Shear wave elastography of transverse carpal ligament increased with simulated carpal tunnel pressure.

BACKGROUND: Elevation of carpal tunnel pressure is known to be associated with carpal tunnel syndrome. This study aimed to correlate the shear wave elastography in the transverse carpal ligament (TCL) with carpal tunnel pressures using a cadaveric model. METHODS: Eight human cadaveric hands were dissected to evacuate the tunnels. A medical balloon was inserted into each tunnel and connected to a pressure regulator to simulate tunnel pressure in the range of 0-210 mmHg with an increment of 30 mmHg. Shear wave velocity and modulus was measure in the middle of TCL. RESULTS: SWV and SWE were significantly dependent on the pressure levels (p < 0.001), and positively correlated to the tunnel pressure (SWV: R = 0.997, p < 0.001; SWE: R = 0.996, p < 0.001). Regression analyses showed linear relationship SWV and pressure (SWV = 4.359 + 0.0263 * Pressure, R2 = 0.994) and between SWE and pressure (SWE = 48.927 + 1.248 * Pressure, R2 = 0.996). CONCLUSION: The study indicated that SWV and SWE in the TCL increased linearly as the tunnel pressure increased within the current pressure range. The findings suggested that SWV/SWE in the TCL has the potential for prediction of tunnel pressure and diagnosis of carpal tunnel syndrome.

4-Aminopyridine treatment for nerve injury resulting from radical retro-pubic prostatectomy: a single-center double-blind, randomized, placebo-controlled study.

BACKGROUND: Prostate cancer (PCa) is the most common non-cutaneous malignancy in men and leads to the second most common cause of cancer related mortality in men. Early detection of PCa allows for a potentially curative intervention. Most men will live over a decade from the time of their PCa diagnosis. Thus, treatments must balance curative interventions with their impact on quality of life. Radical prostatectomy (RP) is one such potentially curative intervention but often leads to erectile dysfunction (ED) and urinary incontinence (UI). Approximately 90,000 RPs are performed each year in the USA. Post-operative ED and UI is thought to occur in part from traumatic peripheral nerve injury (TPNI) to the neurovascular bundles that surround the prostate. Thus, patients undergoing RP may be a population that would benefit from clinical studies that look at TPNI. METHODS: The study is a single-institution, double-blinded placebo-controlled, randomized clinical trial in which patients immediately post-RP receive either 4-aminopyrdine (4AP) or placebo in a 1:1 fashion. The primary outcome is evaluation of the efficacy of 4AP in accelerating the early return of baseline erectile and urinary function post-radical prostatectomy. DISCUSSION: This study is critical as it could reduce the morbidity associated with RP, a commonly performed operation, and identify a patient population that may greatly benefit into further TPNI research. TRIAL REGISTRATION: ClinicalTrials.gov NCT03701581. Prospectively registered on October 10, 2018.

A Pharmacogenomics-Based In Silico Investigation of Opioid Prescribing in Post-operative Spine Pain Management and Personalized Therapy.

Considering the variability in individual responses to opioids and the growing concerns about opioid addiction, prescribing opioids for postoperative pain management after spine surgery presents significant challenges. Therefore, this study undertook a novel pharmacogenomics-based in silico investigation of FDA-approved opioid medications. The DrugBank database was employed to identify all FDA-approved opioids. Subsequently, the PharmGKB database was utilized to filter through all variant annotations associated with the relevant genes. In addition, the dpSNP ( https://www.ncbi.nlm.nih.gov/snp/ ), a publicly accessible repository, was used. Additional analyses were conducted using STRING-MODEL (version 12), Cytoscape (version 3.10.1), miRTargetLink.2, and NetworkAnalyst (version 3). The study identified 125 target genes of FDA-approved opioids, encompassing 7019 variant annotations. Of these, 3088 annotations were significant and pertained to 78 genes. During variant annotation assessments (VAA), 672 variants remained after filtration. Further in-depth filtration based on variant functions yielded 302 final filtered variants across 56 genes. The Monoamine GPCRs pathway emerged as the most significant signaling pathway. Protein-protein interaction (PPI) analysis revealed a fully connected network comprising 55 genes. Gene-miRNA Interaction (GMI) analysis of these 55 candidate genes identified miR-16-5p as a pivotal miRNA in this network. Protein-Drug Interaction (PDI) assessment showed that multiple drugs, including Ibuprofen, Nicotine, Tramadol, Haloperidol, Ketamine, L-Glutamic Acid, Caffeine, Citalopram, and Naloxone, had more than one interaction. Furthermore, Protein-Chemical Interaction (PCI) analysis highlighted that ABCB1, BCL2, CYP1A2, KCNH2, PTGS2, and DRD2 were key targets of the proposed chemicals. Notably, 10 chemicals, including carbamylhydrazine, tetrahydropalmatine, Terazosin, beta-methylcholine, rubimaillin, and quinelorane, demonstrated dual interactions with the aforementioned target genes. This comprehensive review offers multiple strong, evidence-based in silico findings regarding opioid prescribing in spine pain management, introducing 55 potential genes. The insights from this report can be applied in exome analysis as a pharmacogenomics (PGx) panel for pain susceptibility, facilitating individualized opioid prescribing through genotyping of related variants. The article also points out that African Americans represent an important group that displays a high catabolism of opioids and suggest the need for a personalized therapeutic approach based on genetic information.

