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Background: Anterior cruciate ligament (ACL) reconstruction (ACLR) has higher failure rates in young active patients returning to sports as compared with older, less active individuals. Augmentation of ACLR with an anterolateral procedure has been shown to reduce failure rates; however, indications for this procedure have yet to be clearly defined. Purpose/Hypothesis: The purpose of this study was to identify predictors of ACL graft failure in high-risk patients and determine key indications for when hamstring ACLR should be augmented by a lateral extra-articular tenodesis (LET). We hypothesized that different preoperative characteristics and surgical variables may be associated with graft failure characterized by asymmetric pivot shift and graft rupture. Study Design: Case-control study; Level of evidence, 3. Methods: Data were obtained from the Stability 1 Study, a multicenter randomized controlled trial of young active patients undergoing autologous hamstring ACLR with or without a LET. We performed 2 multivariable logistic regression analyses, with asymmetric pivot shift and graft rupture as the dependent variables. The following were included as predictors: LET, age, sex, graft diameter, tear chronicity, preoperative high-grade knee laxity, preoperative hyperextension on the contralateral side, medial meniscal repair/excision, lateral meniscal repair/excision, posterior tibial slope angle, and return-to-sports exposure time and level. Results: Of the 618 patients in the Stability 1 Study, 568 with a mean age of 18.8 years (292 female; 51.4%) were included in this analysis. Asymmetric pivot shift occurred in 152 (26.8%) and graft rupture in 43 (7.6%). The addition of a LET (odds ratio [OR], 0.56; 95% CI, 0.37-0.83) and increased graft diameter (OR, 0.62; 95% CI, 0.44-0.87) were significantly associated with lower odds of asymmetric pivot shift. The addition of a LET (OR, 0.40; 95% CI, 0.18-0.91) and older age (OR, 0.83; 95% CI, 0.72-0.96) significantly reduced the odds of graft rupture, while greater tibial slope (OR, 1.15; 95% CI, 1.01-1.32), preoperative high-grade knee laxity (OR, 3.27; 95% CI, 1.45-7.41), and greater exposure time to sport (ie, earlier return to sport) (OR, 1.18; 95% CI, 1.08-1.29) were significantly associated with greater odds of rupture. Conclusion: The addition of a LET and larger graft diameter were significantly associated with reduced odds of asymmetric pivot shift. Adding a LET was protective of graft rupture, while younger age, greater posterior tibial slope, high-grade knee laxity, and earlier return to sport were associated with increased odds of graft rupture. Orthopaedic surgeons should consider supplementing hamstring autograft ACLR with a LET in young active patients with morphological characteristics that make them at high risk of reinjury.

Background: Anterior cruciate ligament (ACL) reconstructions (ACLRs) with graft diameters Purpose: To investigate the differences in clinical outcomes between 4-strand (4S) and 5S hamstring autografts for ACLR in patients who underwent ACLR alone or concomitantly with a lateral extra-articular tenodesis (LET) procedure. Study Design: Cohort study; Level of evidence, 2. Methods: Data from the STABILITY study were analyzed to compare a subgroup of patients undergoing ACLR alone or with a concomitant LET procedure (ACLR + LET) with a minimum graft diameter of 8mm that had either a 4S or 5S hamstring autograft configuration. The primary outcome was clinical failure, a composite of rotatory laxity and/or graft failure. The secondary outcome measures consisted of 2 patient-reported outcome scores (PROs)—namely, the ACL Quality of Life Questionnaire (ACL-QoL) and the International Knee Documentation Committee (IKDC) score at 24 months postoperatively. Results: Of the 618 patients randomized in the STABILITY study, 399 (228 male; 57%) fit the inclusion criteria for this study. Of these, 191 and 208 patients underwent 4S and 5S configurations of hamstring ACLR, respectively, with a minimum graft diameter of 8mm. Both groups had similar characteristics other than differences in anthropometric factors—namely, sex, height, and weight, and Beighton scores. The primary outcomes revealed no difference between the 2 groups in rotatory stability (odds ratio [OR], 1.19; 95% CI, 0.77-1.84; P = .42) or graft failure (OR, 1.13; 95% CI, 0.51-2.50; P = .76). There was no significant difference between the groups in Lachman ( P = .46) and pivot-shift ( P = .53) test results at 24 months postoperatively. The secondary outcomes revealed no differences in the ACL-QoL ( P = .67) and IKDC ( P = .83) scores between the 2 subgroups. Conclusion: At the 24-month follow-up, there were no significant differences in clinical failure rates and PROs in an analysis of patients with 4S and 5S hamstring autografts of ≥8mm diameter for ACLR or ACLR + LET. The 5S hamstring graft configuration is a viable option to produce larger-diameter ACL grafts.

