An In Vitro Macrophage Response Study of Silk Fibroin and Silk Fibroin/Nano-Hydroxyapatite Scaffolds for Tissue Regeneration Application.

In recent years, silk fibroin (SF) has been incorporated with low crystallinity nanohydroxyapatite (nHA) as a scaffold for various tissue regeneration applications due to the mechanical strength of SF and osteoconductive properties of nHA. However, currently, there is a lack of understanding of the immune response toward the degradation products of SF with nHA composite after implantation. It is known that particulate fragments from the degradation of a biomaterial can trigger an immune response. As the scaffold is made of degradable materials, the degradation products may contribute to the inflammation. Therefore, in this study, the effects of the enzymatic degradation of the SF/nHA scaffold on macrophage response were investigated in comparison to the control SF scaffold. Since the degradation products of a scaffold can influence macrophage polarization, it can be hypothesized that as the SF and SF/nHA scaffolds were degraded in vitro using protease XIV solution, the degradation products can contribute to the polarization of THP-1-derived macrophages from pro-inflammatory M1 to anti-inflammatory M2 phenotype. The results demonstrated that the initial (day 1) degradation products of the SF/nHA scaffold elicited a pro-inflammatory response, while the latter (day 24) degradation products of the SF/nHA scaffold elicited an anti-inflammatory response. Moreover, the degradation products from the SF scaffold elicited a higher anti-inflammatory response due to the faster degradation of the SF scaffold and a higher amino acid concentration in the degradation solution. Hence, this paper can help elucidate the contributory effects of the degradation products of SF and SF/nHA scaffolds on macrophage response and provide greater insights into designing silk-based biomaterials with tunable degradation rates that can modulate macrophage response for future tissue regeneration applications.

Integrated imaging probe and bispecific antibody development enables in vivo targeting of glypican-3-expressing hepatocellular carcinoma.

Glypican-3 (GPC3) is a proteoglycan with high sensitivity and specificity for hepatocellular carcinoma (HCC). We describe the integrated development and validation of a GPC3-targeting optical imaging probe and T-cell redirecting antibody (TRAB) as a theranostic strategy for the detection and treatment of HCC. A novel TRAB targeting GPC3 on HCC tumor cells and the CD3 T-cell receptor as well as a distinct GPC3-specific optical imaging probe were developed from a short peptide. The efficacy of GPC3/CD3 TRAB was evaluated in vitro using interferon-γ release and calcein-AM assays. Patient-derived xenografts (PDX) were used to assess the in vivo efficacy of GPC3/CD3 TRAB and the GPC3 imaging probe for the detection of GPC3+ HCC. GPC3/CD3 TRAB caused a dose-dependent escalation in interferon-γ release from inactive peripheral blood T-cells (P = 0.001) and higher tumor-cell lysis (P = 0.01) compared to controls in vitro. Intratumorally injected GPC3/CD3 TRAB resulted in significant prolongation of tumor doubling time in the GPC3+ PDX mice, with an associated reduction of tumor fluorescent signal from the HiLyte 488- conjugated GPC3 specific peptide on optical imaging. HCC cell targeting using a GPC3/CD3 TRAB derived from a small peptide resulted in effective T-cell activation and induction of a cytotoxic response toward GPC3+ HCC tumor cells both in vitro and in vivo. GPC3-specific optical imaging enabled the detection of the GPC3+ HCC cells and noninvasive monitoring of tumor response to adoptive immunotherapy. The integrated development of a targeted therapeutic and molecular imaging probe provides a novel paradigm for developing cancer theranostics.

Trochleoplasty Provides Good Outcomes for Recurrent Patellofemoral Dislocations with No Clear Superiority across Different Techniques.

Background: Literature is sparse on outcome comparisons between different trochleoplasty techniques in the treatment of patella instability. To date, it is unclear whether there is a technique that offers superior outcomes. This systematic review and meta-analysis aims to compare and evaluate the outcomes of trochleoplasty techniques in the treatment of patellofemoral instability in trochlea dysplasia to establish whether there is an ideal choice of trochleoplasty technique for superior outcomes. Methods: 21 studies involving 880 knees were included. The mean age of the patients was 21.7 years (range 8-49 years). Mean follow-up timeframe of 43.5 months (range 8.8-100 months). Clinical outcomes assessed included rates of recurrence of patellofemoral dislocation, patient satisfaction, Kujala score, International Knee Documentation Committee (IKDC) score, Tegner score, and Lysholm score. Egger's test showed no publication bias across all outcomes assessed. Results: Favourable results were seen across all outcomes assessed and patient satisfaction. Improvements were seen with Kujala, IKDC, and Lysholm scores. Tegner scores showed good return to function. Post-operative dislocation and complication rates were low across the different techniques. Meta-regression for Kujala and IKDC scores showed good outcomes regardless of trochleoplasty technique used (Kujala, p = 0.549, relative risk 492.06; IKDC, p = 0.193, RR 0.001). The exact risk that trochleoplasty poses to the cartilage remains uncertain, as no study had a conservatively managed arm for comparison. Conclusions: Trochleoplasty yielded good outcomes irrespective of technique used with no clear superiority demonstrated in any technique in terms of outcome scores, satisfaction, post-operative dislocation rates or complications.

