Testing the Reliability of Optical Coherence Tomography to Measure Epidermal Thickness and Distinguish Volar and Nonvolar Skin.

In persons with limb loss, prosthetic devices cause skin breakdown, largely because residual limb skin (nonvolar) is not intended to bear weight such as palmoplantar (volar) skin. Before evaluation of treatment efficacy to improve skin resiliency, efforts are needed to establish normative data and assess outcome metric reliability. The purpose of this study was to use optical coherence tomography to (i) characterize volar and nonvolar skin epidermal thickness and (ii) examine the reliability of optical coherence tomography. Four orientations of optical coherence tomography images were collected on 33 volunteers (6 with limb loss) at 2 time points, and the epidermis was traced to quantify thickness by 3 evaluators. Epidermal thickness was greater (P < .01) for volar skin (palm) (265.1 ± 50.9 µm, n = 33) than for both nonvolar locations: posterior thigh (89.8 ± 18.1 µm, n = 27) or residual limb (93.4 ± 27.4 µm, n = 6). The inter-rater intraclass correlation coefficient was high for volar skin (0.887-0.956) but low for nonvolar skin (thigh: 0.292-0.391, residual limb: 0.211-0.580). Correlation improved when comparing only 2 evaluators who used the same display technique (palm: 0.827-0.940, thigh: 0.633-0.877, residual limb: 0.213-0.952). Despite poor inter-rater agreement for nonvolar skin, perhaps due to challenges in identifying the dermal-epidermal junction, this study helps to support the utility of optical coherence tomography to distinguish volar from nonvolar skin.

Mechanical loading of bone-anchored implants during functional performance tests in service members with transfemoral limb loss.

Introduction: For individuals with limb loss, bone-anchored implants create a direct structural and functional connection to a terminal prosthesis. Here, we characterized the mechanical loads distal to the abutment during several functional performance tests in Service members with transfemoral (TF) limb loss, to expand on prior work evaluating more steady-state ambulation on level ground or slopes/stairs. Methods: Two males with unilateral TF limb loss and two males with bilateral TF limb loss participated after two-stage osseointegration (24 and 12 months, respectively). Tri-directional forces and moments were wirelessly recorded through a sensor, fit distal to the abutment, during six functional tests: Timed Up and Go (TUG), Four Square Step Test (FSST), Six Minute Walk Test (6MWT), Edgren Side-Step Test (SST), T-Test (TTEST), and Illinois Agility Test (IAT). Additionally, participants performed a straight-line gait evaluation on a 15 m level walkway at a self-selected speed (0.93-1.24 m/s). Peak values for each component of force and moment were extracted from all six functional tests; percent differences compared each peak with respect to the corresponding mean peak in straight-line walking. Results: Peak mechanical loads were largest during non-steady state components of the functional tests (e.g., side-stepping during SST or TTEST, standing up from the ground during IAT). Relative to walking, peak forces during functional tests were larger by up to 143% (anterior-posterior), 181% (medial-lateral), and 110% (axial); peak moments were larger by up to 108% (flexion-extension), 50% (ab/adduction), and 211% (internal/external rotation). Conclusions: A more comprehensive understanding of the mechanical loads applied to bone-anchored implants during a variety of activities is critical to maximize implant survivability and long-term outcomes, particularly for Service members who are generally young at time of injury and return to active lifestyles.

Effects of a Powered Ankle-Foot Prosthesis and Physical Therapy on Function for Individuals With Transfemoral Limb Loss: Rationale, Design, and Protocol for a Multisite Clinical Trial.