Mast cells contain an abundance of tryptase, and preclinical models have shown elevated serum mast cell tryptase (SMCT) in the setting of posttraumatic joint contractures. Therefore, SMCT emerged as a potential biomarker to help recognize patients with more severe injuries and a higher likelihood of developing contractures. The objective of this study is to assess SMCT levels in participants with varying severity of elbow fractures and/or dislocations. A prospective cohort including 13 participants with more severe injuries that required an operation and 28 participants with less severe injuries managed nonoperatively were evaluated. A control group of eight individuals without elbow injuries was also evaluated. The SMCT levels were measured using an enzyme-linked immunosorbent assay kit specific for human mast cell tryptase. A one-way analysis of variance and Tukey's Honest Significance test was used to assess for statistical significance among and between the three groups. The average time from injury to the collection of the blood samples was 4 ± 2 days. Highly significant differences were identified between the operative, nonoperative, and control groups (P = .0005). In the operative group, SMCT levels were significantly higher than the nonoperative group (P = .0005) and the control group (P = .009), suggesting a correlation between SMCT levels and injury severity. There was no statistically significant difference in SMCT levels between the nonoperative and control groups. The SMCT levels were elevated in participants with acute elbow injuries requiring operative intervention, suggesting that SMCT levels were higher in injuries regarded as more severe.

Objective To assess the use of ketotifen fumarate (KF) to reduce posttraumatic contractures after elbow fractures and/or dislocations. Design Randomized clinical trial. Setting Three hospitals in Calgary, Canada, including one Level 1 trauma center. Participants Adults (n = 151) sustaining operative or nonoperatively managed isolated distal humerus or proximal radius ± ulna fractures or elbow dislocations within 7 days of injury. Interventions KF 5 mg (n = 74) or lactose placebo (PL, n = 77) orally twice daily for 6 weeks. Main outcomes Primary outcome elbow flexion-extension arc range of motion (ROM) at 12 weeks postrandomization. Safety measures including serious adverse events and radiographic fracture line disappearance from 2 to 52 weeks postrandomization. Results The elbow ROM (mean, confidence interval) was not significantly different between KF (122 degrees, 118-127 degrees) and PL (124 degrees, 119-130 degrees) groups (P = 0.56). There was a significant difference in elbow ROM at 12 weeks postrandomization comparing operative (117 degrees, 112-122 degrees) versus nonoperative groups (128 degrees, 124-133 degrees) irrespective of intervention (P = 0.0011). There were 11 serious adverse events (KF = 6, PL = 5) that were those expected in an elbow fracture population potentially taking KF. There was no statistically significant difference in the rates of these events between the groups. The disappearance of fracture lines over the course of time was similar between groups. There was one nonunion in each group. Conclusions In a population of operative and nonoperatively managed elbow fractures and/or dislocations KF did not reduce posttraumatic contractures. The administration of KF in this population was not found to result in a significantly higher number of major adverse events when compared with placebo. Level of evidence Therapeutic Level I. See Instructions for Authors for a complete description of levels of evidence.

Background Injuries and resulting stiffness around joints, especially the elbow, have huge psychological effects by reducing quality of life through interference with normal daily activities such as feeding, dressing, grooming, and reaching for objects. Over the last several years and through numerous research results, the myofibroblast-mast cell-neuropeptide axis of fibrosis had been implicated in post-traumatic joint contractures. Pre-clinical models and a pilot randomized clinical trial (RCT) demonstrated the feasibility and safety of using Ketotifen Fumarate (KF), a mast cell stabilizer to prevent elbow joint contractures. This study aims to evaluate the efficacy of KF in reducing joint contracture severity in adult participants with operately treated elbow fractures and/or dislocations. Methods/design A Phase III randomized, controlled, double-blinded multicentre trial with 3 parallel groups (KF 2 mg or 5 mg or lactose placebo twice daily orally for 6 weeks). The study population consist of adults who are at least 18 years old and within 7 days of injury. The types of injuries are distal humerus (AO/OTA type 13) and/or proximal ulna and/or proximal radius fractures (AO/OTA type 2 U1 and/or 2R1) and/or elbow dislocations (open fractures with or without nerve injury may be included). A stratified randomization scheme by hospital site will be used to assign eligible participants to the groups in a 1:1:1 ratio. The primary outcome is change in elbow flexion-extension range of motion (ROM) arc from baseline to 12 weeks post-randomization. The secondary outcomes are changes in ROM from baseline to 6, 24 & 52 weeks, PROMs at 2, 6, 12, 24 & 52 weeks and impact of KF on safety including serious adverse events and fracture healing. Descriptive analysis for all outcomes will be reported and ANCOVA be used to evaluate the efficacy KF over lactose placebo with respect to the improvement in ROM. Discussion The results of this study will provide evidence for the use of KF in reducing post-traumatic joint contractures and improving quality of life after joint injuries. Trial registration This study was prospectively registered (July 10, 2018) with ClinicalTrials.gov reference: NCT03582176.

