) and 2.7-fold reduction (P < 0.001) in chondrogenic differentiation of murine MPCs and OCPs, respectively, with reduced chondrogenic gene expression. Together, our in vivo models and in vitro cell culture studies demonstrate the importance of TAK1 signaling in chondrogenic differentiation and HO formation and suggest that small molecule inhibition of TAK1 is a promising therapy to limit the formation and progression of HO.