Arthroscopy Association of Canada Position Statement on Opioid Prescription After Arthroscopic Surgery.

Background: Despite the ongoing opioid epidemic, most patients are still prescribed a significant number of opioid medications for pain management after arthroscopic surgery. There is a need for consensus among orthopaedic surgeons and solutions to aid providers in analgesic strategies that reduce the use of opioid pain medications. Purpose: This position statement was developed with a comprehensive systematic review and meta-analysis of exclusively randomized controlled trials (RCTs) to synthesize the best available evidence for managing acute postoperative pain after arthroscopic surgery. Study Design: Position statement. Methods: The Embase, MEDLINE, PubMed, Scopus, and Web of Science databases were searched from inception until August 10, 2022. Keywords included arthroscopy, opioids, analgesia, and pain, and associated variations. We included exclusively RCTs on adult patients to gather the best available evidence for managing acute postoperative pain after arthroscopic surgery. Patient characteristics, pain, and opioid data were extracted, data were analyzed, and trial bias was evaluated. Results: A total of 21 RCTs were identified related to the prescription of opioid-sparing pain medication after arthroscopic surgery. The following recommendations regarding noninvasive, postoperative pain management strategies were made: (1) multimodal oral nonopioid analgesic regimens-including at least 1 of acetaminophen-a nonsteroidal anti-inflammatory drug-can significantly reduce opioid consumption with no change in pain scores; (2) cryotherapy is likely to help with pain management, although the evidence on the optimal method of application (continuous-flow vs ice pack application) is unclear; (3) and (4) limited RCT evidence supports the efficacy of transcutaneous electrical nerve stimulation and relaxation exercises in reducing opioid consumption after arthroscopy; and (5) limited RCT evidence exists against the efficacy of transdermal lidocaine patches in reducing opioid consumption. Conclusion: A range of nonopioid strategies exist that can reduce postarthroscopic procedural opioid consumption with equivalent vocal pain outcomes. Optimal strategies include multimodal analgesia with education and restricted/reduced opioid prescription.

The Effect of Staged Versus Usual Care Physiotherapy on Knee Function Following Anterior Cruciate Ligament Reconstruction.

CONTEXT: The long duration and high cost of anterior cruciate ligament reconstruction (ACLR) rehabilitation can pose barriers to completing rehabilitation, the latter stages of which progress to demanding sport-specific exercises critical for a safe return to sport. A staged approach shifting in-person physiotherapy sessions to later months of recovery may ensure patients undergo the sport-specific portion of ACLR rehabilitation. Design/Objective: To compare postoperative outcomes of knee function in patients participating in a staged ACLR physiotherapy program to patients participating in usual care physiotherapy through a randomized controlled trial. METHODS: One hundred sixty-two patients were randomized to participate in staged (n = 80) or usual care physiotherapy (n = 82) following ACLR and assessed preoperatively and postoperatively at 2 weeks, 6 weeks, 3 months, and 6 months. The staged group completed the ACLR rehabilitation protocol at home for the first 3 months, followed by usual care in-person sessions. The usual care group completed in-person sessions for their entire rehabilitation. Outcome measures included the Lower Extremity Functional Scale, International Knee Documentation Committee Questionnaire, pain, range of motion, strength, and hop testing. RESULTS: There were no statistically significant between-group differences in measures of knee function at 6 months postoperative. Patients in the usual care group reported significantly higher International Knee Documentation Committee scores at 3 months postoperative (mean difference = 5.8; 95% confidence interval,  1.3 to 10.4; P = .01). CONCLUSION: A staged approach to ACLR rehabilitation does not appear to impede knee function at 6 months postoperative but may result in worse patient reported outcomes at early follow-ups.

Cutting Edge: Aire Is a Coactivator of the Vitamin D Receptor.