Background: Persistent anterolateral rotatory laxity after anterior cruciate ligament (ACL) reconstruction (ACLR) has been correlated with poor clinical outcomes and graft failure. Hypothesis: We hypothesized that a single-bundle, hamstring ACLR in combination with a lateral extra-articular tenodesis (LET) would reduce the risk of ACLR failure in young, active individuals. Study Design: Randomized controlled trial; Level of evidence, 1. Methods: This is a multicenter, prospective, randomized clinical trial comparing a single-bundle, hamstring tendon ACLR with or without LET performed using a strip of iliotibial band. Patients 25 years or younger with an ACL-deficient knee were included and also had to meet at least 2 of the following 3 criteria: (1) grade 2 pivot shift or greater, (2) a desire to return to high-risk/pivoting sports, (3) and generalized ligamentous laxity (GLL). The primary outcome was ACLR clinical failure, a composite measure of rotatory laxity or a graft rupture. Secondary outcome measures included the P4 pain scale, Marx Activity Rating Scale, Knee injury Osteoarthritis and Outcome Score (KOOS), International Knee Documentation Committee score, and ACL Quality of Life Questionnaire. Patients were reviewed at 3, 6, 12, and 24 months postoperatively. Results: A total of 618 patients (297 males; 48%) with a mean age of 18.9 years (range, 14-25 years) were randomized. A total of 436 (87.9%) patients presented preoperatively with high-grade rotatory laxity (grade 2 pivot shift or greater), and 215 (42.1%) were diagnosed as having GLL. There were 18 patients lost to follow-up and 11 who withdrew (~5%). In the ACLR group, 120/298 (40%) patients sustained the primary outcome of clinical failure, compared with 72/291 (25%) in the ACLR+LET group (relative risk reduction [RRR], 0.38; 95% CI, 0.21-0.52; P < .0001). A total of 45 patients experienced graft rupture, 34/298 (11%) in the ACLR group compared with 11/291 (4%) in the ACL+LET group (RRR, 0.67; 95% CI, 0.36-0.83; P < .001). The number needed to treat with LET to prevent 1 patient from graft rupture was 14.3 over the first 2 postoperative years. At 3 months, patients in the ACLR group had less pain as measured by the P4 ( P = .003) and KOOS ( P = .007), with KOOS pain persisting in favor of the ACLR group to 6 months ( P = .02). No clinically important differences in patient-reported outcome measures were found between groups at other time points. The level of sports activity was similar between groups at 2 years after surgery, as measured by the Marx Activity Rating Scale ( P = .11). Conclusion: The addition of LET to a single-bundle hamstring tendon autograft ACLR in young patients at high risk of failure results in a statistically significant, clinically relevant reduction in graft rupture and persistent rotatory laxity at 2 years after surgery. Registration: NCT02018354 ( ClinicalTrials.gov identifier)

OBJECTIVES Mast cells have been identified as key mediators of posttraumatic joint contracture, and stabilizing medications (ketotifen) have been shown to decrease contracture severity. Serum mast cell tryptase (SMCT) levels are used clinically to monitor mast cell-mediated conditions. The goals of this study were to determine if SMCT levels are elevated in the setting of joint contracture, if they can be decreased in association with ketotifen therapy, and if they correlate with contracture severity. METHODS This study used a previously developed rabbit model in which 39 animals were divided into 4 groups: operatively created joint contracture (ORC, n = 13), operatively created contracture treated with ketotifen at 2 doses (KF0.5, n = 9; KF1.0, n = 9), and healthy rabbits (NC, n = 8). Range of motion measures were performed at 8 weeks after the surgery. Serum samples were collected on postoperative days 1, 3, 5, 7, 21, 35, and 49. SMCT levels were measured using a rabbit-specific enzyme-linked immunosorbent assay. RESULTS Levels of SMCT were highest in the operatively created joint contracture group and were significantly greater compared with both ketotifen groups (P < 0.001). Levels were highest at postoperative day 1 with a trend to decrease over time. A positive correlation between SMCT levels and contracture severity was observed in all operative groups (P < 0.05). CONCLUSIONS Levels of SMCT are elevated in the setting of joint contracture, decreased in association with ketotifen therapy, and positively correlated with contracture severity. This is the first study to establish a relationship between SMCT and joint injury. Measurement of SMCT may be valuable in identifying those at risk of posttraumatic joint contracture.

