Percutaneous auricular neuromodulation (nerve stimulation) for the treatment of pain following total knee arthroplasty: a randomized, double-masked, sham-controlled pilot study.

BACKGROUND: Percutaneous auricular nerve stimulation (neuromodulation) is an analgesic technique involving the percutaneous implantation of multiple leads at various points on/around the ear followed by the delivery of electric current using an external pulse generator. A device is currently available within the USA cleared to treat symptoms from opioid withdrawal, and multiple reports suggest a possible postoperative analgesic effect. The current randomized, controlled pilot study was undertaken to (1) determine the feasibility and optimize the protocol for a subsequent definitive clinical trial and (2) estimate the treatment effect of auricular neuromodulation on postoperative pain and opioid consumption following total knee arthroplasty. METHODS: Within the recovery room following primary, unilateral, total knee arthroplasty, an auricular neuromodulation device (NSS-2 Bridge, Masimo, Irvine, California, USA) was applied using three percutaneous leads and one ground electrode. Participants were randomized to 5 days of either electrical stimulation or sham stimulation in a double-masked fashion. Participants were discharged with the stimulator in situ and removed the disposable devices at home. The dual primary treatment effect outcome measures were the cumulative opioid use (oral oxycodone) and the mean of the "average" daily pain measured with the Numeric Rating Scale for the first 5 postoperative days. RESULTS: During the first five postoperative days, oxycodone consumption in participants given active stimulation (n=15) was a median (IQR) of 4 mg (2-12) vs 13 mg (5-23) in patients given sham (n=15) treatment (p=0.039). During this same period, the average pain intensity in patients given active stimulation was a median (IQR) of 2.5 (1.5-3.3) vs 4.0 (3.6-4.8) in those given sham (p=0.014). Awakenings due to pain over all eight postoperative nights in participants given active stimulation was a median (IQR) of 5 (3-8) vs 11 (4-14) in those given sham (p<0.001). No device-related localized cutaneous irritation, systemic side effects, or other adverse events were identified. CONCLUSIONS: Percutaneous auricular neuromodulation reduced pain scores and opioid requirements during the initial week after total knee arthroplasty. Given the ease of application as well as the lack of systemic side effects and reported complications, a definitive clinical trial appears warranted. TRIAL REGISTRATION NUMBER: NCT05521516.

Percutaneous Auricular Nerve Stimulation (Neuromodulation) for Analgesia and Opioid-Sparing Following Knee and Hip Arthroplasty: A Proof-of-Concept Case Series.

We present a case series to demonstrate proof-of-concept for the off-label use of an auricular neuromodulation device-originally developed to treat symptoms associated with opioid withdrawal-to instead provide analgesia and opioid-sparing following knee and hip arthroplasties. Within the recovery room, an auricular neuromodulation device (near-field stimulator system 2 [NSS-2] Bridge, Masimo) was applied to 5 patients. Average daily pain at rest and while moving was a median of 0 to 2 as measured on the 0 to 10 numeric rating scale, while median daily oxycodone use was 0 to 2.5 mg until device removal at home on postoperative day 5. One patient avoided opioid use entirely.

A Randomized Controlled Pilot Study Using Ultrasound-Guided Percutaneous Cryoneurolysis of the Infrapatellar Branch of the Saphenous Nerve for Analgesia Following Total Knee Arthroplasty.