Vitamin D deficiency is associated with the development of autoimmunity, which arises from defects in T cell tolerance to self-antigens. Interactions of developing T cells with medullary thymic epithelial cells, which express tissue-restricted Ags, are essential for the establishment of central tolerance. However, vitamin D signaling in the thymus is poorly characterized. We find that stromal and hematopoietic cells in the mouse thymus express the vitamin D receptor (Vdr) and Cyp27b1, the enzyme that produces hormonal 1,25-dihydroxyvitamin D (1,25D). Treatment of cultured thymic slices with 1,25D enhances expression of the critical medullary thymic epithelial cell transcription factor autoimmune regulator (Aire), its colocalization with the Vdr, and enhances tissue-restricted Ag gene expression. Moreover, the Vdr interacts with Aire in a 1,25D-dependent manner and recruits Aire to DNA at vitamin D response elements, where it acts as a Vdr coactivator. These data link vitamin D signaling directly to critical transcriptional events necessary for central tolerance.

"Can You Feel It": An Early Experience with Simulated Vibration to Recreate Glenoid Reaming.

When developing educational simulators, meaningful haptic feedback is important. To our knowledge, no shoulder arthroplasty surgical simulator exists. This study focuses on simulating vibration haptics of glenoid reaming for shoulder arthroplasty using a novel glenoid reaming simulator. Methods: We validated a novel custom simulator constructed using a vibration transducer transmitting simulated reaming vibrations to a powered nonwearing reamer tip through a 3D-printed glenoid. Validation and system fidelity were evaluated by 9 fellowship-trained shoulder surgeon experts performing a series of simulated reamings. We then completed the validation process through a questionnaire focused on experts' experience with the simulator. Results: Experts correctly identified 52% ± 8% of surface profiles and 69% ± 21% of cartilage layers. Experts identified the vibration interface between simulated cartilage and subchondral bone (77% ± 23% of the time), indicating high fidelity for the system. An interclass correlation coefficient for experts' reaming to the subchondral plate was 0.682 (confidence interval 0.262-0.908). On a general questionnaire, the perceived utility of the simulator as a teaching tool was highly ranked (4/5), and experts scored "ease of instrument manipulation" (4.19/5) and "realism of the simulator" (4.11/5) the highest. The mean global evaluation score was 6.8/10 (range 5-10). Conclusions: We examined a simulated glenoid reamer and feasibility of haptic vibrational feedback for training. Experts validated simulated vibration feedback for glenoid simulation reaming, and the results suggested that this may be a useful additional training adjuvant. Level of Evidence: Level II, prospective study.

Low rates of serious complications after open Latarjet procedure at short-term follow-up.

PURPOSE: To report on intraoperative and short-term postoperative adverse events after open Latarjet procedure in patients with recurrent anterior shoulder instability. These complications were classified into different grades of severity based on the treatment required and the learning curve of the procedure. METHODS: Ninety-six patients (102 shoulders) underwent open Latarjet procedure for recurrent post-traumatic anterior glenohumeral instability between 2012 and 2020. The minimum duration of patients' follow-up was 6 months. Adverse events were classified into 3 classes based on the severity and subsequent treatment. The complications in the first 50% of all cases were compared with the latter 50% to evaluate the role of learning curve on the complication rates. RESULTS: The mean follow-up was 7.2 ± 2.8 months. The patients' mean age was 26.7 ± 8.9 years and consisted of 83 (86.4%) male and 13 (13.6%) female patients. The total adverse events rate was 18.6%. Adverse events requiring no additional treatment (class 1) occurred in 6 cases (5.8%) including fibrous union (3.9%) and asymptomatic resorption of the graft (1.9%). Adverse events requiring additional or extended nonoperative management (class 2) occurred in 8 cases (7.8%), including coracoid fracture (2.9%), musculocutaneous nerve palsy (1.9%), axillary nerve palsy (0.9%), suprascapular nerve palsy (0.9%), and stiffness (0.9%). All the nerve palsies recovered without long-term sequelae. Adverse events requiring secondary operative procedures (class 3) occurred in 5 cases (4.9%), including symptomatic hardware (1.9%), medial healing of the graft (0.9%), screw loosening (0.9%), and deep infection (0.9%). The rate of adverse events in revision cases was higher than primary cases in 11.7% and 6.8%, respectively (P = .119). The complication rate was significantly higher in the first half of the surgeons' practice (14.7%) than in the second half (3.9%) (P ≤ .05). CONCLUSIONS: The overall complication rate reported in this open Latarjet series is 18.6%; however, the rate of class 3 adverse events that required additional surgery or long-term medical treatment was only 4.9%. Revision cases had a higher rate of complications than primary cases, and the learning curve has had a significant impact on the rate of adverse events.