Olfactory dysfunction in neurodegenerative conditions such as Parkinson's syndrome and Alzheimer's disease can hallmark disease onset. We hypothesized that patients with diabetes mellitus, a condition featuring peripheral and central neurodegeneration, would have decreased olfaction abilities. We examined participants with diabetic peripheral neuropathy, participants with diabetes without diabetic peripheral neuropathy, and control participants in blinded fashion using standardized Sniffin' Sticks. Diabetic peripheral neuropathy severity was quantified using the Utah Early Neuropathy Scale. Further subcategorization of diabetic peripheral neuropathy based on presence of neuropathic pain was performed with Douleur Neuropathique 4 Questionnaires. Participants with diabetes had decreased olfactory sensitivity, impaired olfactory discrimination abilities, and reduced odor identification skills when compared with controls. However, loss of olfaction ability was, at least partially, attributed to presence of neuropathic pain on subcategory assessment, although pain severity was not associated with dysfunction. Those participants with diabetes without diabetic peripheral neuropathy and those with diabetic peripheral neuropathy without neuropathic pain had similar olfactory function as controls in general. The presence of neuropathic pain, associated with limited attention and concentration, may explain at least a portion of the olfactory dysfunction witnessed in the diabetic patient population.

Aims Gait dysfunction in subjects with diabetes mellitus (DM) contributes to falling and subsequent injuries. Using a portable device (GaitMeter™), we measured gait parameters in DM patients with and without diabetic peripheral neuropathy (DPN) during flat surface walking. We hypothesized that DM patients with DPN and neuropathic pain (NeP) would have greater gait step variability than those with DPN without NeP. Methods Subjects with DPN and at least moderate NeP (DPN-P), DPN without NeP (DPN-NoP), DM without DPN, and control subjects without DM were assessed. Our outcome measure was gait variability for step length and velocity. DPN severity was quantified using the Toronto Clinical Scoring System and the Utah Early Neuropathy Score. Falls and their outcomes were retrospectively quantified. Results Each cohort contained≥20 subjects. Durations of DM and HbA1C were greatest amongst DPN cohorts. DPN-P participants had greater variability of step length and step velocity, except for DM only participants. DPN-P participants also reported greater risk of hospitalizations for fall-related injuries, and greater fear of falling. Modest negative relationships emerged for step length with step velocity, reported falls and pain severity. Conclusions NeP contributes to gait variability, potentially contributing to the risk of falling in DM patients.

Cannabinoids are emerging as potential options for neuropathic pain treatment. This study evaluated an oral cannabinoid, nabilone, in the treatment of refractory human diabetic peripheral neuropathic pain (DPN). We performed a single-center, randomized, double-blind, placebo-controlled, flexible-dose study with an enriched enrollment randomized withdrawal design. DPN subjects with a pain score ≥ 4 (0-10 scale) continued regular pain medications and were administered single-blinded adjuvant nabilone for 4 weeks. Subjects achieving ≥ 30% pain relief (26/37) were then randomized and treated with either flexible-dose nabilone 1-4 mg/day (n=13) or placebo (n=13) in a further 5-week double-blind treatment period, with 30% (11/37) of subjects deemed run-in-phase nabilone nonresponders. For nabilone run-in-phase responders, there was an improvement in the change in mean end-point neuropathic pain vs placebo (mean treatment reduction of 1.27; 95% confidence interval 2.29-0.25, P=0.02), with an average nabilone dose at end point of 2.9 ± 1.1mg/day, and improvements from baseline for the anxiety subscale of the Hospital Anxiety and Depression Scale, the Medical Outcomes Study sleep scale problems index, and the European Quality of Life-5-Domains index score (each P

