Elite Athletes Successfully Return to the Preinjury Level of Sport Following Ankle Syndesmosis Injuries: A Systematic Review and Meta-Analysis.

OBJECTIVE: To comprehensively review and report the outcomes of ankle syndesmotic injury management in elite athletes. DATA SOURCES: Three databases were searched for articles reporting the rate of return to sport following treatment of ankle syndesmotic injuries in elite athletes (collegiate or professional level). Ten articles and 440 athletes were included. Articles reporting the rate of return to sport following high ankle sprain injury in elite athletes. Data collected included demographics, type of treatment received, and return to sport (RTS) information. A random effects model was used. MAIN RESULTS: The estimated overall rate of RTS was 99% (95% CI, 95.5-99.9). The mean time to RTS was 38 ± 18 (range, 14-137) days. Of the 440 athletes, 269 (269/440%, 61%) were treated nonoperatively (nonoperative group); the rate of RTS was 99.6%, and the athletes returned at a mean time of 29 ± 14 (range, 13-45) days. A total of 171 athletes (171 of 440%, 39%) underwent surgical treatment (operative group). All (171 of 171%, 100%) athletes returned at a mean time of 50.3 ± 13 (range, 41-137) days. Almost all athletes who underwent surgery had suture button fixation (164 of 171 athletes, 96%), and the mean time to RTS was 7 weeks with 9.1% complication rate. CONCLUSIONS: Elite athletes with ankle syndesmosis injury return to sport at an extremely high rates, following operative or nonoperative treatment. Return to the preinjury level of competition should be expected at 4 weeks and 7 weeks in high-level athletes who undergo nonoperative and operative management, respectively. Suture button fixation was used by the majority of studies reporting surgical management of ankle syndesmosis injuries in athletes.

Drug-induced modulation of gp130 signalling prevents articular cartilage degeneration and promotes repair.

OBJECTIVE: Human adult articular cartilage (AC) has little capacity for repair, and joint surface injuries often result in osteoarthritis (OA), characterised by loss of matrix, hypertrophy and chondrocyte apoptosis. Inflammation mediated by interleukin (IL)-6 family cytokines has been identified as a critical driver of proarthritic changes in mouse and human joints, resulting in a feed-forward process driving expression of matrix degrading enzymes and IL-6 itself. Here we show that signalling through glycoprotein 130 (gp130), the common receptor for IL-6 family cytokines, can have both context-specific and cytokine-specific effects on articular chondrocytes and that a small molecule gp130 modulator can bias signalling towards anti-inflammatory and antidegenerative outputs. METHODS: High throughput screening of 170 000 compounds identified a small molecule gp130 modulator termed regulator of cartilage growth and differentiation (RCGD 423) that promotes atypical homodimeric signalling in the absence of cytokine ligands, driving transient increases in MYC and pSTAT3 while suppressing oncostatin M- and IL-6-mediated activation of ERK and NF-κB via direct competition for gp130 occupancy. RESULTS: This small molecule increased proliferation while reducing apoptosis and hypertrophic responses in adult chondrocytes in vitro. In a rat partial meniscectomy model, RCGD 423 greatly reduced chondrocyte hypertrophy, loss and degeneration while increasing chondrocyte proliferation beyond that observed in response to injury. Moreover, RCGD 423 improved cartilage healing in a rat full-thickness osteochondral defect model, increasing proliferation of mesenchymal cells in the defect and also inhibiting breakdown of cartilage matrix in de novo generated cartilage. CONCLUSION: These results identify a novel strategy for AC remediation via small molecule-mediated modulation of gp130 signalling.

Innate and adaptive immune cell interaction drives inflammasome activation and hepatocyte apoptosis in murine liver injury from immune checkpoint inhibitors.

Immune checkpoints (CTLA4 & PD-1) are inhibitory pathways that block aberrant immune activity and maintain self-tolerance. Tumors co-opt these checkpoints to avoid immune destruction. Immune checkpoint inhibitors (ICIs) activate immune cells and restore their tumoricidal potential, making them highly efficacious cancer therapies. However, immunotolerant organs such as the liver depend on these tolerogenic mechanisms, and their disruption with ICI use can trigger the unintended side effect of hepatotoxicity termed immune-mediated liver injury from ICIs (ILICI). Learning how to uncouple ILICI from ICI anti-tumor activity is of paramount clinical importance. We developed a murine model to recapitulate human ILICI using CTLA4+/- mice treated with either combined anti-CTLA4 + anti-PDL1 or IgG1 + IgG2. We tested two forms of antisense oligonucleotides to knockdown caspase-3 in a total liver (parenchymal and non-parenchymal cells) or in a hepatocyte-specific manner. We also employed imaging mass cytometry (IMC), a powerful multiplex modality for immunophenotyping and cell interaction analysis in our model. ICI-treated mice had significant evidence of liver injury. We detected cleaved caspase-3 (cC3), indicating apoptosis was occurring, as well as Nod-like receptor protein 3 (NLRP3) inflammasome activation, but no necroptosis. Total liver knockdown of caspase-3 worsened liver injury, and induced further inflammasome activation, and Gasdermin-D-mediated pyroptosis. Hepatocyte-specific knockdown of caspase-3 reduced liver injury and NLRP3 inflammasome activation. IMC-generated single-cell data for 77,692 cells was used to identify 22 unique phenotypic clusters. Spatial analysis revealed that cC3+ hepatocytes had significantly closer interactions with macrophages, Kupffer cells, and NLRP3hi myeloid cells than other cell types. We also observed zones of three-way interaction between cC3+ hepatocytes, CD8 + T-cells, and macrophages. Our work is the first to identify hepatocyte apoptosis and NLRP3 inflammasome activation as drivers of ILICI. Furthermore, we report that the interplay between adaptive and innate immune cells is critical to hepatocyte apoptosis and ILICI.