Active Retrieval Improves Procedural Learning in Orthopedic Surgery.

OBJECTIVE: Tests are shown to enhance learning: this is known as the "testing effect". The benefit of testing is theorized to be through "active retrieval", which is the effortful process of recalling stored knowledge. This differs from "passive studying", such as reading, which is a low effort process relying on recognition. The testing effect is commonly studied in random word list scenarios and is thought to disappear as complexity of material increases. Little is known about the testing effect in complex situations such as procedural learning. Therefore, we investigated if testing improves procedural learning of fracture fixation as compared to "passive studying". DESIGN, SETTING, AND PARTICIPANTS: Fifty participants watched an instructional video of an open reduction internal fixation of a Sawbones™ femur. Participants then performed the procedure under guided supervision (pretest). After randomization, they either read the steps (passive studying group), or wrote down the steps from memory (active retrieval group) for a period of 15 minutes. After a washout period, all participants performed the procedure without guidance (posttest) and then once more, 1 week after the initial testing (retention test). The participants were assessed using the Objective Structured Assessment of Technical Skill. Each performance was video recorded for data analysis purposes. RESULTS: Participants in the passive studying group had significantly higher Objective Structured Assessment of Technical Skill scores during immediate assessment compared to the active retrieval group (p = 0.001), especially with respect to remembering the correct order of the steps (p = 0.002). The percentage of information forgotten was significantly less in the active retrieval group (p = 0.02) at the retention test. CONCLUSION: We demonstrated that, compared to passive studying, testing with active retrieval through writing resulted in better retention of fracture fixation knowledge (i.e., less forgetting). These findings can easily be applied and incorporated in existing curricula. Future studies are needed to determine the effects of different kinds of active retrieval methods such as verbal retrieval (e.g., dictating) in surgical practice.

The ICOS-ICOSL pathway tunes thymic selection.

Negative selection of developing T cells plays a significant role in T-cell tolerance to self-antigen. This process relies on thymic antigen-presenting cells which express both self-antigens and cosignaling molecules. Inducible T-cell costimulator (ICOS) belongs to the CD28 family of cosignaling molecules and binds to ICOS ligand (ICOSL). The ICOS signaling pathway plays important roles in shaping the immune response to infections, but its role in central tolerance is less well understood. Here we show that ICOSL is expressed by subsets of thymic dendritic cells and medullary thymic epithelial cells as well as thymic B cells. ICOS expression is upregulated as T cells mature in the thymus and correlates with T-cell receptor signal strength during thymic selection. We also provide evidence of a role for ICOS signaling in mediating negative selection. Our findings suggest that ICOS may fine-tune T-cell receptor signals during thymic selection contributing to the generation of a tolerant T-cell population.

Pre-existing chromatin accessibility and gene expression differences among naive CD4+ T cells influence effector potential.

CD4+ T cells have a remarkable potential to differentiate into diverse effector lineages following activation. Here, we probe the heterogeneity present among naive CD4+ T cells before encountering their cognate antigen to ask whether their effector potential is modulated by pre-existing transcriptional and chromatin landscape differences. Single-cell RNA sequencing shows that key drivers of variability are genes involved in T cell receptor (TCR) signaling. Using CD5 expression as a readout of the strength of tonic TCR interactions with self-peptide MHC, and sorting on the ends of this self-reactivity spectrum, we find that pre-existing transcriptional differences among naive CD4+ T cells impact follicular helper T (TFH) cell versus non-TFH effector lineage choice. Moreover, our data implicate TCR signal strength during thymic development in establishing differences in naive CD4+ T cell chromatin landscapes that ultimately shape their effector potential.

