Causal relationships between pain, medical treatments, and knee osteoarthritis: A graphical causal model to guide analyses.

OBJECTIVE: Randomized controlled trials (RCTs) are a gold standard for estimating the benefits of clinical interventions, but their decision-making utility can be limited by relatively short follow-up time. Longer-term follow-up of RCT participants is essential to support treatment decisions. However, as time from randomization accrues, loss to follow-up and competing events can introduce biases and require covariate adjustment even for intention-to-treat effects. We describe a process for synthesizing expert knowledge and apply this to long-term follow-up of an RCT of treatments for meniscal tears in patients with knee osteoarthritis (OA). METHODS: We identified 2 post-randomization events likely to impact accurate assessment of pain outcomes beyond 5 years in trial participants: loss to follow-up and total knee replacement (TKR). We conducted literature searches for covariates related to pain and TKR in individuals with knee OA and combined these with expert input. We synthesized the evidence into graphical models. RESULTS: We identified 94 potential covariates potentially related to pain and/or TKR among individuals with knee OA. Of these, 46 were identified in the literature review and 48 by expert panelists. We determined that adjustment for 50 covariates may be required to estimate the long-term effects of knee OA treatments on pain. CONCLUSION: We present a process for combining literature reviews with expert input to synthesize existing knowledge and improve covariate selection. We apply this process to the long-term follow-up of a randomized trial and show that expert input provides additional information not obtainable from literature reviews alone.

Male Sex, Western Ontario Shoulder Instability Index Score, and Sport as Predictors of Large Labral Tears of the Shoulder: A Multicenter Orthopaedic Outcomes Network (MOON) Shoulder Instability Cohort Study.

PURPOSE: To identify factors predictive of a large labral tear at the time of shoulder instability surgery. METHODS: As part of the Multicenter Orthopaedic Outcomes Network (MOON) Shoulder Instability cohort, patients undergoing open or arthroscopic shoulder instability surgery for a labral tear were evaluated. Patients with >270° tears were defined as having large labral tears. To build a predictive logistic regression model for large tears, the Feasible Solutions Algorithm was used to add significant interaction effects. RESULTS: After applying exclusion criteria, 1235 patients were available for analysis. There were 222 females (18.0%) and 1013 males (82.0%) in the cohort, with an average age of 24.7 years (range 12 to 66). The prevalence of large tears was 4.6% (n = 57), with the average tear size being 141.9°. Males accounted for significantly more of the large tears seen in the cohort (94.7%, P = .01). Racquet sports (P = .01), swimming (P = .02), softball (P = .05), skiing (P = .04), and golf (P = .04) were all associated with large labral tears, as was a higher Western Ontario Shoulder Instability Index (WOSI; P = .01). Age, race, history of dislocation, and injury during sport were not associated with having a larger tear. Using our predictive logistic regression model for large tears, patients with a larger body mass index (BMI) who played contact sports were also more likely to have large tears (P = .007). CONCLUSIONS: Multiple factors were identified as being associated with large labral tears at the time of surgery, including male sex, preoperative WOSI score, and participation in certain sports including racquet sports, softball, skiing, swimming, and golf. LEVEL OF EVIDENCE: I, prognostic study.

Epidemiology of the Frequency, Etiology, Direction, and Severity (FEDS) system for classifying glenohumeral instability.

HYPOTHESIS: The purpose of this multicenter epidemiologic study was to determine the distribution of patients within the Frequency, Etiology, Direction, and Severity (FEDS) classification system to determine which categories are of clinical importance. METHODS: Shoulder instability patients were identified using International Classification of Diseases, Ninth Revision coding data from 3 separate institutions from 2005-2010. Data were collected retrospectively. Details of instability were recorded in accordance with the FEDS classification system. Each patient was assigned a classification within the FEDS system. After all patients were assigned to a group, each group was individually analyzed and compared with the other groups. RESULTS: There are a total of 36 possible combinations within the FEDS system. Only 16 categories were represented by at least 1% of our patient population. Six categories captured at least 5% of all patients with shoulder instability. Only 2 categories represented greater than 10% of the population: solitary, traumatic, anterior dislocation, with 95 patients (24.8%), and occasional, traumatic, anterior dislocation, with 63 patients (16.4%). CONCLUSIONS: There are 16 categories within the FEDS classification that are clinically significant. Solitary, traumatic, anterior dislocation and occasional, traumatic, anterior dislocation were the most frequently observed in our cohort.

