Smallest Clinically Meaningful Improvement in Amputation-Related Pain and Brief Pain Inventory Scores as Defined by Patient Reports of Global Improvement After Cryoneurolysis: a Retrospective Analysis of a Randomized, Controlled Clinical Trial.

BACKGROUND: The smallest meaningful improvement in pain scores (minimal clinically important difference [MCID]) after an analgesic intervention is essential information when both interpreting published data and designing a clinical trial. However, limited information is available for patients with chronic pain conditions, and what is published is derived from studies involving pharmacologic and psychological interventions. We here calculate these values based on data collected from 144 participants of a previously published multicenter clinical trial investigating the effects of a single treatment with percutaneous cryoneurolysis. METHODS: In the original trial, we enrolled patients with a lower-limb amputation and established phantom pain. Each received a single-injection femoral and sciatic nerve block with lidocaine and was subsequently randomized to receive either ultrasound-guided percutaneous cryoneurolysis or sham treatment at these same locations. Investigators, participants, and clinical staff were masked to treatment group assignment with the exception of the treating physician performing the cryoneurolysis, who had no subsequent participant interaction. At both baseline and 4 months (primary end point), participants rated their phantom limb pain based on a numeric rating scale (NRS) and their interference of pain on physical and emotional functioning as measured with the Brief Pain Inventory's interference subscale. They subsequently qualitatively defined the change using the 7-point ordinal Patient Global Impression of Change (PGIC). The smallest clinically meaningful improvements in phantom limb pain and Brief Pain Inventory scores were calculated using an anchor-based method based on the PGIC. RESULTS: The median (interquartile range [IQR]) phantom pain NRS (0-10) improvements at 4 months considered small, medium, and large were 1 [1-1], 3 [3-4], and 4 [3-6], respectively. The median improvements in the Brief Pain Inventory interference subscale (0-70) associated with a small, medium, and large analgesic changes were 16 [6-18], 24 [22-31], and 34 [22-46]. The proportions of patients that experienced PGIC ≥5 were 33% and 36% in the active and placebo groups, respectively. The relative risk of a patient experiencing PGIC ≥5 in the active group compared to the sham group with 95% confidence interval was 0.9 (0.6-1.4), P = .667. CONCLUSIONS: Amputees with phantom limb pain treated with percutaneous cryoneurolysis rate analgesic improvements as clinically meaningful similar to pharmacologic treatments, although their MCID for the Brief Pain Inventory was somewhat larger than previously published values. This information on patient-defined clinically meaningful improvements will facilitate interpretation of available studies and guide future trial design.

Ultrasound-guided Percutaneous Cryoneurolysis to Treat Chronic Postamputation Phantom Limb Pain: A Multicenter Randomized Controlled Trial.

BACKGROUND: Postamputation phantom pain is notoriously persistent with few validated treatments. Cryoneurolysis involves the application of low temperatures to reversibly ablate peripheral nerves. The authors tested the hypothesis that a single cryoneurolysis treatment would decrease phantom pain 4 months later. METHODS: The authors enrolled patients with a lower-limb amputation and established phantom pain. Each received a single-injection femoral and sciatic nerve block with lidocaine and was subsequently randomized to receive either ultrasound-guided percutaneous cryoneurolysis or sham treatment at these same locations. The primary outcome was the change in average phantom pain intensity between baseline and 4 months as measured with a numeric rating scale (0 to 10), after which an optional crossover treatment was offered. Investigators, participants, and clinical staff were masked to treatment group assignment with the exception of the treating physician performing the cryoneurolysis, who had no subsequent participant interaction. RESULTS: Pretreatment phantom pain scores were similar in both groups, with a median [quartiles] of 5.0 [4.0, 6.0] for active treatment and 5.0 [4.0, 7.0] for sham. After 4 months, pain intensity decreased by 0.5 [-0.5, 3.0] in patients given cryoneurolysis (n = 71) versus 0 [0, 3] in patients given sham (n = 73), with an estimated difference (95% CI) of -0.1 (-1.0 to 0.7), P = 0.759. Following their statistical gatekeeping protocol, the authors did not make inferences or draw conclusions on secondary endpoints. One serious adverse event occurred after a protocol deviation in which a femoral nerve cryolesion was induced just below the inguinal ligament-instead of the sensory-only saphenous nerve-which resulted in quadriceps weakness, and possibly a fall and clavicle fracture. CONCLUSIONS: Percutaneous cryoneurolysis did not decrease chronic lower extremity phantom limb pain 4 months after treatment. However, these results were based upon the authors' specific study protocol, and since the optimal cryoneurolysis treatment parameters such as freeze duration and anatomic treatment location remain unknown, further research is warranted.