Arthroscopic Versus Mini-open Rotator Cuff Repair: A Randomized Trial and Meta-analysis.

BACKGROUND: Patients with complete rotator cuff tears who fail a course of nonoperative therapy can benefit from surgical repair. PURPOSE: This randomized trial compared mini-open (MO) versus all-arthroscopic (AA) rotator cuff repair. STUDY DESIGN: Randomized controlled trial; Level of evidence, 1. METHODS: Patients with rotator cuff tears were randomized to undergo MO or AA repair at 9 centers by 23 surgeons. The primary outcome (Western Ontario Rotator Cuff Index [WORC]) and secondary outcomes (American Shoulder and Elbow Surgeons [ASES] score, Shoulder Pain and Disability Index [SPADI] pain subscale, 12-Item Short Form Health Survey [SF-12], reported medication use, adverse events), as well as measurements of range of motion and strength, were collected at 1 month before surgery; at 2 and 6 weeks postoperatively; and at 3, 6, 12, 18, and 24 months postoperatively. A blinded radiologist evaluated rotator cuff integrity on magnetic resonance imaging (MRI) at baseline and 1 year. Intention-to-treat analysis of covariance with the preoperative WORC score, age, and tear size as covariates assessed continuous outcomes. Sex differences were assessed. A meta-analysis synthesized the primary outcome between MO and AA repair with previous trials. RESULTS: From 954 patients screened, 411 were ineligible (276 because of recovery with physical therapy), 449 were screened at surgery (175 ineligible), and 274 completed follow-up (138 MO and 136 AA). The AA and MO groups were similar before surgery. WORC scores improved from 40 preoperatively to 89 (AA) and 93 (MO) at 2 years, for an adjusted mean difference of 3.4 (95% CI, -0.4 to 7.2). There were no statistically significant differences between the AA and MO groups at any time point. All secondary patient-reported outcomes were not significantly different between the MO and AA groups, except the 2-year SPADI pain score (8 vs 12, respectively; P = .02). A similar recovery in range of motion and strength occurred in both groups over time. MRI indicated minimal improvement in muscle relative to fat (AA: n = 3; MO: n = 2), with most worsening (AA: n = 25; MO: n = 24) or remaining unchanged (AA: n = 70; MO: n = 70). Opioid use was significantly reduced after surgery (from 21% to 5%). The meta-analysis indicated no significant standardized mean difference between groups in the primary outcome across all pooled studies (standardized mean difference, -0.06 [95% CI, -0.34 to 0.22]). CONCLUSION: Both AA and MO rotator cuff repair provide large clinical benefits, with few adverse events. There is strong evidence of equivalent clinical improvements. TRIAL REGISTRATION: NCT00128076.

p16INK4a Regulates Cellular Senescence in PD-1-Expressing Human T Cells.

T-cell dysfunction arising upon repeated antigen exposure prevents effective immunity and immunotherapy. Using various clinically and physiologically relevant systems, we show that a prominent feature of PD-1-expressing exhausted T cells is the development of cellular senescence features both in vivo and ex vivo. This is associated with p16INK4a expression and an impaired cell cycle G1 to S-phase transition in repeatedly stimulated T cells. We show that these T cells accumulate DNA damage and activate the p38MAPK signaling pathway, which preferentially leads to p16INK4a upregulation. However, in highly dysfunctional T cells, p38MAPK inhibition does not restore functionality despite attenuating senescence features. In contrast, p16INK4a targeting can improve T-cell functionality in exhausted CAR T cells. Collectively, this work provides insights into the development of T-cell dysfunction and identifies T-cell senescence as a potential target in immunotherapy.

Strength and Numbers: The Role of Affinity and Avidity in the 'Quality' of T Cell Tolerance.