The multifaceted role of inhibitory interneurons in the dorsal lateral geniculate nucleus.

Intrinsic interneurons within the dorsal lateral geniculate nucleus (dLGN) provide a feed-forward inhibitory pathway for afferent visual information originating from the retina. These interneurons are unique because in addition to traditional axodendritic output onto thalamocortical neurons, these interneurons have presynaptic dendrites that form dendrodendritic synapses onto thalamocortical neurons as well. These presynaptic dendrites, termed F2 terminals, are tightly coupled to the retinogeniculate afferents that synapse onto thalamocortical relay neurons. Retinogeniculate stimulation of F2 terminals can occur through the activation of ionotropic and/or metabotropic glutamate receptors. The stimulation of ionotropic glutamate receptors can occur with single stimuli and produces a short-lasting inhibition of the thalamocortical neuron. By contrast, activation of metabotropic glutamate receptors requires tetanic activation and results in longer-lasting inhibition in the thalamocortical neuron. The F2 terminals are predominantly localized to the distal dendrites of interneurons, and the excitation and output of F2 terminals can occur independent of somatic activity within the interneuron thereby allowing these F2 terminals to serve as independent processors, giving rise to focal inhibition. By contrast, strong transient depolarizations at the soma can initiate a backpropagating calcium-mediated potential that invades the dendritic arbor activating F2 terminals and leading to a global form of inhibition. These distinct types of output, focal versus global, could play an important role in the temporal and spatial roles of inhibition that in turn impacts thalamocortical information processing.

Calmodulin activity regulates group I metabotropic glutamate receptor-mediated signal transduction and synaptic depression.

Group I metabotropic glutamate receptors (mGluR), including mGluR1 and mGluR 5 (mGluR1/5), are coupled to Gq and modulate activity-dependent synaptic plasticity. Direct activation of mGluR1/5 causes protein translation-dependent long-term depression (LTD). Although it has been established that intracellular Ca(2+) and the Gq-regulated signaling molecules are required for mGluR1/5 LTD, whether and how Ca(2+) regulates Gq signaling and upregulation of protein expression remain unknown. Through pharmacological inhibition, we tested the function of the Ca(2+) sensor calmodulin (CaM) in intracellular signaling triggered by the activation of mGluR1/5. CaM inhibitor N-[4-aminobutyl]-5-chloro-2-naphthalenesulfonamide hydrochloride (W13) suppressed the mGluR1/5-stimulated activation of extracellular signal-regulated kinase 1/2 (ERK1/2) and p70-S6 kinase 1 (S6K1) in hippocampal neurons. W13 also blocked the mGluR1/5 agonist-induced synaptic depression in hippocampal slices and in anesthetized mice. Consistent with the function of CaM, inhibiting the downstream targets Ca(2+) /CaM-dependent protein kinases (CaMK) blocked ERK1/2 and S6K1 activation. Furthermore, disruption of the CaM-CaMK-ERK1/2 signaling cascade suppressed the mGluR1/5-stimulated upregulation of Arc expression. Altogether, our data suggest CaM as a new Gq signaling component for coupling Ca(2+) and protein upregulation and regulating mGluR1/5-mediated synaptic modification.

Patch clamp electrophysiology and capillary electrophoresis-mass spectrometry metabolomics for single cell characterization.