Polytomous Rasch Analyses of Surgeons' Decision-Making on Choice of Procedure in Endoscopic Lumbar Spinal Stenosis Decompression Surgeries.

BACKGROUND: With the growing prevalence of lumbar spinal stenosis, endoscopic surgery, which incorporates techniques such as transforaminal, interlaminar, and unilateral biportal (UBE) endoscopy, is increasingly considered. However, the patient selection criteria are debated among spine surgeons. OBJECTIVE: This study used a polytomous Rasch analysis to evaluate the factors influencing surgeon decision-making in selecting patients for endoscopic surgical treatment of lumbar spinal stenosis. METHODS: A comprehensive survey was distributed to a representative sample of 296 spine surgeons. Questions encompassed various patient-related and clinical factors, and responses were captured on a logit scale graphically displaying person-item maps and category probability curves for each test item. Using a Rasch analysis, the data were subsequently analyzed to determine the latent traits influencing decision-making. RESULTS: The Rasch analysis revealed that surgeons' preferences for transforaminal, interlaminar, and UBE techniques were easily influenced by comfort level and experience with the endoscopic procedure and patient-related factors. Harder-to-agree items included technological aspects, favorable clinical outcomes, and postoperative functional recovery and rehabilitation. Descriptive statistics suggested interlaminar as the best endoscopic spinal stenosis decompression technique. However, logit person-item analysis integral to the Rasch methodology showed highest intensity for transforaminal followed by interlaminar endoscopic lumbar stenosis decompression. The UBE technique was the hardest to agree on with a disordered person-item analysis and thresholds in category probability curve plots. CONCLUSION: Surgeon decision-making in selecting patients for endoscopic surgery for lumbar spinal stenosis is multifaceted. While the framework of clinical guidelines remains paramount, on-the-ground experience-based factors significantly influence surgeons' selection of patients for endoscopic lumbar spinal stenosis surgeries. The Rasch methodology allows for a more granular psychometric evaluation of surgeon decision-making and accounts better for years-long experience that may be lost in standardized clinical guideline development. This new approach to assessing spine surgeons' thought processes may improve the implementation of evidence-based protocol change dictated by technological advances was endorsed by the Interamerican Society for Minimally Invasive Spine Surgery (SICCMI), the International Society for Minimal Intervention in Spinal Surgery (ISMISS), the Mexican Spine Society (AMCICO), the Brazilian Spine Society (SBC), the Society for Minimally Invasive Spine Surgery (SMISS), the Korean Minimally Invasive Spine Society (KOMISS), and the International Society for the Advancement of Spine Surgery (ISASS).

Comparative Analysis of Learning Curve, Complexity, Psychological Stress, and Work Relative Value Units for CPT 62380 Endoscopic Lumbar Spinal Decompression vs Traditional Lumbar Spine Surgeries: A Paired Rasch Survey Study.