The ability of T cells to identify foreign antigens and mount an efficient immune response while limiting activation upon recognition of self and self-associated peptides is critical. Multiple tolerance mechanisms work in concert to prevent the generation and activation of self-reactive T cells. T cell tolerance is tightly regulated, as defects in these processes can lead to devastating disease; a wide variety of autoimmune diseases and, more recently, adverse immune-related events associated with checkpoint blockade immunotherapy have been linked to a breakdown in T cell tolerance. The quantity and quality of antigen receptor signaling depend on a variety of parameters that include T cell receptor affinity and avidity for peptide. Autoreactive T cell fate choices (e.g., deletion, anergy, regulatory T cell development) are highly dependent on the strength of T cell receptor interactions with self-peptide. However, less is known about how differences in the strength of T cell receptor signaling during differentiation influences the 'function' and persistence of anergic and regulatory T cell populations. Here, we review the literature on this subject and discuss the clinical implications of how T cell receptor signal strength influences the 'quality' of anergic and regulatory T cell populations.

NR4A3 Mediates Thymic Negative Selection.

Central tolerance aims to limit the production of T lymphocytes bearing TCR with high affinity for self-peptide presented by MHC molecules. The accumulation of thymocytes with such receptors is limited by negative selection or by diversion into alternative differentiation, including T regulatory cell commitment. A role for the orphan nuclear receptor NR4A3 in negative selection has been suggested, but its function in this process has never been investigated. We find that Nr4a3 transcription is upregulated in postselection double-positive thymocytes, particularly those that have received a strong selecting signal and are destined for negative selection. Indeed, we found an accumulation of cells bearing a negative selection phenotype in NR4A3-deficient mice as compared with wild-type controls, suggesting that Nr4a3 transcriptional induction is necessary to limit accumulation of self-reactive thymocytes. This is consistent with a decrease of cleaved caspase-3+-signaled thymocytes and more T regulatory and CD4+Foxp3-HELIOS+ cells in the NR4A3-deficient thymus. We further tested the role for NR4A3 in negative selection by reconstituting transgenic mice expressing the OVA Ag under the control of the insulin promoter with bone marrow cells from OT-I Nr4a3 +/+ or OT-I Nr4a3 -/- mice. Accumulation of autoreactive CD8 thymocytes and autoimmune diabetes developed only in the absence of NR4A3. Overall, our results demonstrate an important role for NR4A3 in T cell development.

Arthroscopy Association of Canada Position Statement on Exercise for Knee Osteoarthritis: A Systematic Review of Guidelines.

BACKGROUND: Exercise is widely regarded to improve pain and function in patients with knee osteoarthritis (OA) through building supportive muscle mass, facilitating weight loss, and through the other beneficial effects associated with it. PURPOSE: To explore literature that presents clinical guidelines for the use of exercise in the treatment of knee OA to inform an evidence-based position statement for the Arthroscopy Association of Canada. STUDY DESIGN: Position statement. METHODS: PubMed, MEDLINE, Embase, and Cochrane databases were searched for guidelines commenting on the role of exercise for knee OA. The search was limited to guidelines published in the last 10 years. Articles were screened for relevance, focusing on recently published research with clinical guidelines. Inclusion criteria involved all articles providing clinical guidelines for exercise and knee OA. RESULTS: Eight guidelines were identified. All eight recommended exercise as an important component of treatment for knee OA, with 6/8 strongly recommending it. CONCLUSION: Exercise is an effective and important component of the non-pharmacological management of knee OA. The Arthroscopy Association of Canada strongly recommends the use of exercise in the management of knee OA.

CD5 levels define functionally heterogeneous populations of naïve human CD4+ T cells.

Studies in murine models show that subthreshold TCR interactions with self-peptide are required for thymic development and peripheral survival of naïve T cells. Recently, differences in the strength of tonic TCR interactions with self-peptide, as read-out by cell surface levels of CD5, were associated with distinct effector potentials among sorted populations of T cells in mice. However, whether CD5 can also be used to parse functional heterogeneity among human T cells is less clear. Our study demonstrates that CD5 levels correlate with TCR signal strength in human naïve CD4+ T cells. Further, we describe a relationship between CD5 levels on naïve human CD4+ T cells and binding affinity to foreign peptide, in addition to a predominance of CD5hi T cells in the memory compartment. Differences in gene expression and biases in cytokine production potential between CD5lo and CD5hi naïve human CD4+ T cells are consistent with observations in mice. Together, these data validate the use of CD5 surface levels as a marker of heterogeneity among human naïve CD4+ T cells with important implications for the identification of functionally biased T- cell populations that can be exploited to improve the efficacy of adoptive cell therapies.