BACKGROUND: Powered ankle-foot prosthetic devices can generate net positive mechanical work during gait, which mimics the physiological ankle. However, gait deviations can persist in individuals with transfemoral limb loss because of habit or lack of rehabilitation. Prosthetic research efforts favor the design or evaluation of prosthetic componentry and rarely incorporate any type of rehabilitation, despite evidence suggesting that it is critical for minimizing gait imbalances. Given the accelerated rate of innovation in prosthetics, there is a fundamental knowledge gap concerning how individuals with transfemoral limb loss should learn to correctly use powered ankle-foot devices for maximum functional benefit. Because of the recent advances in prosthetic technology, there is also a critical unmet need to develop guidelines for the prescription of advanced prosthetic devices that incorporate both physical and psychological components to identify appropriate candidates for advanced technology. OBJECTIVE: The primary goal of this investigation is to examine the roles of advanced prosthetic technology and a device-specific rehabilitative intervention on gait biomechanics, functional efficacy, and pain in individuals with transfemoral limb loss. The secondary goal is to develop preliminary rehabilitation guidelines for advanced lower limb prosthetic devices to minimize gait imbalances and maximize function and to establish preliminary guidelines for powered ankle-foot prosthetic prescription. METHODS: This prospective, multisite study will enroll 30 individuals with unilateral transfemoral limb loss. At baseline, participants will undergo a full gait analysis and assessment of function, neurocognition, cognitive load, subjective preferences, and pain using their current passive prosthesis. The participants will then be fitted with a powered ankle-foot device and randomized into 2 equal groups: a powered device with a device-specific rehabilitation intervention (group A) or a powered device with the current standard of practice (group B). Group A will undergo 4 weeks of device-specific rehabilitation. Group B will receive the current standard of practice, which includes basic device education but no further device-specific rehabilitation. Data collection procedures will then be repeated after 4 weeks and 8 weeks of powered ankle use. RESULTS: This study was funded in September 2017. Enrollment began in September 2018. Data collection will conclude by March 2024. The initial dissemination of results is expected in August 2024. CONCLUSIONS: The projected trends indicate that the number of individuals with limb loss will dramatically increase in the United States. The absence of effective, evidence-based interventions may make individuals with transfemoral limb loss more susceptible to increased secondary physical conditions and degenerative changes. With this expected growth, considerable resources will be required for prosthetic and rehabilitation services. Identifying potential mechanisms for correcting gait asymmetries, either through advanced prosthetic technology or rehabilitative interventions, can provide a benchmark for understanding the optimal treatment strategies for individuals with transfemoral limb loss. TRIAL REGISTRATION: ClinicalTrials.gov NCT03625921; https://clinicaltrials.gov/study/NCT03625921. INTERNATIONAL REGISTERED REPORT IDENTIFIER (IRRID): DERR1-10.2196/53412.

The Influence of Active, Passive, and Manual Therapy Interventions for Low Back Pain on Opioid Prescription and Health Care Utilization.

OBJECTIVE: The aim of this study was to explore associations between the utilization of active, passive, and manual therapy interventions for low back pain (LBP) with 1-year escalation-of-care events, including opioid prescriptions, spinal injections, specialty care visits, and hospitalizations. METHODS: This was a retrospective cohort study of 4827 patients identified via the Military Health System Data Repository who received physical therapist care for LBP in 4 outpatient clinics between January 1, 2015 and January 1, 2018. One-year escalation-of-care events were evaluated based on type of physical therapist interventions (ie, active, passive, or manual therapy) received using adjusted odds ratios. RESULTS: Most patients (89.9%) received active interventions. Patients with 10% higher proportion of visits that included at least 1 passive intervention had a 3% to 6% higher likelihood of 1-year escalation-of-care events. Similarly, with 10% higher proportion of passive to active interventions used during the course of care, there was a 5% to 11% higher likelihood of 1-year escalation-of-care events. When compared to patients who received active interventions only, the likelihood of incurring 1-year escalation-of-care events was 50% to 220% higher for those who received mechanical traction and 2 or more different passive interventions, but lower by 50% for patients who received manual therapy. CONCLUSION: Greater use of passive interventions for LBP was associated with elevated odds of 1-year escalation-of-care events. In addition, the use of specific passive interventions such as mechanical traction in conjunction with active interventions resulted in suboptimal escalation-of-care events, while the use of manual therapy was associated with more favorable downstream health care outcomes. IMPACT: Physical therapists should be judicious in the use of passive interventions for the management of LBP as they are associated with greater likelihood of receiving opioid prescriptions, spinal injections, and specialty care visits.

Exploring relationships among multi-disciplinary assessments for knee joint health in service members with traumatic unilateral lower limb loss: a two-year longitudinal investigation.