Analysis of Sheep and Goat IAPP Provides Insight into IAPP Amyloidogenicity and Cytotoxicity.

Human islet amyloid polypeptide (hIAPP) plays a role in glucose regulation but forms pancreatic amyloid deposits in type 2 diabetes, and that process contributes to ß-cell dysfunction. Not all species develop diabetes, and not all secrete an IAPP that is amyloidogenic in vitro under normal conditions, a perfect correlation currently exists between both. Studies of IAPPs from such organisms can provide clues about the high amyloidogenicity of hIAPP and can inform the design of soluble analogues of hIAPP. Sheep and goat IAPP are among the most divergent from hIAPP, with 13 and 11 substitutions, respectively, including an unusual Tyr to His substitution at the C-terminus. The properties of sheep and goat IAPP were examined in solution and in the presence of anionic vesicles, resulting in no observed amyloid formation, even at increased concentrations. Furthermore, both peptides are considerably less toxic to cultured ß-cells than hIAPP. The effect of the Y37H replacements was studied in the context of hIAPP, as was a Y37R substitution. Buffer- and salt-dependent effects were observed. There was little impact on the time to form amyloid in phosphate-buffered saline; however, a significant deceleration was observed in Tris buffer, and amyloid formation was slower in the absence of added salt. The Y37H substitution had little impact on toxicity, while the Y37R replacement led to a 30% decrease in toxicity compared with that of hIAPP. The implications for the amyloidogenicity of hIAPP and the design of soluble analogues of the human peptide are discussed.

Dietary Linoleic Acid and Its Oxidized Metabolites Exacerbate Liver Injury Caused by Ethanol via Induction of Hepatic Proinflammatory Response in Mice.

Alcoholic liver disease is a major human health problem leading to significant morbidity and mortality in the United States and worldwide. Dietary fat plays an important role in alcoholic liver disease pathogenesis. Herein, we tested the hypothesis that a combination of ethanol and a diet rich in linoleic acid (LA) leads to the increased production of oxidized LA metabolites (OXLAMs), specifically 9- and 13-hydroxyoctadecadienoic acids (HODEs), which contribute to a hepatic proinflammatory response exacerbating liver injury. Mice were fed unsaturated (with a high LA content) or saturated fat diets (USF and SF, respectively) with or without ethanol for 10 days, followed by a single binge of ethanol. Compared to SF+ethanol, mice fed USF+ethanol had elevated plasma alanine transaminase levels, enhanced hepatic steatosis, oxidative stress, and inflammation. Plasma and liver levels of 9- and 13-HODEs were increased in response to USF+ethanol feeding. We demonstrated that primarily 9-HODE, but not 13-HODE, induced the expression of several proinflammatory cytokines in vitro in RAW264.7 macrophages. Finally, deficiency of arachidonate 15-lipoxygenase, a major enzyme involved in LA oxidation and OXLAM production, attenuated liver injury and inflammation caused by USF+ethanol feeding but had no effect on hepatic steatosis. This study demonstrates that OXLAM-mediated induction of a proinflammatory response in macrophages is one of the potential mechanisms underlying the progression from alcohol-induced steatosis to alcoholic steatohepatitis.

High-resolution ultrasound in combat-related peripheral nerve injuries.

INTRODUCTION: Peripheral nerve injuries (PNI) sustained in combat are typically severe and are frequently associated with marked soft tissue damage, anatomic distortion, and retained metallic fragments. These features complicate clinical and electrodiagnostic assessment and may preclude MRI. METHODS: We describe 4 cases of military personnel who sustained high-velocity gunshot wounds or blasts with metal fragment injuries in which high resolution peripheral nerve ultrasound (US) proved beneficial. RESULTS: In these cases, the clinical and electrodiagnostic exams provided inadequate localization and severity data of the nerve injuries, and MRI was either precluded or provided no additional information. In each case, US disclosed focal nerve segment abnormalities, including regions of focal enlargement and nerve discontinuity with end-bulb neuroma, which guided surgical planning for nerve repair. The findings on US were subsequently confirmed intra-operatively. CONCLUSIONS: High resolution peripheral nerve US is a useful modality in assessment of combat-related PNI. Muscle Nerve, 2016 Muscle Nerve 54: 1139-1144, 2016.

The processing intermediate of human amylin, pro-amylin(1-48), has in vivo and in vitro bioactivity.