BACKGROUND: Effective 1 January 2017, single-level endoscopic lumbar discectomy received a Category I Current Procedural Terminology (CPT) code 62380. However, no work relative value units (RVUs) are currently assigned to the procedure. An international team of endoscopic spine surgeons conducted a study, endorsed by several spine societies, analyzing the learning curve, difficulty, psychological intensity, and estimated work RVUs of endoscopic lumbar spinal decompression compared with other common lumbar spine surgeries. METHODS: A survey comparing CPT 62380 to 10 other comparator CPT codes reflective of common spine surgeries was developed to assess the work RVUs in terms of learning curve, difficulty, psychological intensity, and work effort using a paired Rasch method. RESULTS: The survey was sent to 542 spine specialists. Of 322 respondents, 150 completed the survey for a 43.1% completion rate. Rasch analysis of the submitted responses statistically corroborated common knowledge that the learning curve with lumbar endoscopic spinal surgery is steeper and more complex than with traditional translaminar lumbar decompression surgeries. It also showed that the psychological stress and mental and work effort with the lumbar endoscopic decompression surgery were perceived to be higher by responding spine surgeons compared with posterior comparator decompression and fusion surgeries and even posterior interbody and posterolateral fusion surgeries. The regression analysis of work effort vs procedural difficulty showed the real-world evaluation of the lumbar endoscopic decompression surgery described in CPT code 62380 with a calculated work RVU of 18.2464. CONCLUSION: The Rasch analysis suggested the valuation for the endoscopic lumbar decompression surgery should be higher than for standard lumbar surgeries: 111.1% of the laminectomy with exploration and/or decompression of spinal cord and/or cauda equina (CPT 63005), 118.71% of the laminectomy code (CPT 63047), which includes foraminotomy and facetectomy, 152.1% of the hemilaminectomy code (CPT 63030), and 259.55% of the interlaminar or interspinous process stabilization/distraction without decompression code (CPT 22869). This research methodology was endorsed by the Interamerican Society for Minimally Invasive Spine Surgery (SICCMI), the Mexican Society of Spinal Surgeons (AMCICO), the International Society For Minimally Invasive Spine Surgery (ISMISS), the Brazilian Spine Society (SBC), the Society for Minimally Invasive Spine Surgery (SMISS), the Korean Minimally Invasive Spine Surgery (KOMISS), and the International Society for the Advancement of Spine Surgery (ISASS). CLINICAL RELEVANCE: This study provides an updated reimbursement recommendation for endoscopic spine surgery. LEVEL OF EVIDENCE: Level 3.

Randomized Clinical Trials and Observational Tribulations: Providing Clinical Evidence for Personalized Surgical Pain Management Care Models.

Proving clinical superiority of personalized care models in interventional and surgical pain management is challenging. The apparent difficulties may arise from the inability to standardize complex surgical procedures that often involve multiple steps. Ensuring the surgery is performed the same way every time is nearly impossible. Confounding factors, such as the variability of the patient population and selection bias regarding comorbidities and anatomical variations are also difficult to control for. Small sample sizes in study groups comparing iterations of a surgical protocol may amplify bias. It is essentially impossible to conceal the surgical treatment from the surgeon and the operating team. Restrictive inclusion and exclusion criteria may distort the study population to no longer reflect patients seen in daily practice. Hindsight bias is introduced by the inability to effectively blind patient group allocation, which affects clinical result interpretation, particularly if the outcome is already known to the investigators when the outcome analysis is performed (often a long time after the intervention). Randomization is equally problematic, as many patients want to avoid being randomly assigned to a study group, particularly if they perceive their surgeon to be unsure of which treatment will likely render the best clinical outcome for them. Ethical concerns may also exist if the study involves additional and unnecessary risks. Lastly, surgical trials are costly, especially if the tested interventions are complex and require long-term follow-up to assess their benefit. Traditional clinical testing of personalized surgical pain management treatments may be more challenging because individualized solutions tailored to each patient's pain generator can vary extensively. However, high-grade evidence is needed to prompt a protocol change and break with traditional image-based criteria for treatment. In this article, the authors review issues in surgical trials and offer practical solutions.

A critical role for erythropoietin on vagus nerve Schwann cells in intestinal motility.

BACKGROUND: Dysmotility and postoperative ileus (POI) are frequent major clinical problems post-abdominal surgery. Erythropoietin (EPO) is a multifunctional tissue-protective cytokine that promotes recovery of the intestine in various injury models. While EPO receptors (EPOR) are present in vagal Schwann cells, the role of EPOR in POI recovery is unknown because of the lack of EPOR antagonists or Schwann-cell specific EPOR knockout animals. This study was designed to explore the effect of EPO via EPOR in vagal nerve Schwann cells in a mouse model of POI. RESULTS: The structural features of EPOR and its activation by EPO-mediated dimerization were understood using structural analysis. Later, using the Cre-loxP system, we developed a myelin protein zero (Mpz) promoter-driven knockout mouse model of Schwann cell EPOR (MpzCre-EPORflox/flox / Mpz-EPOR-KO) confirmed using PCR and qRT-PCR techniques. We then measured the intestinal transit time (ITT) at baseline and after induction of POI with and without EPO treatment. Although we have previously shown that EPO accelerates functional recovery in POI in wild type mice, EPO treatment did not improve functional recovery of ITT in POI of Mpz-EPOR-KO mice. CONCLUSIONS: To the best of our knowledge, this is the first pre-clinical study to demonstrate a novel mouse model of EPOR specific knock out on Schwan cells with an effect in the gut. We also showed novel beneficial effects of EPO through vagus nerve Schwann cell-EPOR in intestinal dysmotility. Our findings suggest that EPO-EPOR signaling in the vagus nerve after POI is important for the functional recovery of ITT.