Motivated by the complex and multifactorial etiologies of osteoarthritis, here we use a comprehensive approach evaluating knee joint health after unilateral lower limb loss. Thirty-eight male Service members with traumatic, unilateral lower limb loss (mean age = 38 yr) participated in a prospective, two-year longitudinal study comprehensively evaluating contralateral knee joint health (i.e., clinical imaging, gait biomechanics, physiological biomarkers, and patient-reported outcomes); seventeen subsequently returned for a two-year follow-up visit. For this subset with baseline and follow-up data, outcomes were compared between timepoints, and associations evaluated between values at baseline with two-year changes in tri-compartmental joint space. Upon follow-up, knee joint health worsened, particularly among seven Service members who presented at baseline with no joint degeneration (KL = 0) but returned with evidence of degeneration (KL ≥ 1). Joint space narrowing was associated with greater patellar tilt (r[12] = 0.71, p = 0.01), external knee adduction moment (r[13] = 0.64, p = 0.02), knee adduction moment impulse (r[13] = 0.61, p = 0.03), and CTX-1 concentration (r[11] = 0.83, p = 0.001), as well as lesser KOOSSport and VR-36General Health (r[16] = - 0.69, p = 0.01 and r[16] = - 0.69, p = 0.01, respectively). This longitudinal, multi-disciplinary investigation highlights the importance of a comprehensive approach to evaluate the fast-progressing onset of knee osteoarthritis, particularly among relatively young Service members with lower limb loss.

Demographics and Comorbidities of United States Service Members with Combat-Related Lower Extremity Limb Salvage.

INTRODUCTION: This retrospective study describes the demographics and injury characteristics of a recently identified cohort of US Service members with combat-related lower extremity limb salvage (LS). METHODS: US Service members with combat trauma were identified from the Expeditionary Medical Encounter Database and Military Health System Data Repository and stratified into primary amputation (PA), LS, and non-threatened limb trauma (NTLT) cohorts based on ICD-9 codes. Disparities in demographic factors and injury characteristics were investigated across cohorts and within the LS cohort based on limb retention outcome. RESULTS: Cohort demographics varied by age but not by sex, branch, or rank. The mechanism of injury and injury characteristics were found to be different between the cohorts, with the LS cohort exhibiting more blast injuries and greater injury burden than their peers with NTLT. A sub-analysis of the LS population revealed more blast injuries and fewer gunshot wounds in those that underwent secondary amputation. Neither demographic factors nor total injury burden varied with limb retention outcome, despite slight disparities in AIS distribution within the LS cohort. CONCLUSIONS: In accordance with historic dogma, the LS population presents high injury severity. Demographics and injury characteristics are largely invariant with respect to limb retention outcomes, despite secondary amputation being moderately more prevalent in LS patients with blast-induced injuries. Further study of this population is necessary to better understand the factors that impact the outcomes of LS in the Military Health System.

A Data-Driven Method to Discriminate Limb Salvage from Other Combat-Related Extremity Trauma.

INTRODUCTION: The aim of this study was to address and enhance our ability to study the clinical outcome of limb salvage (LS), a commonly referenced but ill-defined clinical care pathway, by developing a data-driven approach for the identification of LS cases using existing medical code data to identify characteristic diagnoses and procedures, and to use that information to describe a cohort of US Service members (SMs) for further study. METHODS: Diagnosis code families and inpatient procedure codes were compiled and analyzed to identify medical codes that are disparately associated with a LS surrogate population of SMs who underwent secondary amputation within a broader cohort of 3390 SMs with lower extremity trauma (AIS > 1). Subsequently, the identified codes were used to define a cohort of all SMs who underwent lower extremity LS which was compared with the opinion of a panel of military trauma surgeons. RESULTS: The data-driven approach identified a population of n = 2018 SMs who underwent LS, representing 59.5% of the combat-related lower extremity (LE) trauma population. Validation analysis revealed 70% agreement between the data-driven approach and gold standard SME panel for the test cases studied. The Kappa statistic (κ = 0.55) indicates a moderate agreement between the data-driven approach and the expert opinion of the SME panel. The sensitivity and specificity were identified as 55.6% (expert range of 51.8-66.7%) and 87% (expert range of 73.9-91.3%), respectively. CONCLUSIONS: This approach for identifying LS cases can be utilized to enable future high-throughput retrospective analyses for studying both short- and long-term outcomes of this underserved patient population.