Amylin is released by pancreatic beta-cells in response to a meal and its major soluble mature form (37 amino acid-peptide) produces its biological effects by activating amylin receptors. Amylin is derived from larger propeptides that are processed within the synthesizing beta-cell. There are suggestions that a partially processed form, pro-amylin(1-48) is also secreted. We tested the hypothesis that pro-amylin(1-48) has biological activity and that human pro-amylin(1-48) may also form toxic pre-amyloid species. Amyloid formation, the ability to cross-seed and in vitro toxicity were similar between human pro-amylin(1-48) and amylin. Human pro-amylin(1-48) was active at amylin-responsive receptors, though its potency was reduced at rat, but not human amylin receptors. Pro-amylin(1-48) was able to promote anorexia by activating neurons of the area postrema, amylin's primary site of action, indicating that amylin can tolerate significant additions at the N-terminus without losing bioactivity. Our studies help to shed light on the possible roles of pro-amylin(1-48) which may be relevant for the development of future amylin-based drugs.

Active Duty Service Members Newly Presenting With Low Back Pain in Fiscal Year 2017: Health Care Utilization, Access to Care, and Private Sector Costs Over 2-year Follow-up.

INTRODUCTION: Low back pain (LBP) has accounted for the most medical encounters every year for the past decade among Active Duty Service Members (ADSMs) of the U.S. Armed Forces. The objectives of this retrospective, descriptive study were to classify LBP by clinical category (Axial, Radicular, and Other) and duration (Acute, Subacute, and Chronic) and examine the LBP-related health care utilization, access to care, and private sector costs for ADSMs over a 2-year follow-up period. MATERIALS AND METHODS: The Military Health System Data Repository was queried in fiscal year 2017 for all ADSMs (ages 18-62) with outpatient encounters documented with any of 67 ICD-10 diagnosis codes indicative of LBP. A 1-year clean period before the first (index) outpatient LBP encounter date was used to ensure no recent history of LBP care. Patients were eligible if continuously enrolled and on active duty for 1 year before and 2 years following the index visit. Patients were excluded for non-musculoskeletal causes for LBP, red flags, or acute trauma within 4 weeks of the index visit and/or systemic illness or pregnancy anytime during the clean or follow-up period. RESULTS: A total of 52,118 ADSMs met the inclusion criteria, and the cohort was classified by duration of LBP symptoms as Acute [17,916 (34.4%)], Subacute [4,119 (7.9%)], and Chronic [30,083 (57.7%)]. Over 2-year follow-up, 419,983 outpatient visits were recorded, with the majority occurring at MTFs [363,570 (86.6%)]. 13,237 (25.4%) of ADSMs in the total cohort were documented with no other LBP-related visits beyond their index encounter. In contrast, the Chronic cohort comprised the highest number of encounters [371,031 (89.2% of total encounters)], including 86% of imaging studies performed for LBP, and accounted for $9,986,606.17 (94.9%) of total private sector costs over the 2-year follow-up period. Interventional pain procedures ($2,983,767.50) and physical therapy ($2,298,779.07) represented the costliest categories in the private sector for the Chronic cohort, whereas Emergency Department ($283,307.43) and physical therapy ($137,035.54) encounters were the top contributors to private sector costs for the Acute and Subacute cohorts, respectively. Overall reliance on the private sector was highest for specialty care, including 10,721 (75.4%) interventional pain procedures and 306 (66.4%) spine surgeries. CONCLUSIONS: Uncovering current trends in health care utilization and access to care for ADSMs newly presenting with LBP is vital for timely and accurate diagnosis, as well as early intervention to prevent progression to chronic LBP and to minimize its negative impact on military readiness and quality of life. This retrospective, descriptive study highlights the burden of chronic LBP on health care utilization and costs within the Military Health System, including reliance on the private sector care, amounting to $10,524,332.04 over the study period.

The Impact of Electronic Health Record-Based Simulation During Intern Boot Camp: Interventional Study.

