Preoperative Opioid Use is Associated with Worse Preoperative Patient Reported Outcomes in Hip Arthroscopy Patients.

OBJECTIVES: The purpose of this study was to define the rate of preoperative opioid use among patients undergoing hip arthroscopy, ascertain which clinical factors are associated with opioid use, and assess the effect of preoperative opioid usage on preoperative patient-reported outcome (PRO) measures. METHODS: A single institution orthopaedic registry was retrospectively analyzed for patients undergoing hip arthroscopy for femoroacetabular impingement syndrome (FAI) with or without labral tear between 2015 and 2022. Patients completed Patient-Reported Outcomes Measurement Information System (PROMIS) in six domains, Numeric Pain Scores (NPS), and Musculoskeletal Outcomes Data Evaluation and Management System expectations domain preoperatively. Patients' charts were reviewed to determine demographic factors and identify any active opioid prescription within 6 weeks before surgery. Bivariate analysis was used to determine associations between preoperative opioid use and baseline PROs. Statistically significant bivariate associations were further tested by multivariate analysis to determine independent predictors. RESULTS: A total of 123 patients were included (age 39.7 ± 12.0 years; 87 females; body mass index 27.4 ± 5.7 kg/m2). There were 21 patients (17%) using opioids preoperatively. Prior orthopaedic or other surgery and lower education level was associated with preoperative opioid use. Patients with preoperative opioid use scored statistically significantly worse compared to those without preoperative opioid use on baseline PROMIS Physical Function (38.6 vs 40.5, p = 0.01), Pain Interference (65.9 vs 60.2, p = 0.001), Fatigue (60.7 vs 51.6, p = 0.005), Social Satisfaction (38.2 vs 43.2, p = 0.007), and Depression (54.2 vs 48.8, p = 0.01). Preoperative opioid use was also associated with statistically significantly worse pre-operative NPS for both the operative hip (6.3 vs 4.6, p = 0.003) and whole body (3.0 vs 1.4, p = 0.008). Preoperative opioid use was an independent predictor of worse baseline PROMIS Pain Interference, Fatigue, Social Satisfaction, and NPS for the operative hip. CONCLUSION: Patients using opioids preoperatively had worse baseline PROs for physical function, pain, social satisfaction, and depression than those not using opioids preoperatively. When controlling for confounding variables, preoperative opioid use was independently predictive of worse baseline pain, fatigue, and social satisfaction. LEVEL OF EVIDENCE: Level III, prognostic study.

Designing Biomimetic 3D-Printed Osteochondral Scaffolds for Enhanced Load-Bearing Capacity.

Osteoarthritis is a debilitating chronic joint disorder that affects millions of people worldwide. Since palliative and surgical treatments cannot completely regenerate hyaline cartilage within the articulating joint, osteochondral (OC) tissue engineering has been explored to heal OC defects. Utilizing computational simulations and three-dimensional (3D) printing, we aimed to build rationale around fabricating OC scaffolds with enhanced biomechanics. First, computational simulations revealed that interfacial fibrils within a bilayer alter OC scaffold deformation patterns by redirecting load-induced stresses toward the top of the cartilage layer. Principal component analysis revealed that scaffolds with 800 µm long fibrils (scaffolds 8A-8H) possessed optimal biomechanical properties to withstand compression and shear forces. While compression testing indicated that OC scaffolds with 800 µm fibrils did not have greater compressive moduli than other scaffolds, interfacial shear tests indicated that scaffold 8H possessed the greatest shear strength. Lastly, failure analysis demonstrated that yielding or buckling models describe interfacial fibril failure depending on fibril slenderness S. Specifically for scaffolds with packing density n = 6 and n = 8, the yielding failure model fits experimental loads with S < 10, while the buckling model fitted scaffolds with S < 10 slenderness. The research presented provides critical insights into designing 3D printed interfacial scaffolds with refined biomechanics toward improving OC tissue engineering outcomes.

Development of a patient specific cartilage graft using magnetic resonance imaging and 3D printing.