Effect of Targeted Cytokine Inhibition on Progression of Post-Traumatic Osteoarthritis Following Intra-Articular Fracture.

Intra-articular fractures (IAF) result in significant and prolonged inflammation, increasing the chances of developing post-traumatic osteoarthritis (PTOA). Interleukin-one beta (IL-1ß) and Tumor Necrosis Factor-alpha (TNF-α) are key inflammatory factors shown to be involved in osteochondral degradation following IAF. As such, use of targeted biologics such as Infliximab (INX), a TNF-α inhibitor, and Anakinra (ANR), an interleukin-one (IL-1) receptor antagonist (IL1RA), may protect against PTOA by damping the inflammatory response to IAF and reducing osteochondral degradation. To test this hypothesis, IAFs were induced in the hindlimb knee joints of rats treated with INX at 10 mg/kg/day, ANR at 100 g/kg/day, or saline (vehicle control) by subcutaneous infusion for a period of two weeks and healing was evaluated at 8-weeks post injury. Serum and synovial fluid (SF) were analyzed for soluble factors. In-vivo microcomputed tomography (µCT) scans assessed bone mineral density and bone morphometry measurements. Cationic CA4+ agent assessed articular cartilage composition via ex vivo µCT. Scoring according to the Osteoarthritis Research Society International (OARSI) guidelines was performed on stained histologic tibia sections at the 56-day endpoint on a 0-6 scale. Systemically, ANR reduced many pro-inflammatory cytokines and reduced osteochondral degradation markers Cross Linked C-Telopeptide Of Type II (CTXII, p < 0.05) and tartrate-resistant acid phosphatase (TRAP, p < 0.05). ANR treatment resulted in increased chemokines; macrophage-chemotractant protein-1 (MCP-1), MPC-3, macrophage inhibitory protein 2 (MIP2) with a concomitant decrease in proinflammatory interleukin-17A (IL17A) at 14 days post-injury within the SF. Microcomputed tomography (µCT) at 56 days post-injury revealed ANR Treatment decreased epiphyseal degree of anisotropy (DA) (p < 0.05) relative to saline. No differences were found with OARSI scoring but contrast-enhanced µCT revealed a reduction in glycosaminoglycan content with ANR treatment. These findings suggest targeted cytokine inhibition, specifically IL-1 signaling, as a monotherapy has minimal utility for improving IAF healing outcomes but may have utility for promoting a more permissive inflammatory environment that would allow more potent disease modifying osteoarthritis drugs to mitigate the progression of PTOA after IAF.

In situ forming biomaterials as muscle void fillers for the provisional treatment of volumetric muscle loss injuries.

Volumetric muscle loss (VML) represents a devastating extremity injury which leads to chronic functional deficits and disability and is unrecoverable through normal healing pathways. When left untreated, the VML pathophysiology creates many challenges towards successful treatment, such as altered residual muscle architecture, excessive fibrosis, and contracture(s). As such, innovative approaches and technologies are needed to prevent or reverse these adverse sequelae. Development of a rationally designed biomaterial technology which is intended to be acutely placed within a VML defect - i.e., to serve as a muscle void filler (MVF) by maintaining the VML defect - could address this clinical unmet need by preventing these adverse sequelae as well as enabling multi-staged treatment approaches. To that end, three biomaterials were evaluated for their ability to serve as a provisional MVF treatment intended to stabilize a VML defect in a rat model for an extended period (28 days): polyvinyl alcohol (PVA), hyaluronic acid and polyethylene glycol combination (HA + PEG), and silicone, a clinically used soft tissue void filler. HA + PEG biomaterial showed signs of deformation, while both PVA and silicone did not. There were no differences between treatment groups for their effects on adjacent muscle fiber count and size distribution. Not surprisingly, silicone elicited robust fibrotic response resulting in a fibrotic barrier with a large infiltration of macrophages, a response not seen with either the PVA or HA + PEG. Taken together, PVA was found to be the best material to be used as a provisional MVF for maintaining VML defect volume while minimizing adverse effects on the surrounding muscle.