INTRODUCTION: Total knee arthroplasty (TKA) is frequently associated with severe, prolonged postsurgical pain, and therefore local anesthetic-based peripheral nerve blocks are commonly used for postoperative analgesia. Cryoneurolysis involves the use of freezing temperatures to provide a reversible sensory (and motor) block with a duration measured in weeks and months, more commensurate with the typical period of post-TKA pain. We therefore conducted a randomized controlled pilot study to evaluate the use of this modality for the treatment of pain following TKA to (1) determine the feasibility of and optimize the study protocol for a subsequent definitive clinical trial; and (2) estimate analgesia and opioid reduction within the first 3 postoperative weeks. METHODS: A convenience sample of 16 patients undergoing primary TKA with a single-injection and/or continuous adductor canal nerve block were randomized to receive either active cryoneurolysis or a sham procedure targeting the infrapatellar branch of the saphenous nerve, in a participant-masked fashion. This was a pilot study with a relatively small number of participants, and therefore resulting data were not analyzed statistically. RESULTS: Compared with participants receiving sham, the active treatment group reported slightly lower average and worst pain scores as well as opioid consumption and sleep disturbances due to pain at a majority of postoperative time points between postoperative days (POD) 4-21. CONCLUSIONS: Preoperative ultrasound-guided cryoneurolysis of the infrapatellar branch of the saphenous nerve is feasible and may provide analgesic benefits for multiple weeks following TKA. A definitive randomized controlled trial appears warranted.

Percutaneous auricular nerve stimulation (neuromodulation) for the treatment of pain: A proof-of-concept case report using total joint arthroplasty as a surrogate for battlefield trauma.

BACKGROUND: There are few effective pain treatments following trauma on the battlefield other than opioids, which are limited by respiratory depression. Ultrasound-guided percutaneous peripheral nerve stimulation ("neuromodulation") has been proposed as an analgesic, but requires physician-level skills, advanced equipment, and an hour to administer. In contrast, percutaneous auricular neuromodulation may be placed by a medic in the field under nonsterile conditions in a few minutes, theoretically provides analgesia for any anatomic location, has no side effects, and no significant risks. It therefore offers the potential to be applied quickly on the battlefield without any of the limitations of opioids. We propose total joint replacement as a surrogate for battlefield trauma and here present a case report to demonstrate proof of concept. METHODS: Following open total knee or hip arthroplasty under spinal anesthesia, two patients had an auricular neuromodulation device applied within the recovery room. Patients were discharged with the unit and contacted daily for 7 days. RESULTS: The devices were each applied in under 3 minutes without difficulty, were well tolerated during use, and removed without complication at home on Day 5. During use, neither patient experienced pain while lying, sitting, or ambulating. Neither required analgesics other than scheduled celecoxib; and a single tablet (50 mg) of tramadol for one patient on postoperative Days 3 and 4 for pain while lowering herself to a seated position. On Days 6 and 7, both patients experienced an increase in pain, one of whom required around-the-clock tramadol. CONCLUSION: Ambulatory postoperative percutaneous auricular neuromodulation is feasible. In these two cases, it appears to have markedly reduced pain scores and opioid requirements free of systemic side effects during the week following major orthopedic surgery. Considering the potential of this modality to treat trauma on the battlefield without systemic side effects, additional investigation appears warranted. LEVEL OF EVIDENCE: Therapeutic/care management; Level V.

Acetabular Bone Marrow Aspiration During Total Hip Arthroplasty.

Biologically augmented surgical treatments of orthopaedic conditions are increasingly popular. Bone marrow aspirate concentrate is a key orthobiologic tissue source, and the field is moving from the standard iliac crest marrow aspiration toward local aspirations of marrow depots that are accessible during the standard-of-care procedures in an attempt to reduce morbidity, surgery time, and cost. Here, we present the aspiration of the standard iliac marrow depot, but through a novel acetabular approach during total hip arthroplasty. This procedure markedly simplifies biologic augmentation with bone marrow aspirate concentrate in this large patient cohort.

Strategies to Identify Mesenchymal Stromal Cells in Minimally Manipulated Human Bone Marrow Aspirate Concentrate Lack Consensus.