CD5 levels reveal distinct basal T-cell receptor signals in T cells from non-obese diabetic mice.

Type 1 diabetes in non-obese diabetic (NOD) mice occurs when autoreactive T cells eliminate insulin producing pancreatic ß cells. While extensively studied in T-cell receptor (TCR) transgenic mice, the contribution of alterations in thymic selection to the polyclonal T-cell pool in NOD mice is not yet resolved. The magnitude of signals downstream of TCR engagement with self-peptide directs the development of a functional T-cell pool, in part by ensuring tolerance to self. TCR interactions with self-peptide are also necessary for T-cell homeostasis in the peripheral lymphoid organs. To identify differences in TCR signal strength that accompany thymic selection and peripheral T-cell maintenance, we compared CD5 levels, a marker of basal TCR signal strength, on immature and mature T cells from autoimmune diabetes-prone NOD and -resistant B6 mice. The data suggest that there is no preferential selection of NOD thymocytes that perceive stronger TCR signals from self-peptide engagement. Instead, NOD mice have an MHC-dependent increase in CD4+ thymocytes and mature T cells that express lower levels of CD5. In contrast, T cell-intrinsic mechanisms lead to higher levels of CD5 on peripheral CD8+ T cells from NOD relative to B6 mice, suggesting that peripheral CD8+ T cells with higher basal TCR signals may have survival advantages in NOD mice. These differences in the T-cell pool in NOD mice may contribute to the development or progression of autoimmune diabetes.

Differential expression of tissue-restricted antigens among mTEC is associated with distinct autoreactive T cell fates.

Medullary thymic epithelial cells (mTEC) contribute to the development of T cell tolerance by expressing and presenting tissue-restricted antigens (TRA), so that developing T cells can assess the self-reactivity of their antigen receptors prior to leaving the thymus. mTEC are a heterogeneous population of cells that differentially express TRA. Whether mTEC subsets induce distinct autoreactive T cell fates remains unclear. Here, we establish bacterial artificial chromosome (BAC)-transgenic mouse lines with biased mTEClo or mTEChi expression of model antigens. The transgenic lines support negative selection of antigen-specific thymocytes depending on antigen dose. However, model antigen expression predominantly by mTEClo supports TCRαß+ CD8αα intraepithelial lymphocyte development; meanwhile, mTEChi-restricted expression preferentially induces Treg differentiation of antigen-specific cells in these models to impact control of infectious agents and tumor growth. In summary, our data suggest that mTEC subsets may have a function in directing distinct mechanisms of T cell tolerance.

MHC-Independent Thymic Selection of CD4 and CD8 Coreceptor Negative αß T Cells.

It is becoming increasingly clear that unconventional T cell subsets, such as NKT, γδ T, mucosal-associated invariant T, and CD8αα T cells, each play distinct roles in the immune response. Subsets of these cell types can lack both CD4 and CD8 coreceptor expression. Beyond these known subsets, we identify CD4-CD8-TCRαß+, double-negative (DN) T cells, in mouse secondary lymphoid organs. DN T cells are a unique unconventional thymic-derived T cell subset. In contrast to CD5high DN thymocytes that preferentially yield TCRαß+ CD8αα intestinal lymphocytes, we find that mature CD5low DN thymocytes are precursors to peripheral DN T cells. Using reporter mouse strains, we show that DN T cells transit through the immature CD4+CD8+ (double-positive) thymocyte stage. Moreover, we provide evidence that DN T cells can differentiate in MHC-deficient mice. Our study demonstrates that MHC-independent thymic selection can yield DN T cells that are distinct from NKT, γδ T, mucosal-associated invariant T, and CD8αα T cells.