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Complex bidirectional cross talk between adipocytes and adipose tissue immune cells plays an important role in regulating adipose function, inflammation, and insulin responsiveness. Adipocytes secrete the pleiotropic cytokine IL-6 in response to both inflammatory and catabolic stimuli. Previous studies have suggested that IL-6 secretion from adipocytes in obesity may promote adipose tissue inflammation. Here, we investigated catabolic stimulation of adipocyte IL-6 secretion and its impact on adipose tissue immune cells. In obesity, catecholamine resistance reduces cAMP-driven adipocyte IL-6 secretion in response to catabolic signals. By restoring adipocyte catecholamine sensitivity in obese adipocytes, amlexanox stimulates adipocyte-specific IL-6 secretion. We report that in this context, adipocyte-secreted IL-6 activates local macrophage STAT3 to promote Il4ra expression, thereby sensitizing them to IL-4 signaling and promoting an anti-inflammatory gene expression pattern. Supporting a paracrine adipocyte to macrophage mechanism, these effects could be recapitulated using adipocyte conditioned media to pretreat bone marrow-derived macrophages prior to polarization with IL-4. The effects of IL-6 signaling in adipose tissue are complex and context specific. These results suggest that cAMP-driven IL-6 secretion from adipocytes sensitizes adipose tissue macrophages to IL-4 signaling.

BackgroundAmong breast cancers, the triple-negative breast cancer (TNBC) subtype has the worst prognosis with no approved targeted therapies and only standard chemotherapy as the backbone of systemic therapy. Unique metabolic changes in cancer progression provide innovative therapeutic opportunities. The receptor tyrosine kinases (RTKs) epidermal growth factor receptor (EGFR), and MET receptor are highly expressed in TNBC, making both promising therapeutic targets. RTK signaling profoundly alters cellular metabolism by increasing glucose consumption and subsequently diverting glucose carbon sources into metabolic pathways necessary to support the tumorigenesis. Therefore, detailed metabolic profiles of TNBC subtypes and their response to tyrosine kinase inhibitors may identify therapeutic sensitivities.MethodsWe quantified the metabolic profiles of TNBC cell lines representing multiple TNBC subtypes using gas chromatography mass spectrometry. In addition, we subjected MDA-MB-231, MDA-MB-468, Hs578T, and HCC70 cell lines to metabolic flux analysis of basal and maximal glycolytic and mitochondrial oxidative rates. Metabolic pool size and flux measurements were performed in the presence and absence of the MET inhibitor, INC280/capmatinib, and the EGFR inhibitor, erlotinib. Further, the sensitivities of these cells to modulators of core metabolic pathways were determined. In addition, we annotated a rate-limiting metabolic enzymes library and performed a siRNA screen in combination with MET or EGFR inhibitors to validate synergistic effects.ResultsTNBC cell line models displayed significant metabolic heterogeneity with respect to basal and maximal metabolic rates and responses to RTK and metabolic pathway inhibitors. Comprehensive systems biology analysis of metabolic perturbations, combined siRNA and tyrosine kinase inhibitor screens identified a core set of TCA cycle and fatty acid pathways whose perturbation sensitizes TNBC cells to small molecule targeting of receptor tyrosine kinases.ConclusionsSimilar to the genomic heterogeneity observed in TNBC, our results reveal metabolic heterogeneity among TNBC subtypes and demonstrate that understanding metabolic profiles and drug responses may prove valuable in targeting TNBC subtypes and identifying therapeutic susceptibilities in TNBC patients. Perturbation of metabolic pathways sensitizes TNBC to inhibition of receptor tyrosine kinases. Such metabolic vulnerabilities offer promise for effective therapeutic targeting for TNBC patients.

Background: There have been a large number of patient-reported outcome measures (PROMs) used to assess outcomes after anterior cruciate ligament (ACL) reconstruction (ACLR). Purpose/Hypothesis: The purpose was to determine which PROMs are being commonly used in randomized clinical trials (RCTs) to assess patients undergoing ACLR and to compare the responsiveness between them. It was hypothesized that the International Knee Documentation Committee (IKDC) score would be the most commonly used and responsive PROM among patients undergoing ACLR. Study Design: Meta-analysis. Level of evidence, 2. Methods: PRISMA (Preferred Reporting Items for Systematic Reviews and Meta-Analyses) guidelines were followed, and relevant studies were extracted from the PubMed/MEDLINE and Web of Science databases. The inclusion criteria were English-language RCTs reporting on PROMs after ACLR. For articles meeting our inclusion criteria for responsiveness analysis (≥2 PROMs reported, 1 year minimum follow-up, and reported pre- and postoperative PROM means and standard deviations), the responsiveness between PROMs was compared using effect size (ES) and relative efficiency (RE). Results: A total of 108 articles met the inclusion criteria, comprising 9034 patients (mean age, 29.9 years; mean body mass index, 24.3; mean follow-up time, 36.1 months). There were 34 PROMs identified. The top 3 most commonly reported PROMs were the IKDC (n = 68; 63.0%), Lysholm (n = 65; 60.2%), and Tegner (n = 47; 43.5%) scores. The 2 PROMs with the highest ES were the ACL–Quality of Life (QoL) (3.37) and Knee Injury and Osteoarthritis Outcome Score (KOOS) QoL (2.07) scores. Compared with other PROMs, Lysholm and KOOS QoL scores had the greatest RE values. The Lysholm score had a greater RE than the KOOS Pain (RE, 1.17), KOOS Symptoms (RE, 1.22), KOOS Activities of Daily Living (ADL) (RE, 1.42), KOOS Sport/Recreation (RE, 1.55), KOOS QoL (RE, 1.41), and Tegner (RE, 2.89) scores. KOOS QoL had a greater RE than the IKDC (RE, 1.32), KOOS Pain (RE, 1.60), KOOS Symptoms (RE, 2.12), KOOS ADL (RE, 3.03), KOOS Sport/Recreation (RE, 1.27), and Tegner (RE, 2.06) scores. Conclusion: The IKDC score is the most commonly reported PROM in RCTs after ACLR; however, the Lysholm and KOOS QoL scores demonstrated the highest responsiveness in patients undergoing ACLR compared with other PROMs. [ABSTRACT FROM AUTHOR]