The visual selection of specific cells within an ex vivo brain slice, combined with whole-cell patch clamp recording and capillary electrophoresis (CE)-mass spectrometry (MS)-based metabolomics, yields high chemical information on the selected cells. By providing access to a cell's intracellular environment, the whole-cell patch clamp technique allows one to record the cell's physiological activity. A patch clamp pipet is used to withdraw ∼3 pL of cytoplasm for metabolomic analysis using CE-MS. Sampling the cytoplasm, rather than an intact isolated neuron, ensures that the sample arises from the cell of interest and that structures such as presynaptic terminals from surrounding, nontargeted neurons are not sampled. We sampled the rat thalamus, a well-defined system containing gamma-aminobutyric acid (GABA)-ergic and glutamatergic neurons. The approach was validated by recording and sampling from glutamatergic thalamocortical neurons, which receive major synaptic input from GABAergic thalamic reticular nucleus neurons, as well as neurons and astrocytes from the ventral basal nucleus and the dorsal lateral geniculate nucleus. From the analysis of the cytoplasm of glutamatergic cells, approximately 60 metabolites were detected, none of which corresponded to the compound GABA. However, GABA was successfully detected when sampling the cytoplasm of GABAergic neurons, demonstrating the exclusive nature of our cytoplasmic sampling approach. The combination of whole-cell patch clamp with single cell cytoplasm metabolomics provides the ability to link the physiological activity of neurons and astrocytes with their neurochemical state. The observed differences in the metabolome of these neurons underscore the striking cell to cell heterogeneity in the brain.

Local dendrodendritic inhibition regulates fast synaptic transmission in visual thalamus.

Inhibition from thalamic interneurons plays a critical role in modulating information transfer between thalamus and neocortex. Interestingly, these neurons yield inhibition via two distinct outputs: presynaptic dendrites that innervate thalamocortical relay neurons and axonal outputs. Since the dendrites of thalamic interneurons are the primary targets of incoming synaptic information, it has been hypothesized that local synaptic input could produce highly focused dendritic output. To gain additional insight into the computational power of these presynaptic dendrites, we have combined two-photon laser scanning microscopy, glutamate uncaging, and whole-cell electrophysiological recordings to locally activate dendritic terminals and study their inhibitory contribution to rat thalamocortical relay neurons. Our findings demonstrate that local dendritic release from thalamic interneurons is controlled locally by AMPA/NMDA receptor-mediated recruitment of L-type calcium channels. Moreover, by mapping these connections with single dendrite resolution we not only found that presynaptic dendrites preferentially target proximal regions, but such actions differ significantly across branches. Furthermore, local stimulation of interneuron dendrites did not result in global excitation, supporting the notion that these interneurons can operate as multiplexors, containing numerous independently operating input-output devices.

Activity-dependent regulation of retinogeniculate signaling by metabotropic glutamate receptors.

Thalamocortical neurons in dorsal lateral geniculate nucleus (dLGN) dynamically convey visual information from retina to the neocortex. Activation of metabotropic glutamate receptors (mGluRs) exerts multiple effects on neural integration in dLGN; however, their direct influence on the primary sensory input, namely retinogeniculate afferents, is unknown. In the present study, we found that pharmacological or synaptic activation of type 1 mGluRs (mGluR(1)s) significantly depresses glutamatergic retinogeniculate excitation in rat thalamocortical neurons. Pharmacological activation of mGluR(1)s attenuates excitatory synaptic responses in thalamocortical neurons at a magnitude sufficient to decrease suprathreshold output of these neurons. The reduction in both NMDA and AMPA receptor-dependent synaptic responses results from a presynaptic reduction in glutamate release from retinogeniculate terminals. The suppression of retinogeniculate synaptic transmission and dampening of thalamocortical output was mimicked by tetanic activation of retinogeniculate afferent in a frequency-dependent manner that activated mGluR(1)s. Retinogeniculate excitatory synaptic transmission was also suppressed by the glutamate transport blocker TBOA (dl-threo-ß-benzyloxyaspartic acid), suggesting that mGluR(1)s were activated by glutamate spillover. The data indicate that presynaptic mGluR(1) contributes to an activity-dependent mechanism that regulates retinogeniculate excitation and therefore plays a significant role in the thalamic gating of visual information.

Dampened dopamine-mediated neuromodulation in prefrontal cortex of fragile X mice.