Mobility Solutions After a Lower Extremity Fracture and Applicability to Battlefield and Wilderness Medicine.

The potential for delayed evacuation of injured Service members from austere environments highlights the need to develop solutions that can stabilize a wound and enable mobility during these prolonged casualty care (PCC) scenarios. Lower extremity fractures have traditionally been treated by immobilization (splinting) followed by air evacuation - a paradigm not practical in PCC scenarios. In the civilian sector, treatment of extremity injuries sustained during remote recreational activities have similar challenges, particularly when adverse weather or terrain precludes early ground or air rescue. This review examines currently available fracture treatment solutions to include splinting, orthotic devices, and biological interventions and evaluates their feasibility: 1) for prolonged use in austere environments and 2) to enable patient mobilization. This review returned three common types of splints to include: a simple box splint, pneumatic splints, and traction splints. None of these splinting techniques allowed for ambulation. However, fixed facility-based orthotic interventions that include weight-bearing features may be combined with common splinting techniques to improve mobility. Biologically-focused technologies to stabilize a long bone fracture are still in their infancy. Integrating design features across these technologies could generate advanced treatments which would enable mobility, thus maximizing survivability until patient evacuation is feasible.

Characterization of initial ankle-foot prosthesis prescription patterns in U.S. Service members following unilateral transtibial amputation.

Introduction: The purpose of this study was to explore relationships between patient-specific characteristics and initial ankle-foot prosthesis prescription patterns among U.S. Service members with unilateral transtibial limb loss. Methods: A retrospective review of health records identified 174 individuals with unilateral transtibial limb loss who received care at Walter Reed National Military Medical Center between 2001 and 2019. We examined patient-specific factors such as demographics, participant duty status at injury and amputation, amputation etiology, and timing between injury, amputation, and initial prescription. The type of first prescribed ankle-foot prosthesis was categorized as energy storing and return - nonarticulating, energy storing and return - articulating, or computer controlled. Results: Sex, amputation etiology, time from injury to initial prescription, and time from amputation to initial prescription differed by type of initial ankle-foot prosthesis prescription. Service members with shorter intervals between injury-initial prescription and amputation-initial prescription, and those injured by combat blast, were more likely to receive a non-articulating device. Incorporating sex, time from injury-initial prescription, time from amputation-initial prescription, and amputation etiology as predictors of prosthesis type, we were able to correctly classify 72% of all first prostheses prescribed. Discussion: Patient-specific characteristics such as sex, the time between injury-initial prescription, time from amputation-initial prescription and amputation etiology are essential characteristics that influence initial ankle-foot prosthesis prescription patterns in U.S. Service members.

Development and characterization of an intra-articular fracture mediated model of post-traumatic osteoarthritis.

PURPOSE: This study aimed to develop and characterize a closed intra-articular fracture (IAF) mediated post-traumatic osteoarthritis (PTOA) model in rats to serve as a testbed for putative disease modifying interventions. METHODS: Male rats were subject to a 0 Joule (J), 1 J, 3 J, or 5 J blunt-force impact to the lateral aspect of the knee and allowed to heal for 14 and 56 days. Micro-CT was performed at time of injury and at the specified endpoints to assess bone morphometry and bone mineral density measurements. Cytokines and osteochondral degradation markers were assayed from serum and synovial fluid via immunoassays. Histopathological analyses were performed on decalcified tissues and assessed for evidence of osteochondral degradation. RESULTS: High-energy (5 J) blunt impacts consistently induced IAF to the proximal tibia, distal femur, or both while lower energy (1 J and 3 J) impacts did not. CCL2 was found to be elevated in the synovial fluid of rats with IAF at both 14- and 56-days post-injury while COMP and NTX-1 were upregulated chronically relative to sham controls. Histological analysis showed increased immune cell infiltration, increased osteoclasts and osteochondral degradation with IAF relative to sham. CONCLUSION: Based on results from the current study, our data indicates that a 5 J blunt-forced impact adequately and consistently induces hallmark osteoarthritic changes to the articular surface and subchondral bone at 56 days after IAF. Marked development of PTOA pathobiology suggest this model will provide a robust testbed for screening putative disease modifying interventions that might be translated to the clinic for militarily relevant, high-energy joint injuries.