The Changing Environment in Postgraduate Education in Orthopedic Surgery and Neurosurgery and Its Impact on Technology-Driven Targeted Interventional and Surgical Pain Management: Perspectives from Europe, Latin America, Asia, and The United States.

Personalized care models are dominating modern medicine. These models are rooted in teaching future physicians the skill set to keep up with innovation. In orthopedic surgery and neurosurgery, education is increasingly influenced by augmented reality, simulation, navigation, robotics, and in some cases, artificial intelligence. The postpandemic learning environment has also changed, emphasizing online learning and skill- and competency-based teaching models incorporating clinical and bench-top research. Attempts to improve work-life balance and minimize physician burnout have led to work-hour restrictions in postgraduate training programs. These restrictions have made it particularly challenging for orthopedic and neurosurgery residents to acquire the knowledge and skill set to meet the requirements for certification. The fast-paced flow of information and the rapid implementation of innovation require higher efficiencies in the modern postgraduate training environment. However, what is taught typically lags several years behind. Examples include minimally invasive tissue-sparing techniques through tubular small-bladed retractor systems, robotic and navigation, endoscopic, patient-specific implants made possible by advances in imaging technology and 3D printing, and regenerative strategies. Currently, the traditional roles of mentee and mentor are being redefined. The future orthopedic surgeons and neurosurgeons involved in personalized surgical pain management will need to be versed in several disciplines ranging from bioengineering, basic research, computer, social and health sciences, clinical study, trial design, public health policy development, and economic accountability. Solutions to the fast-paced innovation cycle in orthopedic surgery and neurosurgery include adaptive learning skills to seize opportunities for innovation with execution and implementation by facilitating translational research and clinical program development across traditional boundaries between clinical and nonclinical specialties. Preparing the future generation of surgeons to have the aptitude to keep up with the rapid technological advances is challenging for postgraduate residency programs and accreditation agencies. However, implementing clinical protocol change when the entrepreneur-investigator surgeon substantiates it with high-grade clinical evidence is at the heart of personalized surgical pain management.

Effects of 4-Aminopyridine on Combined Nerve and Muscle Injury and Bone Loss.

PURPOSE: Musculoskeletal injuries are common, and peripheral nerve injury (PNI) causes significant muscle and bone loss within weeks. After PNI, 4-aminopyridine (4-AP) improves functional recovery and muscle atrophy. However, it is unknown whether 4-AP has any effect on isolated traumatic muscle injury and PNI-induced bone loss. METHODS: A standardized crush injury was performed on the sciatic nerve and muscles in mice, and the mice were assigned to receive normal saline or 4-AP treatment daily for 21 days. The postinjury motor and sensory function recovery was assessed, injured muscles were processed for histomorphometry, and the tibial bone was scanned for bone density. RESULTS: 4-Aminopyridine significantly accelerated the postinjury motor and sensory function recovery, improved muscle histomorphometry, increased muscle satellite cell numbers, and shifted muscle fiber types after combined nerve and muscle injury. Importantly, the 4-AP treatment significantly reduced PNI-induced bone loss. In contrast, in the case of isolated muscle injury, 4-AP had no effect on functional recovery and bone density, but it improved muscle-specific histomorphometry to a limited extent. CONCLUSIONS: These findings demonstrate the potential beneficial effects of 4-AP on the recovery of muscle morphology and bone density after combined muscle and nerve injury. CLINICAL RELEVANCE: Nerve injuries frequently involve muscle and result in rapid muscle and bone atrophy. In this scenario, 4-AP, in addition to accelerating nerve functional recovery, might work as an adjunctive agent to improve the recovery of injured muscle and attenuate PNI-induced bone loss.

Functional recovery and muscle atrophy in pre-clinical models of peripheral nerve transection and gap-grafting in mice: effects of 4-aminopyridine.

