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.

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.

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.

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.

Retrospective characterization of a rat model of volumetric muscle loss.

Volumetric muscle loss (VML) is a pervasive injury within contemporary combat and a primary driver of disability among injured Service members. As such, VML has been a topic of investigation over the past decade as the field has sought to understand the pathology of these injuries and to develop treatment strategies which restore the form and function of the involved musculature. To date, much of this work has been performed in disparate animal models that vary significantly in terms of the species utilized, the muscle (or muscle group) affected, and the volume of muscle lost. Moreover, variation exists in the reporting of anatomical and functional outcomes within these models. When taken together, the ability to successfully assess comparative efficacy of promising therapies is currently limited. As such, greater scrutiny on the characterization of these VML models is needed to better assess the quality of evidence supporting further translation of putative therapies. Thus, the objective of this study was to retrospectively characterize anatomical and functional outcomes associated with one such VML model - the 6 mm biopsy punch model of the rat tibialis anterior muscle. Through these efforts, it was shown that this model is highly reproducible and consistent across a large number of experiments. As such, the data presented herein represent a reasonable benchmark for the expected performance of this model with utility for drawing inferences across studies and identifying therapies which have shown promise within the preclinical domain, and thus are ready for further translation towards the clinic.

Evaluation of licofelone as an adjunct anti-inflammatory therapy to biologic scaffolds in the treatment of volumetric muscle loss.

Biologic scaffolds (BS) are the most widely studied therapeutics for the treatment of volumetric muscle loss (VML) owing to their purported effects on cell proliferation, chemotaxis, migration, and differentiation. Despite these claims, variability in reports on the nature of the immune response to their implantation suggests that BS-associated inflammation may be limiting their regenerative efficacy. To address this shortcoming, this study sought to evaluate licofelone (ML3000), a dual 5-LOX/COX inhibitor, as an anti-inflammatory adjunct therapy to a BS in the treatment of VML. Utilizing a well-established rat VML model, a micronized BS was used to treat the VML injury, with or without administration of licofelone. Functional, molecular, and histological outcomes were assessed at both 7- and 28-day post-injury time points. While the BS + licofelone group exhibited decreased transcription of pro-inflammatory markers (Tnf, Ccl5, Nos2) relative to the BS only control group, no differences in expression profile of a panel of inflammatory-related soluble factors were observed between groups. A modest reduction in type I collagen was observed in the licofelone-treated group, but no meaningful differences in histologic presentation of repaired tissue were observed between groups. Furthermore, no differences in end organ functional capacity were observed between groups. Moving forward, efforts related to modulating the wound healing environment of VML should focus on polypharmaceutical strategies that target multiple aspects of the early pathophysiology of VML so as to provide an environment that is sufficiently permissive for local regenerative therapies to promote restoration of myofiber number.

The Role of the Inflammatory Response in Mediating Functional Recovery Following Composite Tissue Injuries.

Composite tissue injuries (CTI) are common among US Military Service members during combat operations, and carry a high potential of morbidity. Furthermore, CTI are often complicated due to an altered wound healing response, resulting in part from a dysregulation of the innate and adaptive immune responses. Unlike normal wound healing, in CTI, disruptions occur in innate immune responses, altering neutrophil functions, macrophage activation and polarization, further impacting the functions of T regulatory cells. Additionally, the biological underpinnings of these unfavorable wound healing conditions are multifactorial, including various processes, such as: ischemia, hypoxia, low nutrient levels, and altered cell metabolic pathways, among others, all of which are thought to trigger anergy in immune cells and destabilize adaptive immune responses. As a result, impaired wound healing is common in CTI. Herein, we review the altered innate and adaptive immune cells and their metabolic status and responses following CTI, and discuss the role a multi-pronged immunomodulatory approach may play in facilitating improved outcomes for afflicted patients.

Resolving the Burden of Low Back Pain in Military Service Members and Veterans (RESOLVE): Protocol for a Multisite Pragmatic Clinical Trial.