Criteria for Advanced Prosthetic Foot Prescription: Rationale, Design, and Protocol for a Multisite, Randomized Controlled Trial.

BACKGROUND: The prescription of prosthetic ankle-foot devices is often based on the professional judgment of the limb loss care team or limited evidentiary research. Current prosthetic research efforts have focused on the design and development of prosthetic devices rather than on understanding which devices are the most appropriate to prescribe. This investigation will evaluate biomechanical, functional, and subjective outcome measures to help determine the optimal prescription parameters of prosthetic ankle-foot devices. OBJECTIVE: This study aims to develop evidence-based guidelines for limb loss care teams for the appropriate prescription of commercially available prosthetic ankle-foot devices to improve function and satisfaction. METHODS: This investigation will be a multisite, randomized, crossover clinical trial targeting the enrollment of 100 participants. Participants will use 3 different types of prosthetic devices (energy storing and returning, articulating, and powered) in random order. Participants will be fitted and trained with each device and then separately use each device for a 1-week acclimation period. Following each 1-week acclimation period, participants will be evaluated using several functional measures and subjective surveys. A random subset of participants (30/100, 30%) will also undergo full-body gait analysis, following each 1-week acclimation period, to collect biomechanical data during level ground and incline and decline walking. After all individual device evaluations, participants will be given all 3 prostheses concurrently for 4 weeks of home and community use to capture user preference. Activity monitoring and a guided interview will be used to determine overall user preference. RESULTS: The study was funded in August 2017, and data collection began in 2018. Data collection is expected to be completed before July 2023. Initial dissemination of results is expected to occur in the winter of 2023. CONCLUSIONS: By identifying biomechanical, functional, and subjective outcomes that are sensitive to differences in prosthetic ankle-foot devices, a benchmark of evidence can be developed to guide effective prosthetic prescription. TRIAL REGISTRATION: ClinicalTrials.gov NCT03505983; https://clinicaltrials.gov/ct2/show/NCT03505983. INTERNATIONAL REGISTERED REPORT IDENTIFIER (IRRID): DERR1-10.2196/45612.

Minced muscle autografting improves bone healing but not muscle function in a porcine composite injury model.

Composite tissue injuries (CTIs) in extremities include segmental bone defects (SBDs) and volumetric muscle loss. The objective of this study was to determine if skeletal muscle autografting with minced muscle grafts (MMGs) could improve healing in an SBD and improve muscle function in a porcine CTI model that includes an SBD and adjacent volumetric muscle loss injury. Adult Yucatan Minipigs were stratified into three groups including specimens with an isolated SBD, an SBD with volumetric muscle loss (CTI), and an SBD with volumetric muscle loss treated with MMG (CTI + MMG). Bone healing was quantified with serial x-rays and postmortem computed tomography scanning. Muscle function was quantified with a custom in vivo force transducer. Muscle tissue content was determined by biochemical analyses and histology. Anterior cortex-modified Radiographic Union Score for Tibia fractures (mRUSTs) decreased from 2.7 to 1.9 (p = 0.003) in CTI versus SBD animals. MMG improved anterior mRUST scores to 2.5 in CTI + MMG specimens (p = 0.030 compared to CTI specimens) and overall mRUST scores increased from 9.4 in CTI specimens to 11.1 in CTI + MMG specimens (p = 0.049). Residual strength deficits at euthanasia were 42% in SBD (p < 0.001), 44% in CTI (p < 0.001), and 48% in CTI + MMG (p < 0.001) compared to preoperative values. There were no differences in strength deficits between the three groups. Biochemical and histologic analyses demonstrated scattered differences between the three groups compared to contralateral muscle. MMG improved bone healing. However, the primary cause of muscle dysfunction and biochemical changes was the presence of an SBD. Clinical significance: Early mitigation of SBDs may be necessary to prevent muscle damage and weakness in patients sustaining composite extremity trauma.