Background: Anterior cruciate ligament (ACL) ruptures occur frequently, with ACL reconstruction among the most commonly performed orthopaedic sports surgeries. The remnant ACL is typically debrided for visualization. However, further evidence has suggested that this remnant tissue contains a wealth of proprioceptive nerve fibers and a vascular blood supply. Theoretically, preserving the ACL remnant may improve joint proprioception and graft synovialization. Therefore, ACL hybrid remnant preservation reconstruction (HRPR) was developed to preserve and tension the native remnant in combination with an ACL reconstruction. Indications: Patients with proximal tears or femoral-sided avulsions, Sherman type 1 or 2, may be indicated for ACL-HRPR. Technique Description: In this technique, we use a bone–patellar tendon–bone (BTB) autograft, which can be harvested based on the surgeon's preference. After performing a diagnostic arthroscopy, the notch of the knee is debrided, with care to preserve the tibial ACL remnant. The tibial remnant is then undermined with electrocautery. Nonabsorbable suture is passed through the remnant tissue. A tibial guide is placed, and a pin is drilled just posterior to the tibial insertion. Next, the appropriately sized tibial tunnel is drilled just posterior to the tibial remnant insertion. Using an anteromedial-portal technique with the knee maximally flexed, an over-the-top guide with appropriate offset is used to insert the guide pin, and the femoral tunnel is drilled. The proximal graft bone block and the remnant sutures are then passed through the femoral tunnel. Metal screws are then inserted to fix the BTB graft bone blocks on the femoral side, followed by the tibial side. Backup fixation is also used by placing a biocomposite anchor 1 cm distal to the tibial tunnel. Results: A myriad of techniques exist for preserving the ACL remnant. For the present surgical technique, a retrospective cohort revealed that patients undergoing ACL-HRPR achieved full range of motion without extension loss and equivalent patient-reported outcomes, without increased complication rates. Discussion/Conclusions: For patients with femoral-sided ACL tears or avulsion, ACL-HRPR is a viable option that may augment traditional ACL reconstruction. Patient Consent Disclosure Statement: The author(s) attests that consent has been obtained from any patient(s) appearing in this publication. If the individual may be identifiable, the author(s) has included a statement of release or other written form of approval from the patient(s) with this submission for publication. [ABSTRACT FROM AUTHOR]

Study Design: General population utility valuation study. Objective: To develop a technique for calculating utilities from the Neck Disability Index (NDI) score. Methods: We recruited a sample of 1200 adults from a market research panel. Using an online discrete choice experiment (DCE), participants rated 10 choice sets based on NDI health states. A multi-attribute utility function was estimated using a mixed multinomial-logit regression model (MIXL). The sample was partitioned into a training set used for model fitting and validation set used for model evaluation. Results: The regression model demonstrated good predictive performance on the validation set with an AUC of.77 (95% CI:.76-.78). The regression model was used to develop a utility scoring rubric for the NDI. Regression results also revealed that participants did not regard all NDI items as equally important. The rank order of importance was (in decreasing order): pain intensity = work; personal care = headache; concentration = sleeping; driving; recreation; lifting; and lastly reading. Conclusions: This study provides a simple technique for converting the NDI score to utilities and quantify the relative importance of individual NDI items. The ability to evaluate quality-adjusted life-years using these utilities for cervical spine pain and disability could facilitate economic analysis and aid in allocation of healthcare resources. [ABSTRACT FROM AUTHOR]

Hip and core injuries are common in National Football League (NFL) athletes; however, the impact following injury remains unclear. The goal of this manuscript was to determine the impact of nonoperative hip and core injuries on return to play and performance. NFL athletes who sustained a hip or core injury treated nonoperatively between 2010 and 2016 were identified. Offensive and defensive power ratings were calculated for each player's injury season and two seasons before and after to assess longitudinal impact. A matched control group without an identified hip and/or core injury was assembled for comparison. A total of 41 offensive and 71 defensive players with nonoperative hip or core injury were analyzed. All athletes returned to play; offensive and defensive players missed 4.0 ± 5.2 and 3.1 ± 2.6 games after injury, respectively. Offensive players played fewer cumulative career games returning from core injury versus hip (23.5 ± 20.6 vs 41.0 ± 26.4). Defensive players played fewer games (58.1 ± 41.1 versus 37.4 ± 27.1, p < 0.05) with lower defensive power rating (133.9 ± 128.5 versus 219.8 ± 212.2, p < 0.05) cumulatively after hip or core injury. Additionally, 2 years following injury, defensive players played fewer games compared to controls (9.5 ± 7.0 versus 10.9 ± 6.8, p < 0.05). Following hip injury specifically, NFL defenders played fewer games (39.8 ± 27.9 vs 61.9 ± 38.8; p < 0.05) and had a lower defensive power rating (145.9 ± 131.7 vs 239.0 ± 205.9; p < 0.05) compared to before injury. Overall, NFL players return to play following nonoperative hip and core injuries. Defensive players played in fewer games following hip or core injury compared to controls; offensive players were unaffected. Hip injuries have a greater impact on performance compared to core injuries in defensive athletes; offensive players played fewer games upon return from core injury. [ABSTRACT FROM AUTHOR]