OBJECTIVES: The goal of this project was to develop and validate a patient-specific, anatomically correct graft for cartilage restoration using magnetic resonance imaging (MRI) data and 3-dimensional (3D) printing technology. The specific aim was to test the accuracy of a novel method for 3D printing and implanting individualized, anatomically shaped bio-scaffolds to treat cartilage defects in a human cadaveric model. We hypothesized that an individualized, anatomic 3D-printed scaffold designed from MRI data would provide a more optimal fill for a large cartilage defect compared to a generic flat scaffold. METHODS: Four focal cartilage defects (FCDs) were created in paired human cadaver knees, age <40 years, in the weight-bearing surfaces of the medial femoral condyle (MFC), lateral femoral condyle (LFC), patella, and trochlea of each knee. MRIs were obtained, anatomic grafts were designed and 3D printed for the left knee as an experimental group, and generic flat grafts for the right knee as a control group. Grafts were implanted into corresponding defects and fixed using tissue adhesive. Repeat post-implant MRIs were obtained. Graft step-off was measured as the distance in mm between the surface of the graft and the native cartilage surface in a direction perpendicular to the subchondral bone. Graft contour was measured as the gap between the undersurface of the graft and the subchondral bone in a direction perpendicular to the joint surface. RESULTS: Graft step-off was statistically significantly better for the anatomic grafts compared to the generic grafts in the MFC (0.0 â€‹± â€‹0.2 â€‹mm vs. 0.7 â€‹± â€‹0.5 â€‹mm, p â€‹< â€‹0.001), LFC (0.1 â€‹± â€‹0.3 â€‹mm vs. 1.0 â€‹± â€‹0.2 â€‹mm, p â€‹< â€‹0.001), patella (-0.2 â€‹± â€‹0.3 â€‹mm vs. -1.2 â€‹± â€‹0.4 â€‹mm, p â€‹< â€‹0.001), and trochlea (-0.4 â€‹± â€‹0.3 vs. 0.4 â€‹± â€‹0.7, p â€‹= â€‹0.003). Graft contour was statistically significantly better for the anatomic grafts in the LFC (0.0 â€‹± â€‹0.0 â€‹mm vs. 0.2 â€‹± â€‹0.4 â€‹mm, p â€‹= â€‹0.022) and trochlea (0.0 â€‹± â€‹0.0 â€‹mm vs. 1.4 â€‹± â€‹0.7 â€‹mm, p â€‹< â€‹0.001). The anatomic grafts had an observed maximum step-off of -0.9 â€‹mm and a maximum contour mismatch of 0.8 â€‹mm. CONCLUSION: This study validates a process designed to fabricate anatomically accurate cartilage grafts using MRI and 3D printing technology. Anatomic grafts demonstrated superior fit compared to generic flat grafts. LEVEL OF EVIDENCE: Level IV.

Enhanced fear memory after social defeat in mice is dependent on interleukin-1 receptor signaling in glutamatergic neurons.

Chronic stress is associated with increased anxiety, cognitive deficits, and post-traumatic stress disorder. Repeated social defeat (RSD) in mice causes long-term stress-sensitization associated with increased microglia activation, monocyte accumulation, and enhanced interleukin (IL)-1 signaling in endothelia and neurons. With stress-sensitization, mice have amplified neuronal, immune, and behavioral responses to acute stress 24 days later. This is clinically relevant as it shares key aspects with post-traumatic stress disorder. The mechanisms underlying stress-sensitization are unclear, but enhanced fear memory may be critical. The purpose of this study was to determine the influence of microglia and IL-1R1 signaling in neurons in the development of sensitization and increased fear memory after RSD. Here, RSD accelerated fear acquisition, delayed fear extinction, and increased cued-based freezing at 0.5 day. The enhancement in contextual fear memory after RSD persisted 24 days later. Next, microglia were depleted with a CSF1R antagonist prior to RSD and several parameters were assessed. Microglia depletion blocked monocyte recruitment to the brain. Nonetheless, neuronal reactivity (pCREB) and IL-1ß RNA expression in the hippocampus and enhanced fear memory after RSD were microglial-independent. Because IL-1ß RNA was prominent in the hippocampus after RSD even with microglia depletion, IL-1R1 mediated signaling in glutamatergic neurons was assessed using neuronal Vglut2+/IL-1R1-/- mice. RSD-induced neuronal reactivity (pCREB) in the hippocampus and enhancement in fear memory were dependent on neuronal IL-1R1 signaling. Furthermore, single-nuclei RNA sequencing (snRNAseq) showed that RSD influenced transcription in specific hippocampal neurons (DG neurons, CA2/3, CA1 neurons) associated with glutamate signaling, inflammation and synaptic plasticity, which were neuronal IL-1R1-dependent. Furthermore, snRNAseq data provided evidence that RSD increased CREB, BDNF, and calcium signaling in DG neurons in an IL-1R1-dependent manner. Collectively, increased IL-1R1-mediated signaling (monocytes/microglia independent) in glutamatergic neurons after RSD enhanced neuronal reactivity and fear memory.

Biomechanical Comparison of Four- versus Six-Strand Transosseous Suture Repair for Patellar Tendon Rupture.