BACKGROUND: There is a need to identify and quantify mesenchymal stromal cells (MSCs) in human bone marrow aspirate concentrate (BMAC) source tissues, but current methods to do so were established in cultured cell populations. Given that surface marker and gene expression change in cultured cells, it is doubtful that these strategies are valid to quantify MSCs in fresh BMAC. PURPOSE: To establish the presence, quantity, and heterogeneity of BMAC-derived MSCs in minimally manipulated BMAC using currently available strategies. STUDY DESIGN: Descriptive laboratory study. METHODS: Five published strategies to identify MSCs were compared for suitability and efficiency to quantify clinical-grade BMAC-MSCs and cultured MSCs at the single cell transcriptome level on BMAC samples being used clinically from 15 orthopaedic patients and on 1 cultured MSC sample. Strategies included (1) the guidelines by the International Society for Cellular Therapy (ISCT), (2) CD271 expression, (3) the Ghazanfari et al transcriptional profile, (4) the Jia et al transcriptional profile, and (5) the Silva et al transcriptional profile. RESULTS: ISCT guidelines did not identify any MSCs in BMAC at the transcriptional level and only 1 in 9 million cells at the protein level. Of 12,850 BMAC cells, 9 expressed the CD271 gene. Only 116 of 396 Ghazanfari genes were detected in BMAC, whereas no cells expressed all of them. No cells expressed all Jia genes, but 25 cells expressed at least 13 of 22. No cells expressed all Silva genes, but 19 cells expressed at least 8 of 23. Most importantly, the liberalized strategies tended to identify different cells and most of them clustered with immune cells. CONCLUSION: Currently available methods need to be liberalized to identify any MSCs in fresh human BMAC and lack consensus at the single cell transcriptome and protein expression levels. These different cells should be isolated and challenged to establish phenotypic differences. CLINICAL RELEVANCE: This study demonstrated that improved strategies to quantify MSC concentrations in BMAC for clinical applications are urgently needed. Until then, injected minimally manipulated MSC doses should be reported as rough estimates or as unknown.

Surgical site peptidylarginine deaminase 4 (PAD4), a biomarker of NETosis, correlates with insulin resistance in total joint arthroplasty patients: A preliminary report.

While obesity and insulin resistance are known risk factors for wound complications after total joint arthroplasty (TJA), the biologic causes remain to be elucidated. Recently, neutrophil extracellular trap formation (NETosis) was identified as a mediator of delayed wound healing in insulin resistant states. Herein, we explored the relationship between obesity, insulin resistance and biomarkers of NET formation in TJA subjects. We enrolled 14 obese (body mass index [BMI]≥30 kg/m2), and 15 lean (BMI<30 kg/m2) subjects undergoing primary knee or hip TJA. On the day of surgery, skeletal muscle proximal to the operated joint and plasma were collected. Protein abundance of NETosis biomarkers, peptidylarginine deaminase 4 (PAD4) and neutrophil elastase (NE) were assessed in skeletal muscle by immunoblotting and metabolic parameters (glucose, insulin, triglycerides, free fatty acids) and cell-free double-stranded DNA (cf-dsDNA) were assessed in plasma and were correlated with obesity and insulin resistance (as measured by the homeostatic model assessment for insulin resistance). When comparing lean and obese subjects, there were no significant differences in plasma cf-dsDNA or skeletal muscle NE or PAD4 abundance. In contrast, skeletal muscle PAD4 abundance, but not NE or plasma cf-dsDNA, was positively correlated with insulin resistance. Compared to insulin sensitive subjects, insulin resistant TJA subjects have higher expression of PAD4 at the surgical site and therefore may have higher rates of NET formation, which may lead to delayed surgical site wound healing.

Metabolic Syndrome Is Associated With Higher Risk of Wound Complications After Total Hip Arthroplasty.