Fragile X syndrome (FXS) is the most common form of inheritable mental retardation caused by transcriptional silencing of the Fmr1 gene resulting in the absence of fragile X mental retardation protein (FMRP). The role of this protein in neurons is complex and its absence gives rise to diverse alterations in neuronal function leading to neurological disorders including mental retardation, hyperactivity, cognitive impairment, obsessive-compulsive behaviour, seizure activity and autism. FMRP regulates mRNA translation at dendritic spines where synapses are formed, and thus the lack of FMRP can lead to disruptions in synaptic transmission and plasticity. Many of these neurological deficits in FXS probably involve the prefrontal cortex, and in this study, we have focused on modulatory actions of dopamine in the medial prefrontal cortex. Our data indicate that dopamine produces a long-lasting enhancement of evoked inhibitory postsynaptic currents (IPSCs) mediated by D1-type receptors seen in wild-type mice; however, such enhancement is absent in the Fmr1 knock-out (Fmr1 KO) mice. The facilitation of IPSCs produced by direct cAMP stimulation was unaffected in Fmr1 KO, but D1 receptor levels were reduced in these animals. Our results show significant disruption of dopaminergic modulation of synaptic transmission in the Fmr1 KO mice and this alteration in inhibitory activity may provide insight into potential targets for the rescue of deficits associated with FXS.

Age-dependent actions of dopamine on inhibitory synaptic transmission in superficial layers of mouse prefrontal cortex.

Numerous developmental changes in the nervous system occur during the first several weeks of the rodent lifespan. Therefore, many characteristics of neuronal function described at the cellular level from in vitro slice experiments conducted during this early time period may not generalize to adult ages. We investigated the effect of dopamine (DA) on inhibitory synaptic transmission in superficial layers of the medial prefrontal cortex (PFC) in prepubertal [postnatal age (P; days) 12-20], periadolescent (P30-48), and adult (P70-100) mice. The PFC is associated with higher-level cognitive functions, such as working memory, and is associated with initiation, planning, and execution of actions, as well as motivation and cognition. It is innervated by DA-releasing fibers that arise from the ventral tegmental area. In slices from prepubertal mice, DA produced a biphasic modulation of inhibitory postsynaptic currents (IPSCs) recorded in layer II/III pyramidal neurons. Activation of D2-like receptors leads to an early suppression of the evoked IPSC, which was followed by a longer-lasting facilitation of the IPSC mediated by D1-like DA receptors. In periadolescent mice, the D2 receptor-mediated early suppression was significantly smaller compared with the prepubertal animals and absent in adult animals. Furthermore, we found significant differences in the DA-mediated lasting enhancement of the inhibitory response among the developmental groups. Our findings suggest that behavioral paradigms that elicit dopaminergic release in the PFC differentially modulate inhibition of excitatory pyramidal neuron output in prepuberty compared with periadolescence and adulthood in the superficial layers (II/III) of the cortex.

Thalamic microcircuits: presynaptic dendrites form two feedforward inhibitory pathways in thalamus.

In the visual thalamus, retinal afferents activate both local interneurons and excitatory thalamocortical relay neurons, leading to robust feedforward inhibition that regulates the transmission of sensory information from retina to neocortex. Peculiarly, this feedforward inhibitory pathway is dominated by presynaptic dendrites. Previous work has shown that the output of dendritic terminals of interneurons, also known as F2 terminals, are regulated by both ionotropic and metabotropic glutamate receptors. However, it is unclear whether both classes of glutamate receptors regulate output from the same or distinct dendritic terminals. Here, we used focal glutamate uncaging and whole cell recordings to reveal two types of F2 responses in rat visual thalamus. The first response, which we are calling a Type-A response, was mediated exclusively by ionotropic glutamate receptors (i.e., AMPA and NMDA). In contrast, the second response, which we are calling a Type-B response, was mediated by a combination of ionotropic and type 5 metabotropic glutamate receptors (i.e., mGluR(5)). In addition, we demonstrate that both F2 responses are evoked in the same postsynaptic neurons, which are morphologically distinct from neurons in which no F2 responses are observed. Since photostimulation was relatively focal and small in magnitude, these results suggest distinct F2 terminals, or small clusters of terminals, could be responsible for generating the two inhibitory responses observed. Because of the nature of ionotropic and metabotropic glutamate receptors, we predict the efficacy by which the retina communicates with the thalamus would be strongly regulated by 1) the activity level of a given retinogeniculate axon, and 2) the specific type of F2 terminals activated.

The Effect of Aspiration and Corticosteroid Injection After ACL Injury on Postoperative Infection Rate.