BACKGROUND: Surgical repair is indicated for patellar tendon ruptures that result in loss of knee extensor mechanism function. However, biomechanical studies report conflicting results when comparing transosseous suture versus suture anchor repair techniques. This discrepancy may be due to inconsistencies in experimental design as these studies use various numbers of suture strands. Therefore, the main objective of this study is to compare the ultimate load of four- versus six-strand transosseous suture repair. Secondary objectives are to compare gap formation after cyclical loading and mode of failure. METHODS: Six pairs of fresh-frozen cadaveric specimen were randomly allocated to either four- or six-strand transosseous suture repair. Specimen underwent preconditioning cyclical loading and then load to failure. RESULTS: The six-strand repair had a significantly higher maximum load to failure compared with the four-strand repair (mean difference = 319.3 N [57.9%], p = 0.03). There was no significant difference in gap length after cyclical loading or at max load. There were no significant differences in mode of failure. CONCLUSION: Utilizing a six-stand transosseous patella tendon repair construct with one additional suture increases overall construct strength by over 50% compared with a four-strand construct.

Patient-Reported Outcome Measurement Information System Depression and Anxiety in Elective Knee Surgery Patients.

Mental health has been shown to play an important role in patient-reported outcomes (PRO); however, there is a general lack of literature describing patient-reported outcome measurement information system (PROMIS) depression and anxiety computer adaptive tests in elective knee surgery patients. The purpose of our study was to assess the prevalence of depression and anxiety symptoms before and after elective knee surgery and to determine whether these symptoms influence postoperative functional outcomes. An institutional review board-approved prospective orthopaedic registry was retrospectively queried for patients undergoing elective knee surgery from June 2015 to November 2018. Electronic surveys collecting patient demographic information and PROs were administered pre- and postoperatively. Of the 663 patients that completed baseline questionnaires, 466 completed 2-year follow-up (70.3%). PROs included PROMIS depression, PROMIS anxiety, International Knee Documentation Committee Subjective Knee Form (IKDC), and PROMIS physical function (PF). Wilcoxon rank sum and Spearman's rank order correlation were utilized to determine associations between variables. Multivariable analysis was used to control for confounding variables. Average PROMIS depression and anxiety scores significantly improved 2 years after surgery. PROMIS depression and anxiety scores significantly correlated with each other. PROMIS depression and anxiety scores significantly correlated with PROMIS PF and IKDC scores. After controlling for confounders on multivariable analysis, worse 2-year PROMIS anxiety was predictive of less functional improvement and worse 2-year PF and IKDC, while worse 2-year PROMIS depression was predictive of less improvement in IKDC. This study confirms the important relationship between mental health and functional outcomes. Given that psychiatric comorbidities are potentially modifiable with treatment, proper recognition could potentially lead to better orthopaedic outcomes. In addition, the prevalence of depression and anxiety symptoms postoperatively, as documented by PROMIS computer adaptive tests, may act as a barrier to achieving optimal functional outcomes after elective knee surgery. LEVEL OF EVIDENCE: Level III.

Dystrophin deficiency impairs cell junction formation during embryonic myogenesis.

Mutations in the DMD gene lead to Duchenne muscular dystrophy, a severe X-linked neuromuscular disorder that manifests itself as young boys acquire motor functions. DMD is typically diagnosed at 2 to 4 years of age, but the absence of dystrophin negatively impacts muscle structure and function before overt symptoms appear in patients, which poses a serious challenge in the optimization of standards of care. In this report, we investigated the early consequences of dystrophin deficiency during skeletal muscle development. We used single-cell transcriptome profiling to characterize the myogenic trajectory of human pluripotent stem cells and showed that DMD cells bifurcate to an alternative branch when they reach the somite stage. Here, dystrophin deficiency was linked to marked dysregulations of cell junction protein families involved in the cell state transitions characteristic of embryonic somitogenesis. Altogether, this work demonstrates that in vitro, dystrophin deficiency has deleterious effects on cell-cell communication during myogenic development, which should be considered in future therapeutic strategies for DMD.

Impaired cortical neuronal homeostasis and cognition after diffuse traumatic brain injury are dependent on microglia and type I interferon responses.