Are Generative Pretrained Transformer 4 Responses to Developmental Dysplasia of the Hip Clinical Scenarios Universal? An International Review.

OBJECTIVE: There is increasing interest in applying artificial intelligence chatbots like generative pretrained transformer 4 (GPT-4) in the medical field. This study aimed to explore the universality of GPT-4 responses to simulated clinical scenarios of developmental dysplasia of the hip (DDH) across diverse global settings. METHODS: Seventeen international experts with more than 15 years of experience in pediatric orthopaedics were selected for the evaluation panel. Eight simulated DDH clinical scenarios were created, covering 4 key areas: (1) initial evaluation and diagnosis, (2) initial examination and treatment, (3) nursing care and follow-up, and (4) prognosis and rehabilitation planning. Each scenario was completed independently in a new GPT-4 session. Interrater reliability was assessed using Fleiss kappa, and the quality, relevance, and applicability of GPT-4 responses were analyzed using median scores and interquartile ranges. Following scoring, experts met in ZOOM sessions to generate Regional Consensus Assessment Scores, which were intended to represent a consistent regional assessment of the use of the GPT-4 in pediatric orthopaedic care. RESULTS: GPT-4's responses to the 8 clinical DDH scenarios received performance scores ranging from 44.3% to 98.9% of the 88-point maximum. The Fleiss kappa statistic of 0.113 ( P = 0.001) indicated low agreement among experts in their ratings. When assessing the responses' quality, relevance, and applicability, the median scores were 3, with interquartile ranges of 3 to 4, 3 to 4, and 2 to 3, respectively. Significant differences were noted in the prognosis and rehabilitation domain scores ( P < 0.05 for all). Regional consensus scores were 75 for Africa, 74 for Asia, 73 for India, 80 for Europe, and 65 for North America, with the Kruskal-Wallis test highlighting significant disparities between these regions ( P = 0.034). CONCLUSIONS: This study demonstrates the promise of GPT-4 in pediatric orthopaedic care, particularly in supporting preliminary DDH assessments and guiding treatment strategies for specialist care. However, effective integration of GPT-4 into clinical practice will require adaptation to specific regional health care contexts, highlighting the importance of a nuanced approach to health technology adaptation. LEVEL OF EVIDENCE: Level IV.

A novel practical method to predict anterior cruciate ligament hamstring graft size using preoperative MRI.

BACKGROUND: Predicting hamstring graft size preoperatively for anterior cruciate ligament (ACL) reconstruction is important for preempting an insufficient diameter in graft size intraoperatively, possibly leading to graft failure. While there are multiple published methods using magnetic resonance imaging (MRI) picture archiving and communication systems (PACS), most are not feasible and practical. Our study aims to (1) practically predict the ACL hamstring graft size in a numerically continuous manner using the preoperative MRI from any native MRI PACS system, (2) determine the degree of correlation between the predicted and actual graft size, and (3) determine the performance of our prediction method if we define an adequate actual graft size as ≥ 8 mm. METHODS: A retrospective review of 112 patients who underwent primary ACL reconstruction with quadrupled hamstring semitendinosus-gracilis grafts at a tertiary institution was conducted between January 2018 and December 2018. Graft diameter can be predicted in a numerically continuous manner as √[2*(AB + CD)], where A and B are the semitendinosus cross-sectional length and breath, respectively, and C and D are the gracilis cross-sectional length and breath, respectively. RESULTS: A moderately positive correlation exists between the predicted and actual graft diameter (r = 0.661 and p < .001). Our method yields a high specificity of 92.6% and a moderate sensitivity of 67.2% if we define an adequate actual graft size as ≥ 8 mm. An area under receiver-operating characteristic curve shows good discrimination (AUC = 0.856). CONCLUSIONS: We present a practical method to predict the ACL hamstring graft size with high specificity using preoperative MRI measurements.

Patellar tilt, congruence angle, and tibial tubercle-trochlear groove distance are correlated with positive J-sign in adolescents.