BACKGROUND: Injecting bioactive substances into the knee is common in orthopaedic practice, and recently it has been shown to mitigate risk factors for posttraumatic osteoarthritis. Therefore, understanding the influence of these injections on postoperative infection rate is imperative. HYPOTHESIS: Postinjury aspiration and corticosteroid injection (CSI) of the knee before anterior cruciate ligament (ACL) reconstruction (ACLR) would not increase the risk of postoperative infection. STUDY DESIGN: Cohort Study; Level of evidence, 3. METHODS: All patients between the ages of 10 and 65 years who underwent primary bone-patellar tendon-bone ACLR by 1 fellowship-trained sports medicine orthopaedic surgeon between January 1, 2011, and September 8, 2020, at 1 of 2 major academic centers were evaluated for inclusion. A total of 693 patients were included, with 273 patients receiving postinjury and preoperative aspiration and CSI. A postoperative infection was defined as a patient returning to the operating room for an intra-articular washout. The intervals-measured in days-between the CSI and ACLR and between ACLR and the final follow-up were recorded. To further evaluate the infection risk in each cohort (total cohort; aspiration and injection cohort; no aspiration and injection cohort), the upper 95% confidence bound for the infection risk was calculated for each cohort. RESULTS: There were no postoperative infections in the 693 patients included in this study. The upper 95% confidence bounds were 0.4%, 1.1%, and 0.7% for the total cohort, the cohort that underwent aspiration and injection, and the cohort that did not, respectively. The median number of days between the surgical date and that of the aspiration and injection was 34 days, and the mean follow-up for the entire cohort was 337.4 days (95% CI, 307.6-367.3). CONCLUSION: Postinjury and preoperative aspiration and CSI is a safe intervention that can be used before ACLR. Future studies with larger sample sizes, longer patient follow-ups, and multiple surgeons would be helpful to both better understand infection risk and better identify the influence of CSI on preventing posttraumatic osteoarthritis.

Structural and functional changes of deep layer pyramidal neurons surrounding microelectrode arrays implanted in rat motor cortex.

Devices capable of recording or stimulating neuronal signals have created new opportunities to understand normal physiology and treat sources of pathology in the brain. However, it is possible that the tissue response to implanted electrodes may influence the nature of the signals detected or stimulated. In this study, we characterized structural and functional changes in deep layer pyramidal neurons surrounding silicon or polyimide-based electrodes implanted in the motor cortex of rats. Devices were captured in 300 µm-thick tissue slices collected at the 1 or 6 week time point post-implantation, and individual neurons were assessed using a combination of whole-cell electrophysiology and 2-photon imaging. We observed disrupted dendritic arbors and a significant reduction in spine densities in neurons surrounding devices. These effects were accompanied by a decrease in the frequency of spontaneous excitatory post-synaptic currents, a reduction in sag amplitude, an increase in spike frequency adaptation, and an increase in filopodia density. We hypothesize that the effects observed in this study may contribute to the signal loss and instability that often accompany chronically implanted electrodes. STATEMENT OF SIGNIFICANCE: Implanted electrodes in the brain can be used to treat sources of pathology and understand normal physiology by recording or stimulating electrical signals generated by local neurons. However, a foreign body response following implantation undermines the performance of these devices. While several studies have investigated the biological mechanisms of device-tissue interactions through histology, transcriptomics, and imaging, our study is the first to directly interrogate effects on the function of neurons surrounding electrodes using single-cell electrophysiology. Additionally, we provide new, detailed assessments of the impacts of electrodes on the dendritic structure and spine morphology of neurons, and we assess effects for both traditional (silicon) and newer polymer electrode materials. These results reveal new potential mechanisms of electrode-tissue interactions.

The Corticosteroid Meniscectomy Trial of Extended-Release Triamcinolone Injection After Arthroscopic Partial Meniscectomy: Protocol for a Double-Blind Randomized Controlled Trial.