We recently demonstrated a repurposing beneficial effect of 4-aminopyridine (4-AP), a potassium channel blocker, on functional recovery and muscle atrophy after sciatic nerve crush injury in rodents. However, this effect of 4-AP is unknown in nerve transection, gap, and grafting models. To evaluate and compare the functional recovery, nerve morphology, and muscle atrophy, we used a novel stepwise nerve transection with gluing (STG), as well as 7-mm irreparable nerve gap (G-7/0) and 7-mm isografting in 5-mm gap (G-5/7) models in the absence and presence of 4-AP treatment. Following surgery, sciatic functional index was determined weekly to evaluate the direct in vivo global motor functional recovery. After 12 weeks, nerves were processed for whole-mount immunofluorescence imaging, and tibialis anterior muscles were harvested for wet weight and quantitative histomorphological analyses for muscle fiber cross-sectional area and minimal Feret's diameter. Average post-injury sciatic functional index values in STG and G-5/7 models were significantly greater than those in the G-7/0 model. 4-AP did not affect the sciatic functional index recovery in any model. Compared to STG, nerve imaging revealed more misdirected axons and distorted nerve architecture with isografting. While muscle weight, cross-sectional area, and minimal Feret's diameter were significantly smaller in G-7/0 model compared with STG and G-5/7, 4-AP treatment significantly increased right TA muscle mass, cross-sectional area, and minimal Feret's diameter in G-7/0 model. These findings demonstrate that functional recovery and muscle atrophy after peripheral nerve injury are directly related to the intervening nerve gap, and 4-AP exerts differential effects on functional recovery and muscle atrophy.

Erythropoietin promotes M2 macrophage phagocytosis of Schwann cells in peripheral nerve injury.

Following acute sciatic nerve crush injury (SNCI), inflammation and the improper phagocytic clearance of dying Schwann cells (SCs) has effects on remodeling that lead to morbidity and incomplete functional recovery. Therapeutic strategies like the use of erythropoietin (EPO) for peripheral nerve trauma may serve to bring immune cell phagocytotic clearance under control to support debris clearance. We evaluated EPO's effect on SNCI and found EPO treatment increased myelination and sciatic functional index (SFI) and bolstered anti-apoptosis and phagocytosis of myelin debris via CD206+ macrophages when compared to saline treatment. EPO enhanced M2 phenotype activity, both in bone marrow-derived macrophages (BMMØs) and peritoneal-derived macrophages (PMØs) in vitro, as well as in PMØs in vivo. EPO increased efferocytosis of apoptotic sciatic nerve derived Schwann cells (SNSCs) in both settings as demonstrated using immunofluorescence (IF) and flow cytometry. EPO treatment significantly attenuated pro-inflammatory genes (IL1ß, iNOS, and CD68) and augmented anti-inflammatory genes (IL10 and CD163) and the cell-surface marker CD206. EPO also increased anti-apoptotic (Annexin V/7AAD) effects after lipopolysaccharide (LPS) induction in macrophages. Our data demonstrate EPO promotes the M2 phenotype macrophages to ameliorate apoptosis and efferocytosis of dying SCs and myelin debris and improves SN functional recovery following SNCI.

(4-Aminopyridine)-PLGA-PEG as a Novel Thermosensitive and Locally Injectable Treatment for Acute Peripheral Nerve Injury.

Traumatic peripheral nerve injury (TPNI) represents a major medical problem that results in loss of motor and sensory function, and in severe cases, limb paralysis and amputation. To date, there are no effective treatments beyond surgery in selective cases. In repurposing studies, we found that daily systemic administration of the FDA-approved drug 4-aminopyridine (4-AP) enhanced functional recovery after acute peripheral nerve injury. This study was aimed at constructing a novel local delivery system of 4-AP using thermogelling polymers. We optimized a thermosensitive (4-AP)-poly(lactide-co-glycolide)-b-poly(ethylene glycol)-b-poly(lactide-co-glycolide) (PLGA-PEG-PLGA) block copolymer formulation. (4-AP)-PLGA-PEG exhibited controlled release of 4-AP both in vitro and in vivo for approximately 3 weeks, with clinically relevant safe serum levels in animals. Rheological investigation showed that (4-AP)-PLGA-PEG underwent a solution to gel transition at 32 °C, a physiologically relevant temperature, allowing us to administer it to an injured limb while subsequently forming an in situ gel. A single local administration of (4-AP)-PLGA-PEG remarkably enhanced motor and sensory functional recovery on post-sciatic nerve crush injury days 1, 3, 7, 14, and 21. Moreover, immunohistochemical studies of injured nerves treated with (4-AP)-PLGA-PEG demonstrated an increased expression of neurofilament heavy chain (NF-H) and myelin protein zero (MPZ) proteins, two major markers of nerve regeneration. These findings demonstrate that (4-AP)-PLGA-PEG may be a promising long-acting local therapeutic agent in TPNI, for which no pharmacologic treatment exists.

An effective erythropoietin dose regimen protects against severe nerve injury-induced pathophysiological changes with improved neural gene expression and enhances functional recovery.