Cross-Communication Between Knee Osteoarthritis and Fibrosis: Molecular Pathways and Key Molecules.

Knee fibrosis is characterized by the presence of excessive connective tissue due to dysregulated fibroblast activation following local or systemic tissue damage. Knee fibrosis constitutes a major clinical problem in orthopaedics due to the severe limitation in the knee range of motion that leads to compromised function and patient disability. Knee osteoarthritis is an extremely common orthopedic condition that is associated with patient disability and major costs to the health-care systems worldwide. Although knee fibrosis and osteoarthritis (OA) have traditionally been perceived as two separate pathologic entities, recent research has shown common ground between the pathophysiologic processes that lead to the development of these two conditions. The purpose of this review was to identify the pathophysiologic pathways as well as key molecules that are implicated in the development of both knee OA and knee fibrosis in order to understand the relationship between the two diagnoses and potentially identify novel therapeutic targets.

Management Options for Shoulder Impingement Syndrome in Athletes: Insights and Future Directions.

Athletes participating in overhead sports are at particularly high risk of shoulder impingement syndrome. Subcoracoid impingement is defined as impingement of the anterior soft tissues of the shoulder between the coracoid process and the lesser tuberosity. Subacromial impingement syndrome (SIS) occurs due to extrinsic compression of the rotator cuff between the humeral head and coracoacromial structures or intrinsic degeneration of the supraspinatus tendon and subsequent superior migration of the humerus. Internal impingement is a major cause of shoulder pain in overhead athletes, and it occurs due to repetitive impingement of the articular surface of the rotator cuff with the glenoid during maximum abduction and external rotation of the arm. When examining athletes with suspected impingement of the shoulder, it is important to discuss the sport-specific motion that regenerates the symptoms and perform a combination of physical examination tests to improve the diagnostic accuracy. Radiographic evaluation is recommended, and the extent of soft tissue abnormalities can be assessed on ultrasound or magnetic resonance imaging of the shoulder. Management of shoulder impingement syndrome can be conservative or operative, based on the severity and chronicity of symptoms and the associated structural abnormalities. This review provides an update on the management of SIS, subcoracoid impingement, and internal impingement in the athletic population.

Fatty degeneration of the rotator cuff: pathogenesis, clinical implications, and future treatment.

Chronic rotator cuff pathology is often complicated by fatty degeneration of the rotator cuff (FDRC) muscles, an insidious process associated with poor prognosis with or without surgical intervention. Currently there is no treatment for FDRC, and many studies have described a natural course for this disease almost always resulting in further degeneration and morbidity. Recapitulating FDRC using animal injury models, and using imaging-based studies of human FDRC, the pathophysiology of this disease continues to be further characterized. Researchers studying mesenchymal stem cell-derived progenitor cells and known fibrogenic and adipogenic signaling pathways implicated in FDRC seek to clarify the underlying processes driving these changes. While new cell- and molecular-based therapies are being developed, currently the strongest available avenue for improved management of FDRC is the use of novel imaging techniques which allow for more accurate and personalized staging of fatty degeneration. This narrative review summarizes the evidence on the molecular and pathophysiologic mechanisms of FDRC and provides a clinical update on the diagnosis and management of this condition based on the existing knowledge. We also sought to examine the role of newer biologic therapies in the management of RC fatty degeneration and to identify areas of future research.

Rehabilitation Following Ulnar Collateral Ligament Reconstruction in Overhead-Throwing Athletes.

¼: The prevalence of ulnar collateral ligament (UCL) injury and UCL reconstruction (UCL-R) continues to rise, causing morbidity in overhead-throwing athletes. ¼: Postoperative rehabilitation protocols are essential for proper healing of the reconstructed ligament and safely returning athletes to competition, yet there is no uniformly accepted standard of care. ¼: UCL-R rehabilitation has traditionally been guided by expert opinion and conventional wisdom rather than scientific studies, resulting in substantial variability in rehabilitation practices, time to return to play, and outcomes. ¼: Current research efforts aim to closely investigate the biomechanical implications of UCL-R and overhead throwing to better guide rehabilitation and to improve competitive performance and outcomes. ¼: Additional biomechanical and scientific studies on rehabilitation modalities and timing are warranted for systematic analysis, optimization, and standardization of UCL-R rehabilitation.

Long-term repair of porcine articular cartilage using cryopreservable, clinically compatible human embryonic stem cell-derived chondrocytes.

Osteoarthritis (OA) impacts hundreds of millions of people worldwide, with those affected incurring significant physical and financial burdens. Injuries such as focal defects to the articular surface are a major contributing risk factor for the development of OA. Current cartilage repair strategies are moderately effective at reducing pain but often replace damaged tissue with biomechanically inferior fibrocartilage. Here we describe the development, transcriptomic ontogenetic characterization and quality assessment at the single cell level, as well as the scaled manufacturing of an allogeneic human pluripotent stem cell-derived articular chondrocyte formulation that exhibits long-term functional repair of porcine articular cartilage. These results define a new potential clinical paradigm for articular cartilage repair and mitigation of the associated risk of OA.