Neuropsychiatric complications including depression and cognitive decline develop in the years after traumatic brain injury (TBI), negatively affecting quality of life. Microglial and type 1 interferon (IFN-I) responses are associated with the transition from acute to chronic neuroinflammation after diffuse TBI in mice. Thus, the purpose of this study was to determine if impaired neuronal homeostasis and increased IFN-I responses intersected after TBI to cause cognitive impairment. Here, the RNA profile of neurons and microglia after TBI (single nucleus RNA-sequencing) with or without microglia depletion (CSF1R antagonist) was assessed 7 dpi. There was a TBI-dependent suppression of cortical neuronal homeostasis with reductions in CREB signaling, synaptogenesis, and synaptic migration and increases in RhoGDI and PTEN signaling (Ingenuity Pathway Analysis). Microglial depletion reversed 50% of TBI-induced gene changes in cortical neurons depending on subtype. Moreover, the microglial RNA signature 7 dpi was associated with increased stimulator of interferon genes (STING) activation and IFN-I responses. Therefore, we sought to reduce IFN-I signaling after TBI using STING knockout mice and a STING antagonist, chloroquine (CQ). TBI-associated cognitive deficits in novel object location and recognition (NOL/NOR) tasks at 7 and 30 dpi were STING dependent. In addition, TBI-induced STING expression, microglial morphological restructuring, inflammatory (Tnf, Cd68, Ccl2) and IFN-related (Irf3, Irf7, Ifi27) gene expression in the cortex were attenuated in STINGKO mice. CQ also reversed TBI-induced cognitive deficits and reduced TBI-induced inflammatory (Tnf, Cd68, Ccl2) and IFN (Irf7, Sting) cortical gene expression. Collectively, reducing IFN-I signaling after TBI with STING-dependent interventions attenuated the prolonged microglial activation and cognitive impairment.

PROMIS cluster analysis predicts two-year outcomes in knee surgery patients.

Aims & objectives: Meaningful clinical interpretation of orthopaedic patient-reported outcome scores remains challenging. Grouping scores may be more meaningful than individual score analysis. The purpose of this study was to determine if grouping knee surgery patients into four preoperative Patient-Reported Outcomes Measurement Information System (PROMIS) clusters would have prognostic value for two-year postoperative outcomes. Materials & methods: 488 of 697 (70%) patients undergoing elective knee surgery at a single urban institution were enrolled in an orthopaedic registry and completed two-year follow up. Patients were administered questionnaires for PROMIS, International Knee Documentation Committee Score (IKDC), Marx Activity Rating Scale (MARS), and Surgical Satisfaction (SSQ-8). A k-means cluster analysis was performed to identify preoperative PROMIS clusters. Chi-square or Kruskal-Wallis tests were conducted for bivariate analyses. Least-squares multiple linear regression models were performed to identify if cluster group was an independent predictor. Results: Cluster analysis revealed four clusters of patients. Psychological distress was most significant in determining classification. More impaired clusters were associated with higher rates of arthroplasty, African American race, preoperative opioid use, lower income, higher comorbidity index, and other sociodemographic and operative factors. Worse preoperative cluster status was associated with higher chance of achieving minimally clinically important change (MCID) on all metrics except PROMIS Pain Interference (PI), IKDC, and MARS. Multivariable analysis confirmed better preoperative cluster as predictive of better PROMIS Physical Function (PF), PI, IKDC scores, and satisfaction. Worse preoperative cluster was predictive of greater improvement on PF and PI but not IKDC. Conclusion: Preoperative PROMIS clusters have prognostic value in predicting outcomes for knee surgery patients. Better preoperative cluster function predicts superior outcomes. While worse preoperative cluster predicts worse outcome, all clusters still significantly improve, so worse preoperative cluster is not a contraindication to surgery.

Perioperative Opioid Use in Anterior Cruciate Ligament Reconstruction Patients.

Anterior cruciate ligament reconstruction (ACLR) is one of the most commonly performed outpatient orthopaedic procedures, yet there is little data about perioperative opioid prescribing practices. The purposes of this study were to quantify the perioperative opioid prescriptions filled by patients who underwent ACLR and to identify factors associated with greater postoperative opioid use. Patients who underwent ACLR at a single institution between June 2015 and May 2017 were studied using a regional prescription monitoring database to identify all preoperative and postoperative outpatient opioid prescriptions up to 2 years postoperatively. The number of morphine milligram equivalents of each opioid was calculated to determine total morphine milligram equivalents (TMEs) filled preoperatively, at discharge, and refilled postoperatively. Patients who refilled an opioid prescription postoperatively were compared with those who did not. Ninety-nine of 269 (36.8%) total patients refilled an opioid prescription postoperatively. Thirty-three patients (12.3%) required a refill after 2 weeks postoperatively, and no patients refilled after 21 months postoperatively. Fifty-seven patients (21%) received an opioid prescription in the 2 years following surgery that was unrelated to their ACL reconstruction. Increased age, higher body mass index (BMI), government insurance, current or prior tobacco use history, preoperative opioid use, and greater number of medical comorbidities were significantly associated with refilling a prescription opioid. Higher BMI and government insurance were independent predictors of refilling. Higher preoperative TMEs and surgeon were independent predictor of greater refill TMEs. In the opioid-naïve subgroup of 177 patients, only higher BMI was a predictor of refilling, and only greater comorbidities was a predictor of greater refill TMEs. The results demonstrate that preoperative opioid use was associated with postoperative opioid refills and higher refill TMEs in a dose-dependent fashion. A higher percentage of patients received an opioid prescription for reasons unrelated to the ACL reconstruction than refilled a prescription after the first 2 weeks postoperatively.