The functional recovery following non-severing peripheral nerve injury (PNI) is often incomplete. Erythropoietin (EPO) is a pleiotropic hormone and it has been shown to protect peripheral nerves following mild and even moderate severity injuries. However, the effectiveness of EPO in severe PNI is largely unknown. In this study, we sought to investigate the neuroprotective effect of a new dose regimen of EPO in severe sciatic nerve crush injury (SSCI). Adult male mice (8 animals/group) were randomly assigned to sham (normal saline, 0.1 ml/mouse), SSCI (normal saline, 0.1 ml/mouse) and SSCI with EPO (5000 IU/kg) groups. SSCI was performed using calibrated forceps for 30 sec. EPO or normal saline was administered intraperitoneally immediately after the SSCI and at post-injury day1 and 2. The functional recovery after injury was assessed by sciatic function index (SFI), von Frey Test (VFT), and grip strength test. Mice were euthanized on day 7 and 21 and nerves at injury/peri-injury site were processed for gene (quantitative real-time PCR) and protein (immunohistochemistry) expression analysis. EPO significantly improved SFI, VFT, and hind limb paw grip strength from post-injury day 7. EPO demonstrated significant regulatory effects on mRNA expression of inflammatory (IL-1ß and TNF-α), anti-inflammatory (IL-10), angiogenesis (VEGF and eNOS), and myelination (MBP) genes. The protein expression of IL-1ß, F4/80, CD31, NF-κB p65, NF-H, MPZ, and DHE (redox-sensitive probe) was also significantly modulated by EPO treatment. In conclusion, the new dose regimen of EPO augments sciatic nerve functional recovery by mitigating inflammatory, anti-inflammatory, oxidative stress, angiogenesis, and myelination components of SSCI.

Zoledronic Acid Improves Muscle Function in Healthy Mice Treated with Chemotherapy.

Carboplatin is a chemotherapy drug used to treat solid tumors but also causes bone loss and muscle atrophy and weakness. Bone loss contributes to muscle weakness through bone-muscle crosstalk, which is prevented with the bisphosphonate zoledronic acid (ZA). We treated mice with carboplatin in the presence or absence of ZA to assess the impact of bone resorption on muscle. Carboplatin caused loss of body weight, muscle mass, and bone mass, and also led to muscle weakness as early as 7 days after treatment. Mice treated with carboplatin and ZA lost body weight and muscle mass but did not lose bone mass. In addition, muscle function in mice treated with ZA was similar to control animals. We also used the anti-TGFß antibody (1D11) to prevent carboplatin-induced bone loss and showed similar results to ZA-treated mice. We found that atrogin-1 mRNA expression was increased in muscle from mice treated with carboplatin, which explained muscle atrophy. In mice treated with carboplatin for 1 or 3 days, we did not observe any bone or muscle loss, or muscle weakness. In addition, reduced caloric intake in the carboplatin treated mice did not cause loss of bone or muscle mass, or muscle weakness. Our results show that blocking carboplatin-induced bone resorption is sufficient to prevent skeletal muscle weakness and suggests another benefit to bone therapy beyond bone in patients receiving chemotherapy. © 2019 American Society for Bone and Mineral Research.

Alterations in tibiotalar joint reaction force following syndesmotic injury are restored with static syndesmotic fixation.

INTRODUCTION: Syndesmotic injury alters joint mechanics, which may fail to be restored unless an anatomic reduction is obtained. METHODS: A minimally invasive method of measuring joint forces was utilized that does not require significant dissection or intraarticular placement of sensory instruments. Steinmann pins were placed in the tibia and talus of eight fresh-frozen human cadaveric lower extremities and a baseline joint reaction force was determined. A syndesmotic injury was created and reduction (anatomic and anterior malreduction) performed with one or two quadricortical screws and joint reaction forces were measured after the injury and subsequent repairs. FINDINGS: Baseline mean tibiotalar joint reaction force was 31.4 (SD 7.3 N) and syndesmotic injury resulted in a 35% decrease (mean 20.3, SD 8.4 N, p < 0.01). Fixation of the injury using one or two syndesmotic screws resulted in significant increase compared to the injury state (mean 28.7, SD3.9 N, and mean 28.3, SD 6.4 N, p < 0.05), however there was no significant difference between the two methods of fixation. Malreduction of the fibula also increased joint reaction force compared to the injury state (mean 31.5, SD 5.2 N, p < 0.01), however a significant difference was not detected between malreduction and anatomic reduction. INTERPRETATION: The present study demonstrates that syndesmotic injury decreases joint reaction force within the tibiotalar joint, suggesting ankle joint instability. Tibiotalar force was restored with anatomic reduction with either a 1 or 2 quadricortical syndesmotic screws. Furthermore, anterior malreduction restored joint reaction force to levels similar to those observed at baseline and with anatomic reduction. LEVEL OF EVIDENCE: Level V: biomechanical/cadaver study.

