Determining Which Combinatorial Combat-Relevant Factors Contribute to Heterotopic Ossification Formation in an Ovine Model.

Traumatic heterotopic ossification (HO) is frequently observed in Service Members following combat-related trauma. Estimates suggest that ~65% of wounded warriors who suffer limb loss or major extremity trauma will experience some type of HO formation. The development of HO delays rehabilitation and can prevent the use of a prosthetic. To date there are limited data to suggest a standard mechanism for preventing HO. This may be due to inadequate animal models not producing a similar bone structure as human HO. We recently showed that traumatic HO growth is possible in an ovine model. Within that study, we demonstrated that 65% of sheep developed a human-relevant hybrid traumatic HO bone structure after being exposed to a combination of seven combat-relevant factors. Although HO formed, we did not determine which traumatic factor contributed most. Therefore, in this study, we performed individual and various combinations of surgical/traumatic factors to determine their individual contribution to HO growth. Outcomes showed that the presence of mature biofilm stimulated a large region of bone growth, while bone trauma resulted in a localized bone response as indicated by jagged bone at the linea aspera. However, it was not until the combinatory factors were included that an HO structure similar to that of humans formed more readily in 60% of the sheep. In conclusion, data suggested that traumatic HO growth can develop following various traumatic factors, but a combination of known instigators yields higher frequency size and consistency of ectopic bone.

Ex vivo comparison of V.A.C.® Granufoam Silver™ and V.A.C.® Granufoam™ loaded with a first-in-class bis-dialkylnorspermidine-terphenyl antibiofilm agent.

Implementation of negative pressure wound therapy (NPWT) as a standard of care has proven efficacious in reducing both the healing time and likelihood of nosocomial infection among pressure ulcers and traumatic, combat-related injuries. However, current formulations may not target or dramatically reduce bacterial biofilm burden following therapy. The purpose of this study was to determine the antibiofilm efficacy of an open-cell polyurethane (PU) foam (V.A.C.® Granufoam™) loaded with a first-in-class compound (CZ-01179) as the active release agent integrated via lyophilized hydrogel scaffolding. An ex vivo porcine excision wound model was designed to perform antibiofilm efficacy testing in the presence of NPWT. PU foam samples loaded with a 10.0% w/w formulation of CZ-01179 and 0.5% hyaluronic acid were prepared and tested against current standards of care: V.A.C.® Granufoam Silver™ and V.A.C.® Granufoam™. We observed statistically significant reduction of methicillin-resistant Staphylococcus aureus (MRSA) and Acinetobacter baumannii biofilms with the CZ-01179 antibiofilm foam in comparison to current standard of care foams. These findings motivate further development of an antibiofilm PU foam loaded with CZ-01179.

All-cause and cause-specific mortality rates after severe extremity injuries among previously deployed active duty service members.

BACKGROUND: Previous research has shown that active duty military personnel who sustain extremity injuries while in service are at elevated risk for serious physical and psychological health issues that could affect their long-term functioning and quality of life yet longer-term mortality has not been studied in this population. OBJECTIVE: To determine whether rates of all-cause and cause-specific mortality are elevated for active duty U.S. service members who sustained traumatic limb injuries in service, compared to the broader population of deploying service members. To assess differences in mortality rates between service members with traumatic limb injuries that did versus did not result in amputation. DESIGN: Retrospective cohort study; archival Department of Defense deployment, personnel, medical, and death records were combined and analyzed. Standardized mortality ratios (SMR) adjusted for age, sex, and ethnoracial group, along with associated 95% confidence intervals (CIs), were calculated to directly compare all-cause and cause-specific mortality rates in each of the two injury groups to rates in the total study population. SETTING: Not applicable. PARTICIPANTS: Service members who deployed in support of the global war on terror between 2001 and 2016 were eligible for inclusion; the final sample included 1,875,206 individuals surveilled through 2019. INTERVENTION: Not applicable. MAIN OUTCOME MEASURES: All-cause and cause-specific mortality rates. RESULTS: Overall, the number of deaths was over three times higher than expected among service members with amputations (SMR = 3.01; CI: 2.36-3.65), and nearly two times higher among those with serious limb injuries not resulting in amputation (SMR = 1.72; CI: 1.54-1.90) when compared to the larger study population. Rates for both internal and external causes of death were significantly elevated among those with limb injuries. CONCLUSIONS: Long-term mortality rates are elevated among service members with traumatic limb injuries, though mortality patterns may differ based on whether the injury results in amputation. Although further research into causal mechanisms is needed, these results may inform the development of interventions to improve long-term health outcomes among injured military personnel.