BACKGROUND: Physical therapy (PT) is frequently used for the management of low back pain (LBP) within the US Departments of Defense (DOD) and Veterans Affairs (VA). However, variations in PT practice patterns and use of ineffective interventions lower the quality and increase the cost of care. Although adherence to the clinical practice guidelines (CPGs) can improve the outcomes and cost-effectiveness of LBP care, PT CPG adherence remains below 50%. The Resolving the Burden of Low Back Pain in Military Service Members and Veterans (RESOLVE) trial will evaluate the effectiveness of an active PT CPG implementation strategy using an education, audit, and feedback model for reducing pain, disability, medication use, and cost of LBP care within the DOD and VA health care systems. DESIGN: The RESOLVE trial will include 3,300 to 7,260 patients with LBP across three DOD and two VA medical facilities using a stepped-wedge study design. An education, audit, and feedback model will be used to encourage physical therapists to better adhere to the PT CPG recommendations. The Oswestry Disability Index and the Defense and Veterans Pain Rating Scale will be used as primary outcomes. Secondary outcomes will include the LBP-related medication use, medical resource utilization, and biopsychosocial predictors of outcomes. Statistical analyses will be based on the intention-to-treat principle and will use linear mixed models to compare treatment conditions and examine the interactions between treatment and subgrouping status (e.g., limb loss). SUMMARY: The RESOLVE trial will provide a pragmatic approach to evaluate whether better adherence to PT CPGs can reduce pain, disability, medication use, and LBP care cost within the DOD and VA health care systems.

Changes in Trunk and Pelvis Motion Among Persons With Unilateral Lower Limb Loss During the First Year of Ambulation.

OBJECTIVE: To retrospectively investigate trunk-pelvis kinematic outcomes among persons with unilateral transtibial and transfemoral limb loss with time from initial independent ambulation with a prosthesis, while secondarily describing self-reported presence and intensity of low back pain. Over time, increasing trunk-pelvis range of motion and decreasing trunk-pelvis coordination with increasing presence and/or intensity of low back pain were hypothesized. Additionally, less trunk-pelvis range of motion and more trunk-pelvis coordination for persons with more distal limb loss was hypothesized. DESIGN: Inception cohort with up to 5 repeated evaluations, including both biomechanical and subjective outcomes, during a 1-year period (0, 2, 4, 6, 12 months) after initial ambulation with a prosthesis. SETTING: Biomechanics laboratory within military treatment facility. PARTICIPANTS: Twenty-two men with unilateral transtibial limb loss and 10 men with unilateral transfemoral limb loss (N=32). INTERVENTIONS: Not applicable. MAIN OUTCOME MEASURES: Triplanar trunk-pelvis range of motion and intersegmental coordination (continuous relative phase) obtained at self-selected (∼1.30m/s) and controlled (∼1.20m/s) walking velocities. Self-reported presence and intensity of low back pain. RESULTS: An interaction effect between time and group existed for sagittal (P=.039) and transverse (P=.009) continuous relative phase at self-selected walking velocity and transverse trunk range of motion (P=.013) and sagittal continuous relative phase (P=.005) at controlled walking velocity. Trunk range of motion generally decreased, and trunk-pelvis coordination generally increased with increasing time after initial ambulation. Sagittal trunk and pelvis range of motion were always less and frontal trunk-pelvis coordination was always greater for persons with more distal limb loss. Low back pain increased for persons with transtibial limb loss and decreased for persons with transfemoral limb loss following the 4-month time point. CONCLUSIONS: Temporal changes (or lack thereof) in features of trunk-pelvis motions within the first year of ambulation help elucidate relationships between (biomechanical) risk factors for low back pain after limb loss.

Taking the Next Steps in Regenerative Rehabilitation: Establishment of a New Interdisciplinary Field.

The growing field of regenerative rehabilitation has great potential to improve clinical outcomes for individuals with disabilities. However, the science to elucidate the specific biological underpinnings of regenerative rehabilitation-based approaches is still in its infancy and critical questions regarding clinical translation and implementation still exist. In a recent roundtable discussion from International Consortium for Regenerative Rehabilitation stakeholders, key challenges to progress in the field were identified. The goal of this article is to summarize those discussions and to initiate a broader discussion among clinicians and scientists across the fields of regenerative medicine and rehabilitation science to ultimately progress regenerative rehabilitation from an emerging field to an established interdisciplinary one. Strategies and case studies from consortium institutions-including interdisciplinary research centers, formalized courses, degree programs, international symposia, and collaborative grants-are presented. We propose that these strategic directions have the potential to engage and train clinical practitioners and basic scientists, transform clinical practice, and, ultimately, optimize patient outcomes.

A Comparison of Mental Workload in Individuals with Transtibial and Transfemoral Lower Limb Loss during Dual-Task Walking under Varying Demand.