BACKGROUND: Obesity is prevalent among patients undergoing total hip arthroplasty and has been associated with the risk of wound complications, particularly when an anterior approach is used. However, most studies have focused on obesity defined by the body mass index (BMI), without considering the metabolic effects of adiposity. Thus, in this study, we investigated the independent effects of the BMI and metabolic syndrome on wound complications after total hip arthroplasty. METHODS: Among 804 consecutive patients undergoing total hip arthroplasty between October 2013 and July 2016, we evaluated the associations between obesity (BMI ≥30 mg/kg2), metabolic syndrome (defined by the National Cholesterol Education Program Adult Treatment Panel III guidelines), and wound complication (defined as documented wound dehiscence, drainage, erythema, hematoma, infection, or seroma) over a 1-year follow-up period. We used Cox proportional hazards models adjusting for demographics, smoking status, and hospital length of stay. RESULTS: Patients' mean age at time of surgery was 62.0 ± 11.9 years. Forty-seven percent were male, 27.9% were obese, and 11.6% met the definition for metabolic syndrome. Metabolic syndrome was associated with a 4-fold higher risk of wound complication (95% confidence interval: 1.4-11.1) after adjusting for all covariates including the BMI. In unadjusted analysis, obesity was associated with a higher risk of wound complication (hazard ratio: 2.8, 95% confidence interval: 1.3-6.2). However, obesity was not associated with the risk of wound complication after adjusting for the metabolic syndrome (P = .16). CONCLUSIONS: Metabolic syndrome, but not obesity, defined by a BMI ≥30, was associated with wound complications, suggesting that metabolic effects of adiposity may represent a distinct risk factor in the development of wound complications from a higher BMI alone.

Ultrashort echo time quantitative susceptibility mapping (UTE-QSM) for detection of hemosiderin deposition in hemophilic arthropathy: A feasibility study.

PURPOSE: The purpose of this study was to investigate the feasibility of ultrashort echo time quantitative susceptibility mapping (UTE-QSM) for assessment of hemosiderin deposition in the joints of hemophilic patients. METHODS: The UTE-QSM technique was based on three sets of dual-echo 3D UTE Cones data acquired with TEs of 0.032/2.8, 0.2/3.6, and 0.4/4.4 ms. The images were processed with iterative decomposition of water and fat with echo asymmetry and least-squares estimation to estimate the B0 field map in the presence of fat. Then, the projection onto dipole field (PDF) algorithm was applied to acquire a local field map generated by tissues, followed by application of the morphology-enabled dipole inversion (MEDI) algorithm to estimate a final susceptibility map. Three healthy volunteers and three hemophilic patients were recruited to evaluate the UTE-QSM technique's ability to assess hemosiderin in the knee or ankle joint at 3T. One patient subsequently underwent total knee arthroplasty after the MR scan. The synovial tissues harvested from the knee joint during surgery were processed for histological analysis to confirm iron deposition. RESULTS: UTE-QSM successfully yielded tissue susceptibility maps of joints in both volunteers and patients. Multiple regions with high susceptibility over 1 ppm were detected in the affected joints of hemophilic patients, while no localized regions with high susceptibility were detected in asymptomatic healthy volunteers. Histology confirmed the presence of iron in regions where high susceptibility was detected by UTE-QSM. CONCLUSION: The UTE-QSM technique can detect hemosiderin deposition in the joint, and provides a potential sensitive biomarker for the diagnosis and prognosis of hemophilic arthropathy.

Architecture of the Short External Rotator Muscles of the Hip.

BACKGROUND: Muscle architecture, or the arrangement of sarcomeres and fibers within muscles, defines functional capacity. There are limited data that provide an understanding of hip short external rotator muscle architecture. The purpose of this study was thus to characterize the architecture of these small hip muscles. METHODS: Eight muscles from 10 independent human cadaver hips were used in this study (n = 80 muscles). Architectural measurements were made on pectineus, piriformis, gemelli, obturators, quadratus femoris, and gluteus minimus. Muscle mass, fiber length, sarcomere length, and pennation angle were used to calculate the normalized muscle fiber length, which defines excursion, and physiological cross-sectional area (PCSA), which defines force-producing capacity. RESULTS: Gluteus minimus had the largest PCSA (8.29 cm2) followed by obturator externus (4.54 cm2), whereas superior gemellus had the smallest PCSA (0.68 cm2). Fiber lengths clustered into long (pectineus - 10.38 cm and gluteus minimus - 10.30 cm), moderate (obturator internus - 8.77 cm and externus - 8.04 cm), or short (inferior gemellus - 5.64 and superior gemellus - 4.85). There were no significant differences among muscles in pennation angle which were all nearly zero. When the gemelli and obturators were considered as a single functional unit, their collective PCSA (10.00 cm2) exceeded that of gluteus minimus as a substantial force-producing group. CONCLUSIONS: The key findings are that these muscles have relatively small individual PCSAs, short fiber lengths, and low pennation angles. The large collective PCSA and short fiber lengths of the gemelli and obturators suggest that they primarily play a stabilizing role rather than a joint rotating role.