Antibiofilm potential of a negative pressure wound therapy foam loaded with a first-in-class tri-alkyl norspermidine-biaryl antibiotic.

Negative-pressure wound therapy (NPWT) is commonly utilized to treat traumatic injuries sustained on the modern battlefield. However, NPWT has failed to decrease the incidence of deep tissue infections experienced by Wounded Warriors, despite attempts to integrate common antimicrobials, like Ag+ nanoparticles, into the wound dressing. The purpose of this study was to incorporate a unique antibiofilm compound (CZ-01179) into the polyurethane matrix of NPWT foam via lyophilized hydrogel scaffolding. Foam samples with 2.5%, 5.0%, and 10.0% w/w CZ-01179 were produced and antibiofilm efficacy was compared to the current standards of care: V.A.C.® GRANUFOAM SILVER™ and V.A.C.® GRANUFOAM™. Gravimetric analysis and elution kinetics testing confirmed that this loading technique was both repeatable and controllable. Furthermore, zone of inhibition and antibiofilm efficacy testing showed that foam loaded with CZ-01179 had significantly increased activity against planktonic and biofilm phenotypes of methicillin-resistant Staphylococcus aureus and Acinetobacter baumannii compared to the clinical standards. These findings motivate additional ex vivo and in vivo work with NPWT foam loaded with CZ-01179 with the overall objective of reducing NPWT-associated infections that complicate battlefield-related and other wounds.

Developing a combat-relevant translatable large animal model of heterotopic ossification.

Heterotopic ossification (HO) refers to ectopic bone formation, typically in residual limbs following trauma and injury. A review of injuries from Operation Iraqi Freedom (OIF) and Operation Enduring Freedom (OEF) indicated that approximately 70% of war wounds involved the musculoskeletal system, largely in part from the use of improvised explosive devices (IED) and rocket-propelled grenades (RPG). HO is reported to occur in approximately 63%-65% of wounded warriors from OIF and OEF. Symptomatic HO may delay rehabilitation regimens since it often requires modifications to prosthetic limb componentry and socket size. There is limited evidence indicating a mechanism for preventing HO. This may be due to inadequate models, which do not produce HO bone structure that is morphologically similar to HO samples obtained from wounded warfighters injured in theatre. We hypothesized that using a high-power blast of air (shockwave) and simulated battlefield trauma (i.e. bone damage, tourniquet, bacteria, negative pressure wound therapy) in a large animal model, HO would form and have similar morphology to ectopic bone observed in clinical samples. Initial radiographic and micro-computed tomography (CT) data demonstrated ectopic bone growth in sheep 24 weeks post-procedure. Advanced histological and backscatter electron (BSE) analyses showed that 5 out of 8 (63%) sheep produced HO with similar morphology to clinical samples. We conclude that not all ectopic bone observed by radiograph or micro-CT in animal models is HO. Advanced histological and BSE analyses may improve confirmation of HO presence and morphology, which we demonstrated can be produced in a large animal model.

Amputation: Evaluation and Treatment.

Combat extremity injury and amputation is a life threatening injury. Initial surgical care should focus on hemostasis followed by irrigation and debridement of contaminated and nonviable tissue. Preservation of limb length begins at the initial surgical procedure, to include retention of atypical soft tissue flaps for later reconstruction and treatment of proximal fractures. Serial irrigation and debridements are required throughout the MEDEVAC system as the evolving zone of injury becomes more mature, followed by the appropriate timing of closure outside the combat theater.

High Bilateral Amputations and Dismounted Complex Blast Injury (DCBI).