Response Bias for Press Ganey Ambulatory Surgery Surveys after Knee Surgery.

The Press Ganey Ambulatory Surgery (PGAS) survey is an emerging tool used to capture patient satisfaction after elective surgery. Evaluating patient satisfaction is important; however, quality improvement (QI) surveys used to capture the patient experience may be subject to nonresponse bias. An orthopaedic registry was used to retrospectively identify patients who underwent ambulatory knee surgery from June 2015 to December 2019. Multivariable logistic regression was performed to identify independent predictors of PGAS survey nonresponse and response. In the cohort of 1,161 patients, 142 (12.2%) completed the PGAS survey. Multiple logistic regression demonstrated that male sex, Black race, not living with a caretaker, student or unemployment status, and worse preoperative Patient-Reported Outcomes Measurement Information System (PROMIS) fatigue were predictors of nonresponse. The results of this study highlight the presence of nonresponse bias in the PGAS survey after elective knee surgery.

Preoperative Factors Associated with Press Ganey Patient Satisfaction Scores after Anterior Cruciate Ligament Reconstruction.

Patient satisfaction is increasingly used as a metric to evaluate the quality of healthcare services and to determine hospital and physician compensation. The aim of this study was to identify preoperative factors associated with Press Ganey Ambulatory Surgery (PGAS) satisfaction scores, and to evaluate the effect of each PGAS domain score on the total PGAS score variability in patients undergoing anterior cruciate ligament reconstruction (ACLR). A review of a Press Ganey (PG) database at a single center was performed for patients undergoing ACLR between 2015 and 2019. Ninety-nine patients completed the PGAS survey and 54 also completed preoperative demographic and patient-reported outcome measures (PROMs) for an orthopaedic registry. PGAS scores were calculated and bivariate analysis was performed. Multivariable linear regression determined the effect of each of the six PGAS domains on the total PGAS score variability. In the total cohort of 99 patients, no factors were significantly associated with the total PGAS score or any domain scores. For the 54 patients who also participated in the orthopaedic registry, none of the preoperative PROMs were significantly correlated with total PGAS score. However, having a college degree (89 vs. 95 or 97 points; p = 0.02) and continuous femoral nerve catheter (92 vs. 100 points; p = 0.04) was associated with lower personal issue domain scores, while patients with a greater number of prior surgeries had worse registration domain scores (ρ = -0.27; p = 0.049). For the entire cohort, the registration and facility domains contributed the most variability to the total PGAS score, while the physician domain contributed the least. Few preoperative factors are associated with PGAS scores, and total PGAS scores do not significantly correlate with baseline PROMs. Surgeons may have limited ability to improve their PGAS scores given most of the variability in total scores stems from systemic aspects of the patient experience.

Amplified Gliosis and Interferon-Associated Inflammation in the Aging Brain following Diffuse Traumatic Brain Injury.

Traumatic brain injury (TBI) is associated with chronic psychiatric complications and increased risk for development of neurodegenerative pathology. Aged individuals account for most TBI-related hospitalizations and deaths. Nonetheless, neurobiological mechanisms that underlie worsened functional outcomes after TBI in the elderly remain unclear. Therefore, this study aimed to identify pathways that govern differential responses to TBI with age. Here, adult (2 months of age) and aged (16-18 months of age) male C57BL/6 mice were subjected to diffuse brain injury (midline fluid percussion), and cognition, gliosis, and neuroinflammation were determined 7 or 30 d postinjury (dpi). Cognitive impairment was evident 7 dpi, independent of age. There was enhanced morphologic restructuring of microglia and astrocytes 7 dpi in the cortex and hippocampus of aged mice compared with adults. Transcriptional analysis revealed robust age-dependent amplification of cytokine/chemokine, complement, innate immune, and interferon-associated inflammatory gene expression in the cortex 7 dpi. Ingenuity pathway analysis of the transcriptional data showed that type I interferon (IFN) signaling was significantly enhanced in the aged brain after TBI compared with adults. Age prolonged inflammatory signaling and microgliosis 30 dpi with an increased presence of rod microglia. Based on these results, a STING (stimulator of interferon genes) agonist, DMXAA, was used to determine whether augmenting IFN signaling worsened cortical inflammation and gliosis after TBI. DMXAA-treated Adult-TBI mice showed comparable expression of myriad genes that were overexpressed in the cortex of Aged-TBI mice, including Irf7, Clec7a, Cxcl10, and Ccl5 Overall, diffuse TBI promoted amplified IFN signaling in aged mice, resulting in extended inflammation and gliosis.SIGNIFICANCE STATEMENT Elderly individuals are at higher risk of complications following traumatic brain injury (TBI). Individuals >70 years old have the highest rates of TBI-related hospitalization, neurodegenerative pathology, and death. Although inflammation has been linked with poor outcomes in aging, the specific biological pathways driving worsened outcomes after TBI in aging remain undefined. In this study, we identify amplified interferon-associated inflammation and gliosis in aged mice following TBI that was associated with persistent inflammatory gene expression and microglial morphologic diversity 30 dpi. STING (stimulator of interferon genes) agonist DMXAA was used to demonstrate a causal link between augmented interferon signaling and worsened neuroinflammation after TBI. Therefore, interferon signaling may represent a therapeutic target to reduce inflammation-associated complications following TBI.