BACKGROUND: Chronic pain clinics have been created because of the increasing recognition of chronic pain as a very common, debilitating condition that requires specialized care. Neuropathic pain (NeP) is a multifaceted, specialized form of chronic pain that often requires input from multiple disciplines for assessment and management.OBJECTIVE: To determine the impact of an interdisciplinary clinic for evaluation and treatment of patients with NeP.METHODS: Patients with heterogeneous etiologies for NeP were prospectively evaluated using an interdisciplinary approach every six months. Diagnostic evaluation, comorbidity evaluation, education, and pharmacological and/or nonpharmacological management were completed. Severity (visual analogue scale) and features of pain (Modified Brief Pain Inventory), sleep difficulties (Medical Outcomes Study – Sleep Scale), mood/anxiety disruption (Hospital Anxiety and Depression Scale), quality of life (European Quality-of-Life Five-Domain index), health care resources use, patient satisfaction (Pain Treatment Satisfaction Scale and Neuropathic Pain Symptom Inventory) and self-perceived change in well-being (Patient Global Impression of Change scale) were examined at each visit.RESULTS: Pain severity only decreased after one year of follow-up, while anxiety and quality-of-life indexes improved after six months. Moderate improvements of sleep disturbance, less frequent medication use and reduced health care resource use were observed during enrollment at the NeP clinic.DISCUSSION: Despite the limitations of performing a real-world, uncontrolled study, patients with NeP benefit from enrollment in a small interdisciplinary clinic. Education and a complete diagnostic evaluation are hypothesized to lead to improvements in anxiety and, subsequently, pain severity. Questions remain regarding the long-term maintenance of these improvements and the optimal structure of specialized pain clinics.

Diabetes mellitus types 1 and 2 (DM1 and DM2) and/or hypertension (HTN) can contribute to cognitive decline, cerebral atrophy and white matter abnormalities in humans. Adult rat models of streptozotocin-induced DM1 and genetic strains of DM2 and HTN were used to investigate relative contributions of DM and HTN for alterations in cerebral structure and function as well as insulin receptor biology using cognitive testing, magnetic resonance imaging (MRI), and histological and molecular methods. The effects of DM1 or DM2 were generally similar. DM was associated with earlier onset of cognitive impairment than with HTN alone. DM was independently correlated with brain atrophy, whereas HTN had minimal effects on brain volume. The combination of DM and HTN led to identifiable mild hippocampal neuronal loss while either DM or HTN led to synaptic loss. Only DM led to downregulation of the insulin receptor pathways' activation. In contrast, only HTN was associated with vascular luminal reduction and restricted cerebral perfusion on MRI. The impacts of DM and HTN in the brain differ, while their separate contributions can lead to some additive adverse effects within rodent brain grey matter.

Objective: This study evaluated the oral cannabinoid, nabilone, in the treatment of refractory human diabetic peripheral neuropathic pain. Background Cannabinoids are effective for the reduction of neuropathic pain behaviours in animal models of neuropathic pain, but their efficacy in human patients is poorly established. Design/Methods: This was a single center, randomized, double blind, placebo controlled, flexible-dose study with an enriched enrollment randomized withdrawal design. Diabetic subjects with a pain score ≥4 (0–10 scale) continued their regular pain medications and were administered single blinded adjuvant nabilone for 4 weeks. Those subjects achieving ≥30% pain relief were then randomized and treated with either flexible-dose nabilone 1-4 mg/day (n = 13) or placebo (n = 13) in a further 5 week double blind treatment period. Results: Nabilone was associated with a significant improvement in the change in mean end-point pain score vs. placebo; mean treatment difference was a reduction of 1.27 (95% CI, 2.29 to 0.25) (p= 0.02). The average nabilone dose at end point was 2.9±1.1 mg/day. Nabilone was also associated with improvements from baseline when compared to placebo for the anxiety subscale of the Hospital Anxiety and Depression Scale, the Medical Outcomes Study sleep scale sleep problems index, and the European Quality of Life-5 Domains index score (each p Conclusions: Flexible-dose nabilone 1–4 mg/day was effective in relieving neuropathic pain, improvement of disturbed sleep and quality of life, and overall patient status. Nabilone was very well tolerated in patients with diabetic peripheral neuropathic pain. Larger scale studies are required to validate the use of nabilone in neuropathic pain management. Supported by: Unrestricted grant from Valeant Canada. Disclosure: Dr. Toth has received personal compensation for activities with Pfizer and Eli Lilly & Company as a speaker. Dr. Toth has received research support from Pfizer Inc, Valeant Pharmaceuticals International and Eli Lilly & Company. Dr. Mawani has nothing to disclose. Dr. Brady has nothing to disclose. Dr. Chan has nothing to disclose. Dr. Liu has nothing to disclose. Dr. Mehina has nothing to disclose. Dr. Garven has nothing to disclose. Dr. Bestard has nothing to disclose. Dr. Korngut has nothing to disclose.