Percutaneous Peripheral Nerve Stimulation to Control Postoperative Pain, Decrease Opioid Use, and Accelerate Functional Recovery Following Orthopedic Trauma.

Orthopedic trauma is a significant military problem, causing several of the most disabling conditions with high rates of separation from duty and erosion of military readiness. The objective of this report is to summarize the findings of case series of a non-opioid therapy-percutaneous peripheral nerve stimulation (PNS) - and describe its potential for postoperative analgesia, early opioid cessation, and improved function following orthopedic trauma. Percutaneous PNS has been evaluated for the treatment of multiple types of pain, including two case series on postoperative pain following total knee replacement (n = 10 and 8, respectively) and a case series on postamputation pain (n = 9). The orthopedic trauma induced during TKR is highly representative of multiple types of orthopedic trauma sustained by Service members and frequently produces intense, prolonged postoperative pain and extended opioid use following surgery. Collectively, the results of these three clinical studies demonstrated that percutaneous PNS can provide substantial pain relief, reduce opioid use, and improve function. These outcomes suggest that there is substantial potential for the use of percutaneous PNS following orthopedic trauma.

A Feasibility Study of Percutaneous Peripheral Nerve Stimulation for the Treatment of Postoperative Pain Following Total Knee Arthroplasty.

INTRODUCTION: The objective of the present feasibility study was to investigate the use of a new treatment modality-percutaneous peripheral nerve stimulation (PNS)-in controlling the often severe and long-lasting pain following total knee arthroplasty (TKA). METHODS: For patients undergoing a primary, unilateral TKA, both femoral and sciatic open-coil percutaneous leads (SPR Therapeutics, Cleveland, OH) were placed up to seven days prior to surgery using ultrasound guidance. The leads were connected to external stimulators and used both at home and in the hospital for up to six weeks total. RESULTS: In six of seven subjects (86%), the average of daily pain scores across the first two weeks was <4 on the 0-10 Numeric Rating Scale for pain. A majority of subjects (four out of seven; 57%) had ceased opioid use within the first week (median time to opioid cessation for all subjects was six days). Gross sensory/motor function was maintained during stimulation, enabling stimulation during physical therapy and activities of daily living. At 12 weeks following surgery, six of seven subjects had improved by >10% on the Six-Minute Walk Test compared to preoperative levels, and WOMAC scores improved by an average of 85% compared to before surgery. No falls, motor block, or lead infections were reported. CONCLUSIONS: This feasibility study suggests that for TKA, ultrasound-guided percutaneous PNS is feasible in the immediate perioperative period and may provide analgesia without the undesirable systemic effects of opioids or quadriceps weakness induced by local anesthetics-based peripheral nerve blocks.

Proximal Versus Distal Continuous Adductor Canal Blocks: Does Varying Perineural Catheter Location Influence Analgesia? A Randomized, Subject-Masked, Controlled Clinical Trial.