Chronic Cortical Inflammation, Cognitive Impairment, and Immune Reactivity Associated with Diffuse Brain Injury Are Ameliorated by Forced Turnover of Microglia.

Traumatic brain injury (TBI) is associated with an increased risk of cognitive, psychiatric, and neurodegenerative complications that may develop after injury. Increased microglial reactivity following TBI may underlie chronic neuroinflammation, neuropathology, and exaggerated responses to immune challenges. Therefore, the goal of this study was to force turnover of trauma-associated microglia that develop after diffuse TBI and determine whether this alleviated chronic inflammation, improved functional recovery and attenuated reduced immune reactivity to lipopolysaccharide (LPS) challenge. Male mice received a midline fluid percussion injury (mFPI) and 7 d later were subjected to a forced microglia turnover paradigm using CSF1R antagonism (PLX5622). At 30 d postinjury (dpi), cortical gene expression, dendritic complexity, myelin content, neuronal connectivity, cognition, and immune reactivity were assessed. Myriad neuropathology-related genes were increased 30 dpi in the cortex, and 90% of these gene changes were reversed by microglial turnover. Reduced neuronal connectivity was evident 30 dpi and these deficits were attenuated by microglial turnover. TBI-associated dendritic remodeling and myelin alterations, however, remained 30 dpi independent of microglial turnover. In assessments of functional recovery, increased depressive-like behavior, and cognitive impairment 30 dpi were ameliorated by microglia turnover. To investigate microglial priming and reactivity 30 dpi, mice were injected intraperitoneally with LPS. This immune challenge caused prolonged lethargy, sickness behavior, and microglial reactivity in the TBI mice. These extended complications with LPS in TBI mice were prevented by microglia turnover. Collectively, microglial turnover 7 dpi alleviated behavioral and cognitive impairments associated with microglial priming and immune reactivity 30 dpi.SIGNIFICANCE STATEMENT A striking feature of traumatic brain injury (TBI), even mild injuries, is that over 70% of individuals have long-term neuropsychiatric complications. Chronic inflammatory processes are implicated in the pathology of these complications and these issues can be exaggerated by immune challenge. Therefore, our goal was to force the turnover of microglia 7 d after TBI. This subacute 7 d postinjury (dpi) time point is a critical transitional period in the shift toward chronic inflammatory processes and microglia priming. This forced microglia turnover intervention in mice attenuated the deficits in behavior and cognition 30 dpi. Moreover, microglia priming and immune reactivity after TBI were also reduced with microglia turnover. Therefore, microglia represent therapeutic targets after TBI to reduce persistent neuroinflammation and improve recovery.

Correlation of Press Ganey Scores With Early Patient Satisfaction After Anterior Cruciate Ligament Reconstruction.

Background: Patient satisfaction metrics are commonly used to assess the quality of health care and affect reimbursement. The Press Ganey Ambulatory Surgery (PGAS) is a satisfaction survey that has emerged as a prominent quality assessment tool; however, no data exist on whether PGAS scores correlate with early postsurgical satisfaction during the PGAS survey administration period in patients who underwent anterior cruciate ligament reconstruction (ACLR). Purpose: To determine if PGAS scores correlate with measures of satisfaction and patient-reported outcomes (PROs) at 2 weeks postoperatively in ACLR patients. Study Design: Cohort study (diagnosis); Level of evidence, 3. Methods: A retrospective review of patients who underwent ACLR at a single institution was performed. Patients who completed the PGAS survey and PROs at 2 weeks postoperatively were included in the study. Surgical satisfaction was measured with the Surgical Satisfaction Questionnaire (SSQ-8), and PROs included 6 Patient-Reported Outcomes Measurement Information System domains. Bivariate analysis between PGAS and PRO scores was conducted using the Spearman rank correlation coefficient (r S). Results: Of the 716 patients who received the PGAS survey after ACLR, 81 patients completed the survey, and 39 patients also completed PROs and were included in the study. Total converted (mean scaled score) and "top box" (percentages of questions with highest rating selected) PGAS scores showed no significant correlations with the SSQ-8 (r S =-0.24; P = .14). There were no significant correlations between SSQ-8 and PGAS domain scores except for a negative correlation with Facility domain top box scores (r S =-0.33; P = .04), meaning that patients with higher surgical satisfaction had lower PGAS Facility scores. Total PGAS (converted and top box scores) and PGAS domain scores showed no significant correlation with any of the other PROs. Conclusion: PGAS scores showed no significant positive correlation with surgical satisfaction, function, pain, mental health, activity, or expectations of surgery in patients 2 weeks after ACLR. This suggests little to no relationship between PGAS score and surgical satisfaction in the early recovery period after ACLR.