Effects of Adjunct Antifibrotic Treatment within a Regenerative Rehabilitation Paradigm for Volumetric Muscle Loss.

The use of a rehabilitation approach that promotes regeneration has the potential to improve the efficacy of pro-regenerative therapies and maximize functional outcomes in the treatment of volumetric muscle loss (VML). An adjunct antifibrotic treatment could further enhance functional gains by reducing fibrotic scarring. This study aimed to evaluate the potential synergistic effects of losartan, an antifibrotic pharmaceutical, paired with a voluntary wheel running rehabilitation strategy to enhance a minced muscle graft (MMG) pro-regenerative therapy in a rodent model of VML. The animals were randomly assigned into four groups: (1) antifibrotic with rehabilitation, (2) antifibrotic without rehabilitation, (3) vehicle treatment with rehabilitation, and (4) vehicle treatment without rehabilitation. At 56 days, the neuromuscular function was assessed, and muscles were collected for histological and molecular analysis. Surprisingly, we found that the losartan treatment decreased muscle function in MMG-treated VML injuries by 56 days, while the voluntary wheel running elicited no effect. Histologic and molecular analysis revealed that losartan treatment did not reduce fibrosis. These findings suggest that losartan treatment as an adjunct therapy to a regenerative rehabilitation strategy negatively impacts muscular function and fails to promote myogenesis following VML injury. There still remains a clinical need to develop a regenerative rehabilitation treatment strategy for traumatic skeletal muscle injuries. Future studies should consider optimizing the timing and duration of adjunct antifibrotic treatments to maximize functional outcomes in VML injuries.

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.

Fall Prevention Training for Service Members With an Amputation or Limb Salvage Following Lower Extremity Trauma.

INTRODUCTION: Recent military conflicts have resulted in a significant number of lower extremity injuries to U.S. service members that result in amputation or limb preservation (LP) procedures. Service members receiving these procedures report a high prevalence and deleterious consequences of falls. Very little research exists to improve balance and reduce falls, especially among young active populations such as service members with LP or limb loss. To address this research gap, we evaluated the success of a fall prevention training program for service members with lower extremity trauma by (1) measuring fall rates, (2) quantifying improvements in trunk control, and (3) determining skill retention at 3 and 6 months after training. MATERIALS AND METHODS: Forty-five participants (40 males, mean [±SD] age, 34 ± 8 years) with lower extremity trauma (20 with unilateral transtibial amputation, 6 with unilateral transfemoral amputation, 5 with bilateral transtibial amputation, and 14 with unilateral LP procedures) were enrolled. A microprocessor-controlled treadmill was used to produce task-specific postural perturbations which simulated a trip. The training was conducted over a 2-week period and consisted of six 30-minute sessions. The task difficulty was increased as the participant's ability progressed. The effectiveness of the training program was assessed by collecting data before training (baseline; repeated twice), immediately after training (0 month), and at 3 and 6 months post-training. Training effectiveness was quantified by participant-reported falls in the free-living environment before and after training. Perturbation-induced recovery step trunk flexion angle and velocity was also collected. RESULTS: Participants reported reduced falls and improved balance confidence in the free-living environment following the training. Repeated testing before training revealed that there were no pre-training differences in trunk control. The training program improved trunk control following training, and these skills were retained at 3 and 6 months after training. CONCLUSION: This study showed that task-specific fall prevention training reduced falls across a cohort of service members with diverse types of amputations and LP procedures following lower extremity trauma. Importantly, the clinical outcome of this effort (i.e., reduced falls and improved balance confidence) can lead to increased participation in occupational, recreational, and social activities and thus improved quality of life.

Identifying Health-Related Quality of Life Domains After Upper Extremity Transplantation.