Background: Meniscal tear in older adults often accompanies knee osteoarthritis and is commonly treated with arthroscopic partial meniscectomy (APM) when patients have persistent pain after a trial of physical therapy. Cross-sectional evidence suggests that synovitis is associated with baseline pain in this patient population, but little is known about the relationship between synovitis and postoperative recovery or progression of knee osteoarthritis. Purpose/Hypothesis: Intra-articular extended-release triamcinolone may reduce inflammation and thereby improve outcomes and slow disease progression. This article presents the rationale behind the Corticosteroid Meniscectomy Trial (CoMeT) and describes its study design and implementation strategies. Study Design: Randomized controlled trial. Methods: CoMeT is a 2-arm, 3-center, randomized placebo-controlled trial designed to establish the clinical efficacy of extended-release triamcinolone administered via intra-articular injection immediately after APM. The primary outcome is change in Knee injury and Osteoarthritis Outcome Score Pain subscore at 3-month follow-up. Synovial biopsy, joint fluid aspirate, and urine and blood sample analyses will examine the associations between various objective measures of baseline inflammation and pre- and postoperative outcome measures and clinical responses to triamcinolone intervention. Quantitative 3-T magnetic resonance imaging will evaluate cartilage and meniscal composition and 3-dimensional bone shape to detect early joint degeneration. Results: We discuss methodologic innovations and challenges. Conclusion: To our knowledge, this is the first randomized double-blind clinical trial that will analyze the effect of extended-release triamcinolone acetonide on pain, magnetic resonance imaging measures of structural change and effusion/synovitis, soluble biomarkers, and synovial tissue transcriptomics after APM.

Radiographic Changes Five Years After Treatment of Meniscal Tear and Osteoarthritic Changes.

OBJECTIVE: Meniscal tear in persons aged ≥45 years is typically managed with physical therapy (PT), and arthroscopic partial meniscectomy (APM) is offered to those who do not respond. Prior studies suggest APM may be associated with greater progression of radiographic changes. METHODS: We assessed changes between baseline and 60 months in the Kellgren-Lawrence (KL) grade and OARSI radiographic score (including subscores for joint space narrowing and osteophytes) in subjects aged 45-85 years enrolled into a seven-center randomized trial comparing outcomes of APM with PT for meniscal tear, osteoarthritis changes, and knee pain. The primary analysis classified subjects according to treatment received. To balance APM and PT groups, we developed a propensity score and used inverse probability weighting (IPW). We imputed a 60-month change in the OARSI score for subjects who underwent total knee replacement (TKR). In a sensitivity analysis, we classified subjects by randomization group. RESULTS: We analyzed data from 142 subjects (100 APM, 42 PT). The mean ± SD weighted baseline OARSI radiographic score was 3.8 ± 3.5 in the APM group and 4.0 ± 4.9 in the PT group. OARSI scores increased by a mean of 4.1 (95% confidence interval [95% CI] 3.5-4.7) in the APM group and 2.4 (95% CI 1.7-3.2) in the PT group (P < 0.001) due to changes in the osteophyte component. We did not observe statistically significant differences in the KL grade. Sensitivity analyses yielded similar findings to the primary analysis. CONCLUSION: Subjects treated with APM had greater progression in the OARSI score because of osteophyte progression but not in the KL grade. The clinical implications of these findings require investigation.

Predictors of Return to Activity at 2 Years After Anterior Cruciate Ligament Reconstruction Among Patients With High Preinjury Marx Activity Scores: A MOON Prospective Cohort Study.

BACKGROUND: Predictors of return to activity after anterior cruciate ligament reconstruction (ACLR) among patients with relatively high preinjury activity levels remain poorly understood. PURPOSE/HYPOTHESIS: The purpose of this study was to identify predictors of return to preinjury levels of activity after ACLR, defined as achieving a Marx activity score within 2 points of the preinjury value, among patients with Marx activity scores of 12 to 16 who had been prospectively enrolled in the Multicenter Orthopaedic Outcomes Network (MOON) cohort. We hypothesized that age, sex, preinjury activity level, meniscal injuries and/or procedures, and concurrent articular cartilage injuries would predict return to preinjury activity levels at 2 years after ACLR. STUDY DESIGN: Cohort study; Level of evidence, 2. METHODS: All unilateral ACLR procedures from 2002 to 2008 performed in patients enrolled in the MOON, with preinjury Marx activity scores ranging from 12 to 16, were evaluated with a specific focus on return to preinjury activity levels at 2 years postoperatively. Return to activity was defined as a Marx activity score within 2 points of the preinjury value. The proportion of patients able to return to preinjury activity levels was calculated, and multivariable modeling was performed to identify risk factors for patients' inability to return to preinjury activity levels. RESULTS: A total of 1188 patients were included in the final analysis. The median preinjury Marx activity score was 16 (interquartile range, 12-16). Overall, 466 patients (39.2%) were able to return to preinjury levels of activity, and 722 patients (60.8%) were not able to return to preinjury levels of activity. Female sex, smoking at the time of ACLR, fewer years of education, lower 36-Item Short Form Health Survey Mental Component Summary scores, and higher preinjury Marx activity scores were predictive of patients' inability to return to preinjury activity levels. Graft type, revision ACLR, the presence of medial and/or lateral meniscal injuries, a history of meniscal surgery, the presence of articular cartilage injuries, a history of articular cartilage treatment, and the presence of high-grade knee laxity were not predictive of a patient's ability to return to preinjury activity level. CONCLUSION: At 2 years after ACLR, most patients with high preinjury Marx activity scores did not return to their preinjury level of activity. The higher the preinjury Marx activity score that a patient reported at the time of enrollment, the less likely he/she was able to return to preinjury activity level. Smoking and lower mental health at the time of ACLR were the only modifiable risk factors in this cohort that predicted an inability to return to preinjury activity levels. Continued effort and investigation are required to maximize functional recovery after ACLR in patients with high preinjury levels of activity.