BACKGROUND: Accurate data retrieval is an essential part of patient care in the intensive care unit (ICU). The electronic health record (EHR) is the primary method for data storage and data review. We previously reported that residents participating in EHR-based simulations have varied and nonstandard approaches to finding data in the ICU, with subsequent errors in recognizing patient safety issues. We hypothesized that a novel EHR simulation-based training exercise would decrease EHR use variability among intervention interns, irrespective of prior EHR experience. OBJECTIVE: This study aims to understand the impact of a novel, short, high-fidelity, simulation-based EHR learning activity on the intern data gathering workflow and satisfaction. METHODS: A total of 72 internal medicine interns across the 2018 and 2019 academic years underwent a dedicated EHR training session as part of a week-long boot camp early in their training. We collected data on previous EHR and ICU experience for all subjects. Training consisted of 1 hour of guided review of a high-fidelity, simulated ICU patient chart focusing on best navigation practices for data retrieval. Specifically, the activity focused on using high- and low-yield data visualization screens determined by expert consensus. The intervention group interns then had 20 minutes to review a new simulated patient chart before the group review. EHR screen navigation was captured using screen recording software and compared with data from existing ICU residents performing the same task on the same medical charts (N=62). Learners were surveyed immediately and 6 months after the activity to assess satisfaction and preferred EHR screen use. RESULTS: Participants found the activity useful and enjoyable immediately and after 6 months. Intervention interns used more individual screens than reference residents (18 vs 20; P=.008), but the total number of screens used was the same (35 vs 38; P=.30). Significantly more intervention interns used the 10 most common screens (73% vs 45%; P=.001). Intervention interns used high-yield screens more often and low-yield screens less often than the reference residents, which are persistent on self-report 6 months later. CONCLUSIONS: A short, high-fidelity, simulation-based learning activity focused on provider-specific data gathering was found to be enjoyable and to modify navigation patterns persistently. This suggests that workflow-specific simulation-based EHR training throughout training is of educational benefit to residents.

Quantity and Quality of Physical Medicine and Rehabilitation Clerkships in US Medical Schools.

OBJECTIVE: The purpose of this study was to address two underreported issues in undergraduate physical medicine and rehabilitation medical education: quantity and quality of physical medicine and rehabilitation clerkships in US medical schools. DESIGN: A multimethod sequential design was used to evaluate the curricula of US medical schools. Quantity (N = 154) of physical medicine and rehabilitation clerkships was assessed by counting the number of required, selective, and elective clerkships in each medical school. Quality (n = 13) was assessed by conducting a thematic analysis on physical medicine and rehabilitation clerkship curricula to identify learning objectives. These objectives were then compared with learning objectives in a model standard. RESULTS: Whereas few medical schools required a physical medicine and rehabilitation clerkship, most offered elective rotations in physical medicine and rehabilitation. Most medical schools only included 6 of the 12 model standard learning objectives. Medical schools also included 29 learning objectives not present in the model standard. CONCLUSIONS: Physical medicine and rehabilitation clerkships are not underrepresented but are underemphasized, in undergraduate medical schools. Furthermore, these clerkships use inconsistent learning objectives. Thus, findings suggest the need to draw attention to physical medicine and rehabilitation clerkships by offering them as selectives and to develop a list of standardized learning objectives. This exploratory study developed such a groundbreaking list and invites the physical medicine and rehabilitation community to test it.

Isolated Mononeuropathy From Rucksack Palsy: A Case Series.

Although there is increasing awareness of brachial plexopathy secondary to rucksack use, isolated mononeuropathies have been less well described. Three cases of mononeuropathy secondary to rucksack use in military personnel are presented, including injuries to the long thoracic and spinal accessory nerves. We also review several different factors in the proper construction, components, and fitting of the rucksack that should be considered in order to prevent rucksack palsy and provide a concise suggestion for rucksack use and education.

Canine Models of Inherited Musculoskeletal and Neurodegenerative Diseases.

Mouse models of human disease remain the bread and butter of modern biology and therapeutic discovery. Nonetheless, more often than not mouse models do not reproduce the pathophysiology of the human conditions they are designed to mimic. Naturally occurring large animal models have predominantly been found in companion animals or livestock because of their emotional or economic value to modern society and, unlike mice, often recapitulate the human disease state. In particular, numerous models have been discovered in dogs and have a fundamental role in bridging proof of concept studies in mice to human clinical trials. The present article is a review that highlights current canine models of human diseases, including Alzheimer's disease, degenerative myelopathy, neuronal ceroid lipofuscinosis, globoid cell leukodystrophy, Duchenne muscular dystrophy, mucopolysaccharidosis, and fucosidosis. The goal of the review is to discuss canine and human neurodegenerative pathophysiologic similarities, introduce the animal models, and shed light on the ability of canine models to facilitate current and future treatment trials.

Managing Complex Peripheral Nerve Injuries Within the Military Health System: A Multidisciplinary Approach to Treatment, Education, and Research at Walter Reed National Military Medical Center.