BACKGROUND: A continuous adductor canal block provides analgesia after surgical procedures of the knee. Recent neuroanatomic descriptions of the thigh and knee led us to speculate that local anesthetic deposited in the distal thigh close to the adductor hiatus would provide superior analgesia compared to a more proximal catheter location. We therefore tested the hypothesis that during a continuous adductor canal nerve block, postoperative analgesia would be improved by placing the perineural catheter tip 2-3 cm cephalad to where the femoral artery descends posteriorly to the adductor hiatus (distal location) compared to a more proximal location at the midpoint between the anterior superior iliac spine and the superior border of the patella (proximal location). METHODS: Preoperatively, subjects undergoing total knee arthroplasty received an ultrasound-guided perineural catheter inserted either in the proximal or distal location within the adductor canal in a randomized, subject-masked fashion. Subjects received a single injection of lidocaine 2% via the catheter preoperatively, followed by an infusion of ropivacaine 0.2% (8 mL/h basal, 4 mL bolus, 30 minutes lockout) for the study duration. After joint closure, the surgeon infiltrated the entire joint using 30 mL of ropivacaine (0.5%), ketorolac (30 mg), epinephrine (5 µg/mL), and tranexamic acid (2 g). The primary end point was the median level of pain as measured on a numeric rating scale (NRS) during the time period of 8:00 AM to 12:00 PM the day after surgery. RESULTS: For the primary end point, the NRS of subjects with a catheter inserted at the proximal location (n = 24) was a median (10th, 25th-75th, 90th quartiles) of 0.5 (0.0, 0.0-3.2, 5.0) vs 3.0 (0.0, 2.0-5.4, 7.8) for subjects with a catheter inserted in the distal location (n = 26; P = .011). Median and maximum NRSs were lower in the proximal group at all other time points, but these differences did not reach statistical significance. There were no clinically relevant or statistically significant differences between the treatment groups for any other secondary end point, including opioid consumption and ambulation distance. CONCLUSIONS: For continuous adductor canal blocks accompanied by intraoperative periarticular local anesthetic infiltration, analgesia the day after knee arthroplasty is improved with a catheter inserted at the level of the midpoint between the anterior superior iliac spine and the superior border of the patella compared with a more distal insertion closer to the adductor hiatus.

Fall Risk Associated with Continuous Peripheral Nerve Blocks Following Knee and Hip Arthroplasty.

Combined scientific advances in pharmaceutical agents, perineural blocks, and pump delivery capabilities such as those used with continuous peripheral nerve blocks have demonstrated advantages in pain management for patients undergoing joint arthroplasty. This report documents the incidence of falls increased after the implementation of a continuous peripheral nerve block program for patients undergoing knee and hip arthroplasty in an academic medical center.

Vascular remodeling underlies rebleeding in hemophilic arthropathy.

Hemophilic arthropathy is a debilitating condition that can develop as a consequence of frequent joint bleeding despite adequate clotting factor replacement. The mechanisms leading to repeated spontaneous bleeding are unknown. We investigated synovial, vascular, stromal, and cartilage changes in response to a single induced hemarthrosis in the FVIII-deficient mouse. We found soft-tissue hyperproliferation with marked induction of neoangiogenesis and evolving abnormal vascular architecture. While soft-tissue changes were rapidly reversible, abnormal vascularity persisted for months and, surprisingly, was also seen in uninjured joints. Vascular changes in FVIII-deficient mice involved pronounced remodeling with expression of α-Smooth Muscle Actin (SMA), Endoglin (CD105), and vascular endothelial growth factor, as well as alterations of joint perfusion as determined by in vivo imaging. Vascular architecture changes and pronounced expression of α-SMA appeared unique to hemophilia, as these were not found in joint tissue obtained from mouse models of rheumatoid arthritis and osteoarthritis and from patients with the same conditions. Evidence that vascular changes in hemophilia were significantly associated with bleeding and joint deterioration was obtained prospectively by dynamic in vivo imaging with musculoskeletal ultrasound and power Doppler of 156 joints (elbows, knees, and ankles) in a cohort of 26 patients with hemophilia at baseline and during painful episodes. These observations support the hypothesis that vascular remodeling contributes significantly to bleed propagation and development of hemophilic arthropathy. Based on these findings, the development of molecular targets for angiogenesis inhibition may be considered in this disease.

Continuous Adductor Canal Versus Continuous Femoral Nerve Blocks: Relative Effects on Discharge Readiness Following Unicompartment Knee Arthroplasty.