Long-Term Outcomes of Multiligament Knee Injuries.

OBJECTIVE: To characterize long-term outcomes of multiligament knee injuries (MLKIs) using patient-reported outcome measures, physical examination, and knee radiographs. DESIGN: Retrospective clinical follow-up. METHODS: Twenty knees (18 patients) were evaluated at a mean follow-up of 13.1 years (range 11-15 years). The primary outcome measure was the Internal Knee Documentation Committee score. Patients also completed secondary patient-based outcome assessments including Patient-Reported Outcomes Measurement Information System computer adaptive testing, Short Form-36, and Tegner activity score. Sixteen knees (14 patients) also had physical examination and bilateral knee radiographs assessed with the Kellgren-Lawrence score. RESULTS: The mean Internal Knee Documentation Committee score was 56 points, which was significantly lower than the age-matched normative value of 77 ( P = 0.004) and exceeds the minimum clinically important difference of 12 points. Most secondary outcome scores were worse than normative population values. Posttraumatic arthritis was present in 100% of MLKIs that had radiographs. Comparing operative versus nonoperative management, there were no statistical differences in patient demographics, injury characteristics, physical examination, or imaging, but surgical patients had better Short Form-36 Social Functioning (89 vs. 63, P = 0.02) and Tegner scores (4.5 vs. 2.9, P = 0.05). CONCLUSION: The long-term outcomes of MLKIs are generally poor, and posttraumatic radiographic evidence of arthritis seems to be universal . Operative management of these injuries may improve long-term outcomes. Clinicians should be aware of these results when counseling patients. LEVEL OF EVIDENCE: Therapeutic Level IV. See Instructions for Authors for a complete description of levels of evidence.

Computational investigation of interface printing patterns within 3D printed multilayered scaffolds for osteochondral tissue engineering.

Osteoarthritis is a highly prevalent rheumatic musculoskeletal disorder that commonly affects many joints. Repetitive joint overloading perpetuates the damage to the affected cartilage, which undermines the structural integrity of the osteochondral unit. Various tissue engineering strategies have been employed to design multiphasic osteochondral scaffolds that recapitulate layer-specific biomechanical properties, but the inability to fully satisfy mechanical demands within the joint has limited their success. Through computational modeling and extrusion-based bioprinting, we attempted to fabricate a biphasic osteochondral scaffold with improved shear properties and a mechanically strong interface. A 3D stationary solid mechanics model was developed to simulate the effect of lateral shear force on various thermoplastic polymer/hydrogel scaffolds with a patterned interface. Additionally, interfacial shear tests were performed on bioprinted polycaprolactone (PCL)/hydrogel interface scaffolds. The first simulation showed that the PCL/gelatin methacrylate (GelMA) and PCL/polyethylene glycol diacrylate (PEGDA) scaffolds interlocking hydrogel and PCL at interface in a 1:1 ratio possessed the largest average tensile (PCL/GelMA: 80.52 kPa; PCL/PEGDA: 79.75 kPa) and compressive stress (PCL/GelMA: 74.71 kPa; PCL/PEGDA: 73.83 kPa). Although there were significant differences in shear strength between PCL/GelMA and PCL/PEGDA scaffolds, no significant difference was observed among the treatment groups within both scaffold types. Lastly, the hypothetical simulations of potential biphasic 3D printed scaffolds showed that for every order of magnitude decrease in Young's modulus (E) of the soft bioink, all the scaffolds underwent an exponential increase in average displacement at the cartilage and interface layers. The following work provides valuable insights into the biomechanics of 3D printed osteochondral scaffolds, which will help inform future scaffold designs for enhanced regenerative outcomes.

Patient Perception of Being "Completely Better" After Anterior Cruciate Ligament Reconstruction.