OBJECTIVE: To identify the most important health-related quality of life (HRQOL) domains and patient-reported outcomes after upper extremity transplantation (UET) in individuals with upper extremity amputation. DESIGN: Verbatim audio-recordings of individual interviews and focus groups were analyzed using qualitative, grounded theory-based methods to identify important domains of HRQOL and provide guidance for outcomes measurement after UET. SETTING: Individual interviews were conducted by phone. Focus groups were conducted at 5 upper extremity vascularized composite allotransplantation (VCA) centers in the US and at an international conference of VCA experts. PARTICIPANTS: Individual phone interviews were conducted with 5 individuals with lived experience of UET. Thirteen focus groups were conducted with a total of 59 clinical professionals involved in UET. INTERVENTIONS: Not applicable. MAIN OUTCOME MEASURES: Not applicable. RESULTS: Twenty-eight key HRQOL domains were identified, including physical functioning and medical complications, positive and negative emotional functioning, and social participation, relations, and independence. We identified key constructs for use in evaluation of the potentially substantial physical, medical, social, and emotional effects of UET. CONCLUSIONS: This study provides an overview of the most important issues affecting HRQOL after UET, including several topics that are unique to individuals with UET. This information will be used to establish systematic, comprehensive, and longitudinal measurement of post-UET HRQOL outcomes.

Development of a High-Color Flow Cytometry Panel for Immunologic Analysis of Tissue Injury and Reconstruction in a Rat Model.

The rat model is an important resource in biomedical research due to its similarities to the human immune system and its use for functional studies. However, because of the preponderance of mouse models in foundational and mechanistic immunological studies, there is a relative lack of diverse, commercially available flow cytometry antibodies for immunological profiling in the rat model. Available antibodies are often conjugated to common fluorophores with similar peak emission wavelengths, making them hard to distinguish on conventional flow cytometers and restricting more comprehensive immune analysis. This can become a limitation when designing immunological studies in rat injury models to investigate the immune response to tissue injury. In addition, this lack of available antibodies limits the number of studies that can be done on the immune populations in lymphoid organs in other research areas. To address this critical unmet need, we designed a spectral flow cytometry panel for rat models. Spectral cytometry distinguishes between different fluorophores by capturing their full emission spectra instead of their peak emission wavelengths. This flow cytometry panel includes 24 distinct immune cell markers to analyze the innate and adaptive immune response. Importantly, this panel identifies different immune phenotypes, including tolerogenic, Type 1, and Type 2 immune responses. We show that this panel can identify unique immune populations and phenotypes in a rat muscle trauma model. We further validated that the panel can identify distinct adaptive and innate immune populations and their unique phenotypes in lymphoid organs. This panel expands the scope of previous rat panels providing a tool for scientists to examine the immune system in homeostasis and injury while pairing mechanistic immunological studies with functional studies.

Functional Performance Outcomes of a Powered Knee-Ankle Prosthesis in Service Members With Unilateral Transfemoral Limb Loss.

INTRODUCTION: Clinical knowledge surrounding functional outcomes of a powered knee-ankle (PKA) device is limited, particularly among younger and active populations with limb loss. Here, three service members (SM) with unilateral transfemoral limb loss received an optimally tuned PKA prosthesis and device-specific training. MATERIALS AND METHODS: Once proficiency with the PKA device was demonstrated on benchmark activities, and outcomes with the PKA and standard-of-care (SoC) prostheses were obtained via a modified graded treadmill test, 6-minute walk test, and overground gait assessment. RESULTS: All SM demonstrated proficiency with the PKA prosthesis within the minimum three training sessions. With the PKA versus SoC prosthesis, cost of transport during the modified graded treadmill test was 4.0% ± 5.2% lower at slower speeds (i.e., 0.6-1.2 m/s), but 7.0% ± 5.1% greater at the faster walking speeds (i.e., ≥1.4 m/s). For the 6-minute walk test, SM walked 83.9 ± 13.2 m shorter with the PKA versus SoC prosthesis. From the overground gait assessment, SM walked with 20.6% ± 10.5% greater trunk lateral flexion and 31.8% ± 12.8% greater trunk axial rotation ranges of motion, with the PKA versus SoC prosthesis. CONCLUSIONS: Compared to prior work with the PKA in a civilian cohort, although SM demonstrated faster device proficiency (3 versus 12 sessions), SM walked with greater compensatory motions compared to their SoC prostheses (contrary to the civilian cohort). As such, it is important to understand patient-specific factors among various populations with limb loss for optimizing device-specific training and setting functional goals for occupational and/or community reintegration, as well as reducing the risk for secondary complications over the long term.