BACKGROUND: We tested the hypothesis that, following unicompartment knee arthroplasty, a continuous adductor canal block decreases the time to reach 4 discharge criteria compared with a continuous femoral nerve block. METHODS: Subjects were randomized to either an adductor canal or femoral perineural catheter (2-day ropivacaine 0.2% infusion) in an unmasked fashion. The primary outcome was the time to attain 4 discharge criteria: (1) adequate analgesia; (2) intravenous opioid independence; (3) ability to independently stand, walk 3 m, return, and sit down; and (4) ambulate 30 m. RESULTS: Subjects with an adductor canal catheter (n = 15) reached all 4 criteria in a median of 35 hours (interquartile range, 24-43 hours), compared with 40 hours (interquartile range, 27-69 hours) for those with a femoral catheter (n = 15; Wilcoxon rank sum test: P = 0.46; log-rank test: P = 0.16). However, the percentages of subjects (adductor canal: femoral) who reached the 2 mobilization criteria were 27%:0% on postoperative day (POD) 0, 93%:53% on POD 1, and 100%:73% on POD 2. Of adductor canal subjects, 100% were discharge ready by POD 2, compared with only 73% of femoral subjects (P < 0.001). CONCLUSIONS: Compared with a continuous femoral nerve block, a continuous adductor canal block did not appreciably decrease the median number of hours to overall discharge readiness, yet did decrease the number of discrete days until discharge readiness. These results are applicable to only unicompartment knee arthroplasty and must be considered preliminary because of the limited sample size of this pilot study.

Discharge Readiness after Tricompartment Knee Arthroplasty: Adductor Canal versus Femoral Continuous Nerve Blocks-A Dual-center, Randomized Trial.

BACKGROUND: The authors conducted a randomized, controlled, parallel-arm, superiority study to test the hypothesis that a continuous adductor canal block decreases the time to attain four discharge criteria compared with a continuous femoral nerve block after tricompartment knee arthroplasty. METHODS: Subjects undergoing tricompartment knee arthroplasty were randomized using computer-generated lists to either an adductor canal or femoral perineural catheter (3-day ropivacaine 0.2% infusion) in an unmasked manner. The primary outcome was the time to attain four criteria: (1) adequate analgesia; (2) intravenous opioids independence; (3) ability to stand, walk 3 m, return, and sit down; and (4) ambulate 30 m. RESULTS: Subjects with an adductor canal catheter (n = 39) reached all four criteria in a median of 55 h (interquartile, 42 to 63 h) compared with 61 h (49 to 69 h) for those with a femoral catheter (n = 41; 95% CI, -13 to 1 h; P = 0.12). The percentage of subjects who reached the two mobilization criteria on postoperative days 1 and 2 were 72 and 95% for those with an adductor canal catheter (n = 39), but only 27 and 76% in subjects with a femoral catheter (n = 41; both P < 0.001). Differences in pain scores at rest and intravenous opioid requirements were minimal, but femoral infusion improved dynamic analgesia (P = 0.01 to 0.02). CONCLUSION: Compared with a continuous femoral nerve block, a continuous adductor canal block did not appreciably decrease the time to overall discharge readiness even though it did decrease the time until adequate mobilization, primarily because both groups experienced similar analgesia and intravenous opioid requirements that--in most cases--exceeded the time to mobilization.

Integrative omics analysis of rheumatoid arthritis identifies non-obvious therapeutic targets.

Identifying novel therapeutic targets for the treatment of disease is challenging. To this end, we developed a genome-wide approach of candidate gene prioritization. We independently collocated sets of genes that were implicated in rheumatoid arthritis (RA) pathogenicity through three genome-wide assays: (i) genome-wide association studies (GWAS), (ii) differentially expression in RA fibroblast-like synoviocytes (FLS), and (iii) differentially methylation in RA FLS. Integrated analysis of these complementary data sets identified a significant enrichment of multi-evidence genes (MEGs) within pathways relating to RA pathogenicity. One MEG is Engulfment and Cell Motility Protein-1 (ELMO1), a gene not previously considered as a therapeutic target in RA FLS. We demonstrated in RA FLS that ELMO1 is: (i) expressed, (ii) promotes cell migration and invasion, and (iii) regulates Rac1 activity. Thus, we created links between ELMO1 and RA pathogenicity, which in turn validates ELMO1 as a potential RA therapeutic target. This study illustrated the power of MEG-based approaches for therapeutic target identification.