BACKGROUND: Contextualizing patient-reported outcomes (PROs) by defining clinically relevant differences is important. Considering that anterior cruciate ligament reconstruction (ACLR) ideally results in the restoration of normal knee function, an assessment of patients' perception of being "completely better" (CB) may be of particular value. PURPOSE: The purpose of this study was to assess the prevalence and characteristics of patients who self-report a CB status after ACLR. Additionally, we aimed to determine whether PROs were associated with a CB status after ACLR as well as to determine CB status thresholds for 2-year and change in values. STUDY DESIGN: Case-control study; Level of evidence, 3. METHODS: We retrospectively analyzed data from an orthopaedic registry at a single institution. Patients were administered the Patient-Reported Outcomes Measurement Information System (PROMIS) Physical Function (PF), PROMIS Pain Interference (PI), and International Knee Documentation Committee (IKDC) Subjective Knee Form preoperatively and at 2 years after ACLR. Additionally, patients completed a CB anchor question at 2 years after ACLR. Thresholds for 2-year and change in PRO scores associated with achieving a CB status were identified with 90% specificity. RESULTS: Overall, 95 of the 136 patients (69.9%) considered their condition to be CB at 2 years after surgery. The 2-year and change in PROMIS PF, PROMIS PI, and IKDC scores were significantly better in the CB group than in the non-CB group. Thresholds associated with a CB status for 2-year PROMIS PF, PROMIS PI, and IKDC scores were more reliable than those for changes in scores and were ≥63, ≤44, and ≥80, respectively. Thresholds for the change in PROMIS PF, PROMIS PI, and IKDC scores were ≥19, ≤-16, and ≥44, respectively. CONCLUSION: The majority of patients reported that they were CB at 2 years after ACLR. This study may serve as a reference for orthopaedic surgeons and researchers when considering outcomes after ACLR.

Impact of Preoperative Opioid Use on 2-Year Patient-Reported Outcomes in Knee Surgery Patients.

The objectives of this study are to assess perioperative opioid use in patients undergoing knee surgery and to examine the relationship between preoperative opioid use and 2-year postoperative patient-reported outcomes (PROs). We hypothesized that preoperative opioid use and, more specifically, higher quantities of preoperative opioid use would be associated with worse PROs in knee surgery patients. We studied 192 patients undergoing knee surgery at a single urban institution. Patients completed multiple PRO measures preoperatively and 2-year postoperatively, including six patient-reported outcomes measurement information system (PROMIS) domains; the International Knee Documentation Committee (IKDC) questionnaire, numeric pain scale (NPS) scores for the operative knee and the rest of the body, Marx's knee activity rating scale, Tegner's activity scale, International Physical Activity Questionnaire, as well as measures of met expectations, overall improvement, and overall satisfaction. Total morphine equivalents (TMEs) were calculated from a regional prescription monitoring program. Eighty patients (41.7%) filled an opioid prescription preoperatively, and refill TMEs were significantly higher in this subpopulation. Opioid use was associated with unemployment, government insurance, smoking, depression, history of prior surgery, higher body mass index, greater comorbidities, and lower treatment expectations. Preoperative opioid use was associated with significantly worse 2-year scores on most PROs, including PROMIS physical function, pain interference, fatigue, social satisfaction, IKDC, NPS for the knee and rest of the body, and Marx's and Tegner's scales. There was a significant dose-dependent association between greater preoperative TMEs and worse scores for PROMIS physical function, pain interference, fatigue, social satisfaction, NPS body, and Marx's and Tegner's scales. Multivariable analysis confirmed that any preoperative opioid use, but not quantity of TMEs, was an independent predictor of worse 2-year scores for function, activity, and knee pain. Preoperative opioid use and TMEs were neither independent predictors of met expectations, satisfaction, patient-perceived improvement, nor improvement on any PROs. Our findings demonstrate that preoperative opioid use is associated with clinically relevant worse patient-reported knee function and pain after knee surgery.

Biomechanical Aspects of Osteochondral Regeneration: Implications and Strategies for Three-Dimensional Bioprinting.

Osteoarthritis is among the most prevalent of musculoskeletal disorders in the world that causes joint pain, deformity, and limited range of movement. The resulting osteochondral defect can significantly decrease the patient's quality of life, but current treatment options have not demonstrated the capacity to fully regenerate the entire osteochondral microenvironment. Structurally, the osteochondral unit is a composite system composed of three layers-articular cartilage, calcified cartilage, and subchondral bone. Collectively these distinct layers contribute to the distinct biomechanical properties that maintain the health and aid in load transfer during joint articulation. The purpose of this review was to examine the role of the osteochondral interface in tissue engineering. Topics of discussion include the biomechanics of the osteochondral unit and an overview of various strategies for osteochondral interface tissue engineering, with a specific focus on three-dimensional bioprinting. The goal of this review was to elucidate the importance of the osteochondral interface and overview some strategies of developing an interface layer within tissue engineered scaffolds. Impact Statement This review provides an overview of interface tissue engineering for osteochondral regeneration. It offers a detailed investigation into the biomechanics of the osteochondral unit as it relates to tissue engineering, and highlights the strategies that have been utilized to develop the osteochondral interface within tissue engineering scaffolds.