Factors Associated With Humeral Avulsion of Glenohumeral Ligament Lesions in Patients With Anterior Shoulder Instability: An Analysis of the MOON Shoulder Instability Cohort.

Background: Humeral avulsion of the glenohumeral ligament (HAGL) lesions are an uncommon cause of anterior glenohumeral instability and may occur in isolation or combination with other pathologies. As HAGL lesions are difficult to detect via magnetic resonance imaging (MRI) and arthroscopy, they can remain unrecognized and result in continued glenohumeral instability. Purpose: To compare patients with anterior shoulder instability from a large multicenter cohort with and without a diagnosis of a HAGL lesion and identify preoperative physical examination findings, patient-reported outcomes, imaging findings, and surgical management trends associated with HAGL lesions. Study Design: Cross-sectional study; Level of evidence, 3. Methods: Patients with anterior glenohumeral instability who underwent surgical management between 2012 and 2020 at 11 orthopaedic centers were enrolled. Patients with HAGL lesions identified intraoperatively were compared with patients without HAGL lesions. Preoperative characteristics, physical examinations, imaging findings, intraoperative findings, and surgical procedures were collected. The Student t test, Kruskal-Wallis H test, Fisher exact test, and chi-square test were used to compare groups. Results: A total of 21 HAGL lesions were identified in 915 (2.3%) patients; approximately one-third (28.6%) of all lesions were visualized intraoperatively but not identified on preoperative MRI. Baseline characteristics did not differ between study cohorts. Compared with non-HAGL patients, HAGL patients were less likely to have a Hill-Sachs lesion (54.7% vs 28.6%; P = .03) or an anterior labral tear (87.2% vs 66.7%; P = .01) on preoperative MRI and demonstrated increased external rotation when their affected arm was positioned at 90° of abduction (85° vs 90°; P = .03). Additionally, HAGL lesions were independently associated with an increased risk of undergoing an open stabilization surgery (odds ratio, 74.6 [95% CI, 25.2-221.1]; P < .001). Conclusion: Approximately one-third of HAGL lesions were missed on preoperative MRI. HAGL patients were less likely to exhibit preoperative imaging findings associated with anterior shoulder instability, such as Hill-Sachs lesions or anterior labral pathology. These patients underwent open procedures more frequently than patients without HAGL lesions.

Meniscal and Articular Cartilage Predictors of Outcome After Revision ACL Reconstruction: A 6-Year Follow-up Cohort Study.