OBJECTIVES: This study aimed to evaluate the influence of lower limb loss (LL) on mental workload by assessing neurocognitive measures in individuals with unilateral transtibial (TT) versus those with transfemoral (TF) LL while dual-task walking under varying cognitive demand. METHODS: Electroencephalography (EEG) was recorded as participants performed a task of varying cognitive demand while being seated or walking (i.e., varying physical demand). RESULTS: The findings revealed both groups of participants (TT LL vs. TF LL) exhibited a similar EEG theta synchrony response as either the cognitive or the physical demand increased. Also, while individuals with TT LL maintained similar performance on the cognitive task during seated and walking conditions, those with TF LL exhibited performance decrements (slower response times) on the cognitive task during the walking in comparison to the seated conditions. Furthermore, those with TF LL neither exhibited regional differences in EEG low-alpha power while walking, nor EEG high-alpha desynchrony as a function of cognitive task difficulty while walking. This lack of alpha modulation coincided with no elevation of theta/alpha ratio power as a function of cognitive task difficulty in the TF LL group. CONCLUSIONS: This work suggests that both groups share some common but also different neurocognitive features during dual-task walking. Although all participants were able to recruit neural mechanisms critical for the maintenance of cognitive-motor performance under elevated cognitive or physical demands, the observed differences indicate that walking with a prosthesis, while concurrently performing a cognitive task, imposes additional cognitive demand in individuals with more proximal levels of amputation.

Biomechanical and neurocognitive performance outcomes of walking with transtibial limb loss while challenged by a concurrent task.

Individuals who have sustained loss of a lower limb may require adaptations in sensorimotor and control systems to effectively utilize a prosthesis, and the interaction of these systems during walking is not clearly understood for this patient population. The aim of this study was to concurrently evaluate temporospatial gait mechanics and cortical dynamics in a population with and without unilateral transtibial limb loss (TT). Utilizing motion capture and electroencephalography, these outcomes were simultaneously collected while participants with and without TT completed a concurrent task of varying difficulty (low- and high-demand) while seated and walking. All participants demonstrated a wider base of support and more stable gait pattern when walking and completing the high-demand concurrent task. The cortical dynamics were similarly modulated by the task demand for both groups, to include a decrease in the novelty-P3 component and increase in the frontal theta/parietal alpha ratio power when completing the high-demand task, although specific differences were also observed. These findings confirm and extend prior efforts indicating that dual-task walking can negatively affect walking mechanics and/or neurocognitive performance. However, there may be limited additional cognitive and/or biomechanical impact of utilizing a prosthesis in a stable, protected environment in TT who have acclimated to ambulating with a prosthesis. These results highlight the need for future work to evaluate interactions between these cognitive-motor control systems for individuals with more proximal levels of lower limb loss, and in more challenging (ecologically valid) environments.

Regenerative and Rehabilitative Medicine: A Necessary Synergy for Functional Recovery from Volumetric Muscle Loss Injury.

Volumetric muscle loss (VML) is a complex and heterogeneous problem due to significant traumatic or surgical loss of skeletal muscle tissue. The consequences of VML are substantial functional deficits in joint range of motion and skeletal muscle strength, resulting in life-long dysfunction and disability. Traditional physical medicine and rehabilitation paradigms do not address the magnitude of force loss due to VML and related musculoskeletal comorbidities. Recent advancements in regenerative medicine have set forth encouraging and emerging therapeutic options for VML injuries. There is significant potential that combined rehabilitative and regenerative therapies can restore limb and muscle function following VML injury in a synergistic manner. This review presents the current state of the VML field, spanning clinical and preclinical literature, with particular focus on rehabilitation and regenerative medicine in addition to their synergy. Moving forward, multidisciplinary collaboration between clinical and research fields is encouraged in order to continue to improve the treatment of VML injuries and specifically address the encompassing physiology, pathology, and specific needs of this patient population. This is a work of the US Government and is not subject to copyright protection in the USA. Foreign copyrights may apply. Published by S. Karger AG, Basel.

Intercellular adhesion molecule-1 expression by skeletal muscle cells augments myogenesis.