High, combat-related bilateral lower extremity amputations rarely occur in isolation. Dismounted complex blast injury is a devastating and life-threatening constellation of multisystem injuries most commonly due to dismounted contact with improvised explosive devices. Rapid damage control resuscitation and surgery are essential to improve patient survival and minimize both early complications and late sequelae. A coordinated team approach is essential to provide simultaneous airway management, volume resuscitation (ideally with whole blood or ratio transfusion), and immediate control of life-threatening hemorrhage. Temporary aortic or iliac vessel clamping during concurrent exploratory or vascular control laparotomy is frequently required. Stabilization of unstable pelvic fractures is then performed, followed by debridement and irrigation of all wounds, which should be left open, and subsequent provisional stabilization of long bone fractures. The goal of the initial surgical resuscitative endeavor is rapid concurrent control of all sources of hemorrhage to avoid the lethal triad of acidosis, hypothermia and coagulopathy. To this end, multiple surgeons or surgical teams should be utilized whenever feasible. Patients then require ongoing resuscitation followed by early and frequent return to the operating suite throughout the evacuation chain. Utilizing this approach, a high survival rate with reasonable functional outcomes is achievable despite the extreme severity of the DCBI pattern.

Acute Extremity Compartment Syndrome and the Role of Fasciotomy in Extremity War Wounds.

Acute compartment syndrome (CS) is a frequent and potentially devastating complication of blunt and penetrating extremity injuries. Extremity war injuries are particularly susceptible to CS due to associated vascular injuries; high Injury Severity Score; extensive bone and soft tissue injury; and frequent transportation that may limit close monitoring of the injured extremity. Treatment consists of prompt fasciotomy of all compartments in the involved segment, over their full length. Delayed or incomplete fasciotomy is associated with worse outcomes, including muscle necrosis, infection, and amputation. Enhanced pre-deployment training of surgeons decreases the need for revision fasciotomy at higher echelons of care and should be continued in future conflicts. We recommend the liberal use of prophylactic fasciotomy prior to aeromedical evacuation and after limb reperfusion. For leg fasciotomy, we recommend a two-incision approach as it is more reproducible and allows easy vascular exposure when necessary.

Rehabilitation of the Combat Casualty: Lessons Learned from Past and Current Conflicts.

The field of rehabilitation is deeply rooted in military medicine, especially in promoting the restoration of function and community reintegration of injured service members returning from war. Since military operations began in Iraq and Afghanistan over a decade ago, rehabilitative care programs have been integral in supporting the Military Healthcare System in providing high quality comprehensive care for combat casualties and their families, particularly those with complex blast injuries resulting in conditions such as amputation and other limb dysfunction, traumatic brain injury, and spinal cord injury. Fundamental to a successful rehabilitation program is the coordination of interdisciplinary care that not only crosses multiple medical specialties and disciplines, but also promotes ongoing education, research, quality improvement and readiness. This brief article is intended to highlight some of the most important lessons learned from current and past conflicts in delivering the highest quality rehabilitative care to our nation's heroes.

Transformation of Mental Health Care for U.S. Soldiers and Families During the Iraq and Afghanistan Wars: Where Science and Politics Intersect.

The cumulative strain of 14 years of war on service members, veterans, and their families, together with continuing global threats and the unique stresses of military service, are likely to be felt for years to come. Scientific as well as political factors have influenced how the military has addressed the mental health needs resulting from these wars. Two important differences between mental health care delivered during the Iraq and Afghanistan wars and previous wars are the degree to which research has directly informed care and the consolidated management of services. The U.S. Army Medical Command implemented programmatic changes to ensure delivery of high-quality standardized mental health services, including centralized workload management; consolidation of psychiatry, psychology, psychiatric nursing, and social work services under integrated behavioral health departments; creation of satellite mental health clinics embedded within brigade work areas; incorporation of mental health providers into primary care; routine mental health screening throughout soldiers' careers; standardization of clinical outcome measures; and improved services for family members. This transformation has been accompanied by reduction in psychiatric hospitalizations and improved continuity of care. Challenges remain, however, including continued underutilization of services by those most in need, problems with treatment of substance use disorders, overuse of opioid medications, concerns with the structure of care for chronic postdeployment (including postconcussion) symptoms, and ongoing questions concerning the causes of historically high suicide rates, efficacy of resilience training initiatives, and research priorities. It is critical to ensure that remaining gaps are addressed and that knowledge gained during these wars is retained and further evolved.