4-Aminopyridine attenuates muscle atrophy after sciatic nerve crush injury in mice.

INTRODUCTION: We recently demonstrated the beneficial effects of 4-aminopyridine (4-AP), a potassium channel blocker, in enhancing remyelination and recovery of nerve conduction velocity and motor function after sciatic nerve crush injury in mice. Although muscle atrophy occurs very rapidly after nerve injury, the effect of 4-AP on muscle atrophy and intrinsic muscle contractile function is largely unknown. METHODS: Mice were assigned to sciatic nerve crush injury and no-injury groups and were followed for 3, 7, and 14 days with/without 4-AP or saline treatment. Morphological, functional, and transcriptional properties of skeletal muscle were assessed. RESULTS: In addition to improving in vivo function, 4-AP significantly reduced muscle atrophy with increased muscle fiber diameter and contractile force. Reduced muscle atrophy was associated with attenuated expression of atrophy-related genes and increased expression of proliferating stem cells. DISCUSSION: These findings provide new insights into the potential therapeutic benefits of 4-AP against nerve injury-induced muscle atrophy and dysfunction. Muscle Nerve 60: 192-201, 2019.

Pharmacological Attenuation of Electrical Effects in a Model of Compression Neuropathy.

BACKGROUND: Peripheral nerve compression and entrapment can be debilitating. Using a validated animal model of peripheral nerve compression, we examined the utility of 2 drugs approved for other uses in humans, 4-aminopyridine (4-AP) and erythropoietin (EPO), as treatments for surgically induced ischemia and as adjuvants to surgical decompression. METHODS: Peripheral nerve compression was induced in wild-type mice by placing an inert silicone sleeve around the sciatic nerve. Decompression surgery was performed at 6 weeks with mice receiving 4-AP, EPO, or saline solution either during and after compression or only after decompression. A nerve conduction study and morphometric analyses were performed to compare the extent of the injury and the efficacy of the therapies, and the findings were subjected to statistical analysis. RESULTS: During peripheral nerve compression, there was a progressive decline in nerve conduction velocity compared with that in sham-treatment animals, in which nerve conduction velocity remained normal (∼55 m/s). Mice treated with 4-AP or EPO during the compression phase had significantly smaller declines in nerve conduction velocity and increased plateau nerve conduction velocities compared with untreated controls (animals that received saline solution). Histomorphometric analyses of newly decompressed nerves (i.e., nerves that underwent decompression on the day that the mouse was sacrificed) revealed that both treated groups had significantly greater proportions of large (>5-µm) axons than the untreated controls. Following surgical decompression, all animals recovered to a normal baseline nerve conduction velocity by day 15; however, treatment significantly accelerated improvement (in both the 4-AP and the EPO group), even when it was only started after decompression. Histomorphometric analyses at 7 and 15 days following surgical decompression revealed significantly increased myelin thickness and significantly greater proportions of large axons among the treated animals. CONCLUSIONS: Both the 4-AP and the EPO-treated group demonstrated improvements in tissue architectural and electrodiagnostic measurements, both during and after peripheral nerve compression, compared with untreated mice. CLINICAL RELEVANCE: Peripheral nerve decompression is one of the most commonly performed procedures in orthopaedic surgery. We believe that there is reason for some optimism about the translation of our findings to the clinical setting. Our findings in this murine model suggest that 4-AP and EPO may lessen the effects of nerve entrapment and that the use of these agents after decompression may speed and perhaps otherwise optimize recovery after surgery.

Spring ligament tear decreases static stability of the ankle joint.

BACKGROUND: Spring ligament tear is often found in advanced adult acquired flatfoot deformity and its reconstruction in conjunction with the deltoid ligament has been proposed to restore the tibiotalar and talonavicular joint stability. The aim of the present study is to determine the effect of spring ligament injury and subsequent reconstruction on static joint reactive force using a non-invasive method of measurement. METHODS: Ten fresh-frozen human cadaveric lower legs were disarticulated at the knee joint. Static joint reactive force of the tibiotalar and talonavicular joint were measured at baseline, after spring ligament injury, and after ligament reconstruction. Reconstruction consisted of a forked semitendinosis allograft with dual limbs to reconstruct the tibionavicular and tibiocalcaneal ligaments. FINDINGS: The mean baseline joint reactive force of the tibiotalar and talonavicular joints were 37.2 N + 8.1 N and 13.4 N + 4.2 N, respectively. The spring ligament injury model resulted in a significant 29% decrease in tibiotalar joint reactive force. Reconstruction of the tibionavicular limb resulted in a significant increase in tibiotalar and talonavicular joint reactive force compared to those seen in the injury state. Furthermore, the addition of the tibiocalcaneal limb significantly increased tibiotalar joint reactive force compared to those results obtained from the injury state and the tibionavicular limb alone. INTERPRETATION: This is the first study to demonstrate diminished tibiotalar static joint reactive force in a spring ligament injury model with subsequent joint reactive force restoration using two-limbed reconstruction of the deltoid and spring ligament. LEVEL OF EVIDENCE: Biomechanical Study.