We previously demonstrated that the expression of intercellular adhesion molecule-1 (ICAM-1) by skeletal muscle cells after muscle overload contributes to ensuing regenerative and hypertrophic processes in skeletal muscle. The objective of the present study is to reveal mechanisms through which skeletal muscle cell expression of ICAM-1 augments regenerative and hypertrophic processes of myogenesis. This was accomplished by genetically engineering C2C12 myoblasts to stably express ICAM-1, and by inhibiting the adhesive and signaling functions of ICAM-1 through the use of a neutralizing antibody or cell penetrating peptide, respectively. Expression of ICAM-1 by cultured skeletal muscle cells augmented myoblast-myoblast adhesion, myotube formation, myonuclear number, myotube alignment, myotube-myotube fusion, and myotube size without influencing the ability of myoblasts to proliferate or differentiate. ICAM-1 augmented myotube formation, myonuclear accretion, and myotube alignment through a mechanism involving adhesion-induced activation of ICAM-1 signaling, as these dependent measures were reduced via antibody and peptide inhibition of ICAM-1. The adhesive and signaling functions of ICAM-1 also facilitated myotube hypertrophy through a mechanism involving myotube-myotube fusion, protein synthesis, and Akt/p70s6k signaling. Our findings demonstrate that ICAM-1 expression by skeletal muscle cells augments myogenesis, and establish a novel mechanism through which the inflammatory response facilitates growth processes in skeletal muscle.

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.

Spinal Pathology and Muscle Morphologies with Chronic Low Back Pain and Lower Limb Amputation.

INTRODUCTION: Low back pain (LBP) is highly prevalent after lower limb amputation (LLA) and contributes to substantial reductions in quality of life and function. Towards understanding pathophysiological mechanisms underlying LBP after LLA, this article compares lumbar spine pathologies and muscle morphologies between individuals with LBP, with and without LLA. MATERIALS AND METHODS: We queried electronic medical records of Service members with and without LLA who sought care for LBP at military treatment facilities between January 2002 and May 2020. Two groups with cLBP, one with (n = 15) and one without unilateral transtibial LLA (n = 15), were identified and randomly chosen from a larger sample. Groups were matched by age, mass, and sex. Lumbar muscle morphology, Pfirrmann grades, Modic changes, facet arthrosis, Meyerding grades, and lordosis angle were determined from radiographs and magnetic resonance images available in the medical record. Independent t-tests compared variables between cohorts while multiple regression models determined if intramuscular fat influenced Pfirrmann grades. Chi-square determined differences in presence of spondylolysis and facet arthrosis. RESULTS: Lordosis angle was larger with LLA (P = 0.01). Spondylolysis was more prevalent with LLA (P = 0.008; 40%) whereas facet arthrosis was similar between cohorts (P = 0.3). Muscle area was not different between cohorts, yet intramuscular fat was greater with LLA (P ≤ 0.05). Intramuscular fat did not influence Pfirrmann grades (P > 0.15). CONCLUSIONS: Despite similar lumbar muscle size, those with unilateral LLA may be predisposed to progress to symptomatic spondylolisthesis and intramuscular fat. Surgical and/or rehabilitation interventions may mitigate long-term effects of diminished spinal health, decrease LBP-related disability, and improve function for individuals with LLA.

The Influence of Active, Passive, and Manual Therapy Interventions on Escalation of Health Care Events After Physical Therapist Care in Veterans With Low Back Pain.

OBJECTIVE: The objective of this study was to examine the associations between active, passive, and manual therapy interventions with the escalation-of-care events following physical therapist care for veterans with low back pain (LBP). METHODS: A retrospective cohort study was conducted in 3618 veterans who received physical therapist care for LBP between January 1, 2015 and January 1, 2018. The VA Corporate Data Warehouse was utilized to identify LBP-related physical therapist visits and procedures, as well as opioid prescription and non-physical therapy clinic encounters. The association between physical therapist interventions with 1-year escalation-of-care events were assessed using adjusted odds ratios from logistic regression. RESULTS: Nearly all veterans (98%) received active interventions but only a minority (31%) received manual therapy. In the 1-year follow-up period, the odds of receiving an opioid prescription were 30% lower for those who received manual therapy in addition to active interventions, as compared with patients who received only active interventions. Moreover, the odds of receiving primary care, specialty care, and diagnostic testing were 30-130% higher for patients who received electrical stimulation or more than 1 passive intervention in addition to active treatments, as compared with patients who received only active interventions. CONCLUSION: The use of manual therapy along with active interventions was associated with reduced prescription of opioids, while utilization of specific passive interventions such as electrical stimulation or multiple modalities in conjunction with active interventions resulted in increased escalation-of-care events. IMPACT STATEMENT: The use of active interventions, which is supported by most Clinical Practice Guidelines (CPGs), was the cornerstone of physical therapist care for veterans with LBP. However, the use of CPG-recommended manual therapy interventions was low but associated with reduced opioid prescriptions. The use of 2 or more different passive interventions along with active interventions was common (34%) and associated with less-than-optimal escalation-of-care outcomes.

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.

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.

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.