BACKGROUND: Meniscal and chondral damage is common in the patient undergoing revision anterior cruciate ligament (ACL) reconstruction. PURPOSE: To determine if meniscal and/or articular cartilage pathology at the time of revision ACL surgery significantly influences a patient's outcome at 6-year follow-up. STUDY DESIGN: Cohort study; Level of evidence, 3. METHODS: Patients undergoing revision ACL reconstruction were prospectively enrolled between 2006 and 2011. Data collection included baseline demographics, surgical technique, pathology, treatment, and scores from 4 validated patient-reported outcome instruments: International Knee Documentation Committee (IKDC), Knee injury and Osteoarthritis Outcome Score (KOOS), Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC), and Marx Activity Rating Scale. Patients were followed up at 6 years and asked to complete the identical set of outcome instruments. Regression analysis assessed the meniscal and articular cartilage pathology risk factors for clinical outcomes 6 years after revision ACL reconstruction. RESULTS: An overall 1234 patients were enrolled (716 males, 58%; median age, 26 years). Surgeons reported the pathology at the time of revision surgery in the medial meniscus (45%), lateral meniscus (36%), medial femoral condyle (43%), lateral femoral condyle (29%), medial tibial plateau (11%), lateral tibial plateau (17%), patella (30%), and trochlea (21%). Six-year follow-up was obtained on 79% of the sample (980/1234). Meniscal pathology and articular cartilage pathology (medial femoral condyle, lateral femoral condyle, lateral tibial plateau, trochlea, and patella) were significant drivers of poorer patient-reported outcomes at 6 years (IKDC, KOOS, WOMAC, and Marx). The most consistent factors driving outcomes were having a medial meniscal excision (either before or at the time of revision surgery) and patellofemoral articular cartilage pathology. Six-year Marx activity levels were negatively affected by having either a repair/excision of the medial meniscus (odds ratio range, 1.45-1.72; P≤ .04) or grade 3-4 patellar chondrosis (odds ratio, 1.72; P = .04). Meniscal pathology occurring before the index revision surgery negatively affected scores on all KOOS subscales except for sports/recreation (P < .05). Articular cartilage pathology significantly impaired all KOOS subscale scores (P < .05). Lower baseline outcome scores, higher body mass index, being a smoker, and incurring subsequent surgery all significantly increased the odds of reporting poorer clinical outcomes at 6 years. CONCLUSION: Meniscal and chondral pathology at the time of revision ACL reconstruction has continued significant detrimental effects on patient-reported outcomes at 6 years after revision surgery.

Spatially distinct actions of metabotropic glutamate receptor activation in dorsal lateral geniculate nucleus.

Thalamocortical neurons in the dorsal lateral geniculate nucleus (dLGN) dynamically communicate visual information from the retina to the neocortex, and this process can be modulated via activation of metabotropic glutamate receptors (mGluRs). Neurons within dLGN express different mGluR subtypes associated with distinct afferent synaptic pathways; however, the physiological function of this organization is unclear. We report that the activation of mGluR(5), which are located on presynaptic dendrites of local interneurons, increases GABA output that in turn produces an increased inhibitory activity on proximal but not distal dendrites of dLGN thalamocortical neurons. In contrast, mGluR(1) activation produces strong membrane depolarization in thalamocortical neurons regardless of distal or proximal dendritic locations. These findings provide physiological evidence that mGluR(1) appear to be distributed along the thalamocortical neuron dendrites, whereas mGluR(5)-dependent action occurs on the proximal dendrites/soma of thalamocortical neurons. The differential distribution and activation of mGluR subtypes on interneurons and thalamocortical neurons may serve to shape excitatory synaptic integration and thereby regulate information gating through the thalamus.

A Review of Evidence for Infection Reduction With Vancomycin-treated Anterior Cruciate Ligament Grafts.

Septic arthritis after anterior cruciate ligament (ACL) reconstruction is a rare but devastating complication. Several risk factors and known sources of infection have been identified in the literature. There is growing interest and supportive evidence for a targeted invention aimed at graft decontamination, which has led some surgeons to adopt the use of antibiotic solution soaks and/or wraps applied to ACL grafts before graft implantation in an attempt to reduce the risk of postoperative infection. Despite this, adoption of this technique remains relatively low among surgeons because of a variety of factors: (1) lack of awareness, (2) confusion over optimal protocols, (3) concern for graft viability and clinical outcomes, and (4) efforts to minimize the cost of surgery. However, recently published literature demonstrates notable risk reduction for infection, acceptable safety, no detrimental effect on clinical outcomes, and overall cost-effectiveness with the use of vancomycin graft soaks and wraps. Currently, there is a lack of consensus for clinical protocols, and the protocol that is most efficacious remains unclear. The purpose of this review article was to present the current evidence for ACL graft treatment with vancomycin for the prevention of postoperative infection.