Patient-Specific 3-Dimensional Modeling and Its Use for Preoperative Counseling of Patients Undergoing Hip Arthroscopy.

BACKGROUND: Femoroacetabular impingement (FAI) represents complex alterations in the bony morphology of the proximal femur and acetabulum. Imaging studies have become crucial in diagnosis and treatment planning for symptomatic FAI but also have limited patient understanding and satisfaction. Exploration of alternative patient counseling modalities holds promise for improved patient understanding, satisfaction, and ultimately for outcomes. PURPOSE: To compare perceived understanding of functional anatomy and FAI pathomorphology among patients counseled with routine computed tomography (CT), generic hip models, and a 3-dimensional (3D) model printed in accordance with a patient's specific anatomy. STUDY DESIGN: Cohort study; Level of evidence, 2. METHODS: A prospective randomized analysis of patients presenting with radiographically confirmed FAI was conducted between November 2015 and April 2017. Patients were randomized into groups that received preoperative counseling with CT imaging alone, a generic human hip model, or a haptic 3D model of their hip. All groups were subjected to a novel questionnaire examining patient satisfaction and understanding on a variety of topics related to FAI. Data were compared with bivariate and multivariate analyses. Statistical significance was determined as P < .05. RESULTS: Thirty-one patients were included in this study (25 men, 6 women). Ten patients were randomized to the CT-only group, 11 to the generic hip model group, and 10 to receive custom 3D-printed models of their hips. Patients preoperatively counseled with isolated CT imaging or a generic hip model reported greater understanding of their pathophysiology and the role of surgical intervention when compared with those counseled with haptic 3D models (P = .03). At final follow-up, patients counseled with the use of isolated CT imaging or haptic 3D models reported greater increases and retention of understanding as compared with those counseled with generic hip models alone (P = .03). CONCLUSION: Preoperative counseling with haptic 3D hip models does not appear to favorably affect patient-reported understanding or satisfaction with regard to FAI when compared with the use of CT imaging alone. Continued research into alternative counseling means may serve to further improve patient understanding and satisfaction on this complex anatomic phenomenon.

Validity of QuickDASH at day of surgery versus day of initial consultation: Does informed consent make a difference?

INTRODUCTION: The trend toward requiring explicit consent from patients participating in observational research increases time and resources required to perform such research. Informed consent introduces the potential for "consent bias"-either through selection bias or through the "Hawthorne effect," where patients may alter responses based upon the awareness of participation in a study, thus potentially limiting its applicability to a generalized orthopedic practice. We hypothesized that administering Quick Disabilities of the Arm, Shoulder, and Hand Questionnaire (QuickDASH) to patients on the day of surgery with informed consent would alter responses in a statistically and clinically meaningful way compared to patients who complete QuickDASH as a quality control measure. METHODS: We previously instituted the QuickDASH questionnaire as the standard new patient intake and postoperative questionnaire for quality assurance purposes. We retrospectively reviewed data on a cohort of patients who underwent isolated carpal tunnel release (CTR) who had completed preoperative and postoperative QuickDASH forms without providing consent for study participation. Next, a cohort of patients scheduled to undergo isolated CTR who completed the intake questionnaire was approached on the day of surgery for consent to participate in the study. After obtaining consent but prior to surgery, these patients completed a second questionnaire and then completed a postoperative questionnaire on follow-up at a mean of 8 weeks postoperatively. RESULTS: Thirty-nine patients and 35 patients were included in the retrospective and prospective cohorts, respectively. No significant differences were observed in age, gender, symptom duration, nerve conduction study/electromyography results, or disease severity between the two groups. We identified no statistically significant difference in preoperative or postoperative QuickDASH score between the retrospective and prospective cohorts (39.8 ± 22.7 vs. 39.7 ± 19.1 preoperatively; 27.3 ± 24.7 vs. 18.7 ± 13.3 postoperatively) or within the prospective cohort before and after obtaining informed consent. CONCLUSION: Informed consent did not significantly alter patient responses to the QuickDASH questionnaire. These results suggest that both "opt-in" and "opt-out" approaches to observational research in hand surgery provide results that may be applicable to a generalized orthopedic practice. CLINICAL RELEVANCE: This study provides evidence that will inform the interpretation of observational research findings in hand surgery.