INTRODUCTION: Peripheral nerve injuries are a leading cause of disability within the Military Health System (MHS) patient population. Many peripheral nerve injuries (PNIs) are amenable to therapeutic intervention but require a timely diagnosis and prompt referral to a specialty center capable of intervention, as functional outcomes are directly related to the duration between injury and intervention. Even when appropriately identified, PNI management in the MHS is often challenged by the lack of an established pathway for care coordination and a limited awareness of available diagnostic and therapeutic resources. To address these potential shortcomings, the Walter Reed National Military Medical Center Peripheral Nerve Program (WRNMMC PNP) in Bethesda, MD, has been established to provide comprehensive, multidisciplinary care to peripheral nerve-injured patients across the MHS. Additionally, the WRNMMC PNP provides graduate medical education training in PNI management for multiple residency and fellowship programs, and it facilitates critical peripheral nerve research to advance knowledge within the field. MATERIALS AND METHODS: A retrospective review of all patients evaluated by the WRNMMC PNP between December 2015 and April 2019 was conducted in order to identify pertinent patient demographic information, referral patterns, and PNI etiology data. RESULTS: The WRNMMC PNP evaluated 356 patients consisting of active duty, dependents, retirees, and Veterans Affairs patients during the designated study period. These patients were referred by providers from more than nine different specialties from 78 commands across eight countries. The majority of these patients (222 patients) were referred for traumatic PNI. The WRNMMC PNP has also evaluated and treated patients with PNIs stemming from congenital and compressive etiologies. One hundred and one patients referred during this period were treated with surgery, while the remainder were managed through nonoperative means. CONCLUSIONS: The WRNMMC PNP facilitates comprehensive, patient-centered care for PNI patients within the MHS. Moreover, the program helps to prepare the next generation of providers for evaluating and treating PNI patients through its involvement with graduate medical education training. It also conducts critical peripheral nerve research and lays the foundation for collaborations with other institutions involved with peripheral nerve research. In the years ahead, the WRNMMC PNP aims to expand its outreach and capabilities within the MHS through more expansive use of telemedicine consultation and the establishment of satellite peripheral nerve clinic sites.

Reversal of phantom pain and hand-to-face remapping after brachial plexus avulsion.

Following left brachial plexus avulsion, a 20-year-old man had phantom limb pain and remapping of sensation from his paralyzed hand onto his face. Mirror therapy (15 min daily, 5 days/week) led immediately to good movement of the phantom limb with decreased pain. Within 2 weeks following nerve graft surgery, remapping of hand sensation onto the face disappeared along with resolution of phantom limb pain. Mirror therapy coupled with nerve grafting may relieve phantom limb pain due to brachial plexus avulsion and reverse hand-to-face remapping, suggesting that both peripheral and central mechanisms mediate development of phantom limb pain and cortical reorganization/neuroplasticity after brachial plexus avulsion.

Alcoholic Liver Disease: Update on the Role of Dietary Fat.

Alcoholic liver disease (ALD) spans a spectrum of liver pathology, including fatty liver, alcoholic steatohepatitis, and cirrhosis. Accumulating evidence suggests that dietary factors, including dietary fat, as well as alcohol, play critical roles in the pathogenesis of ALD. The protective effects of dietary saturated fat (SF) and deleterious effects of dietary unsaturated fat (USF) on alcohol-induced liver pathology are well recognized and documented in experimental animal models of ALD. Moreover, it has been demonstrated in an epidemiological study of alcoholic cirrhosis that dietary intake of SF was associated with a lower mortality rates, whereas dietary intake of USF was associated with a higher mortality. In addition, oxidized lipids (dietary and in vivo generated) may play a role in liver pathology. The understanding of how dietary fat contributes to the ALD pathogenesis will enhance our knowledge regarding the molecular mechanisms of ALD development and progression, and may result in the development of novel diet-based therapeutic strategies for ALD management. This review explores the relevant scientific literature and provides a current understanding of recent advances regarding the role of dietary lipids in ALD pathogenesis.

Recent advances in bioelectric prostheses.

Worldwide prevalence of amputation has created an increasing demand for improved upper and lower extremity prostheses. Current prosthetics are often uncomfortable and difficult to control and provide limited functional restoration. Moreover, the inability to normalize anthropomorphic biomechanics with a prosthesis increases one's risk of developing long-term health risks such as arthritis, skin breakdown, and pain. Recent advances in bionic prosthetic development hold great promise for rehabilitation and improving quality of life with limb loss. This brief review discusses the current state of advanced prostheses, the integration of robotics in the care of individuals with major limb amputation, and some innovative surgical techniques that are being explored for clinical feasibility.

Fulminant heterotopic ossification after combat-related amputation: a report of 2 cases.

Heterotopic ossification (HO) is the process of abnormal formation of lamellar bone in nonosseous tissues. In this case presentation, we describe patients with aggressive HO, which becomes symptomatic shortly after injury for which we have suggested the term "fulminant heterotopic ossification." These atypical presentations of fulminant HO highlight the necessity for continued research directed at improved understanding of HO and may suggest a role for early partial surgical excision as a definitive management strategy.