PURPOSE: The J-sign is a clinical evaluation tool that assesses for patellar maltracking and is considered positive if lateral translation of the patella in extension, in the pattern of an inverted J is observed. This study aims to determine the association of clinical J-sign with imaging features noted on dynamic kinematic computed tomography (DKCT). METHODS: A retrospective review was conducted by reviewing the clinical records of all patients aged 18 years or younger who had a CT patellar tracking scan done between 1 January 2005 to 31 December 2016 in a single institution. Patients who had the presence or absence of a 'J-sign' evaluated clinically were included. Radiographic parameters evaluated using the axial cuts include the patellar tilt angle, congruence angle, Dejour's classification, femoral sulcus angle, trochlear groove depth, and Wiberg's classification. Patients were then divided into two groups based on the presence or absence of J-sign on clinical examination. The radiographic measurements were then analyzed for association with the presence or absence of J-sign on clinical examination. RESULTS: Patients with a positive J-sign had an increased patellar tilt of 23.3° ± 14.2° and an increased congruence angle of 47.1° ± 28.5° when measured in extension as compared to a patellar tilt of 18.3° ± 10.8° and a congruence angle of 32.1° ± 20.8° in patients with a negative J-sign (p = 0.024 and 0.004, respectively). Comparisons of the change in congruence angles with the knee in full extension and at 20° flexion also yielded significantly higher change of 28.0° ± 20.4° in patients with a positive J-sign as compared to 11.9° ± 17.5° in patients with a negative J-sign. Patients with a positive J-sign also had an increased TT-TG distance of 17.6 ± 5.6 mm as compared to a TT-TG distance of 14.7 ± 6.9 mm in patients with a negative J-sign (p = 0.01). CONCLUSION: Patients with a positive J-sign had an increased patellar tilt and an increased congruence angle when measured in extension. Increased TT-TG distance was also significantly associated with positive J-sign. Patients with a positive J-sign also had a greater change in their congruence angle when measured with the knee in full extension and at 20° of flexion.

Combination of tibial tubercle transfer, medial patellofemoral ligament reconstruction, trochleoplasty and lateral release for patellofemoral instability provides good middle- to long-term outcomes in adolescents.

PURPOSE: There are limited studies that have reported the middle- to long-term outcomes of combined procedures consisting of more than two procedures for patellofemoral instability. The current study aims to investigate and report the middle- to long-term outcomes of a combination procedure of tibial tubercle transfer, medial patellofemoral ligament reconstruction, trochleoplasty and lateral release for patellofemoral instability in patients aged 18 years and below. METHODS: In the cohort study, all patients aged 18 years old or younger who underwent a combination procedure of tibial tubercle transfer, medial patellofemoral ligament reconstruction, trochleoplasty and lateral release for recurrent patellofemoral instability were included. RESULTS: A total of 21 patients were included in the study. All patients had no further patellofemoral dislocation, pain and apprehension following the 4-in-1 surgery (p < 0.01). There was a significant improvement in the Kujala score from 36.1 (SD 12.9) pre-operatively to 93.1 (SD 3.6) post-operatively (p < 0.001). The patients also had a statistically significant improvement in their radiological factors, including the patellar tilt angle (p < 0.001), sulcus angle (p = 0.001), trochlear groove depth (p = 0.041), tibial tubercle-trochlear groove distance (p < 0.001) and Caton-Deschamps index (p = 0.001). CONCLUSION: A combination procedure of tibial tubercle transfer, medial patellofemoral ligament reconstruction, trochleoplasty and lateral release leads to good middle- to long-term subjective, functional and radiographic outcomes for patients with recurrent patellofemoral instability and underlying predisposing factors of increased TT-TG distance of more than 20 mm, Dejour B or D trochlear dysplasia and medial patellofemoral ligament rupture. LEVEL OF EVIDENCE: IV.

Risk factors for a false negative Ortolani and Barlow examination in developmental dysplasia of the hip.

INTRODUCTION: Although universal screening by neonatal clinical examination with Ortolani and Barlow manoeuvres is widely adopted, its role as a sole screening tool is controversial due to its poor sensitivity and failure in identifying hip joints that eventually require surgical intervention. HYPOTHESIS: This study aims to identify risk factors for a false negative Ortolani and Barlow examination in neonatal screening for DDH. The hypothesis is that risk factors for developmental dysplasia of the hips could similarly be risk factors for a false negative Ortolani and Barlow examination. MATERIAL AND METHODS: In the 14-year retrospective cohort study, all newborn infants born in a single institution from 1st January 1999 to 31st December 2013 were screened clinically with the Ortolani/Barlow manoeuvre by a neonatologist. Infants with positive risk factors, despite a normal clinical examination, were then scheduled for bilateral hip ultrasound in the first three months of life and evaluated according to the Graf's method, Harcke's method of dynamic ultrasound screening and Terjesen's method of evaluation for femoral head coverage. RESULTS: A total of 164 infants with normal Ortolani and Barlow examinations were scheduled for bilateral hip ultrasound due to the presence of risk factors. Amongst these, 32 (19.5%) infants were evaluated to have an abnormal hip on ultrasound. Breech position was the only statistically significant risk factor for a false negative Ortolani/Barlow examination (14/34, 41.2% vs. 18/112, 13.8%; p<0.001). DISCUSSION: Sonographic hip examinations are recommended for all infants with breech presentation even if they have a normal Ortolani and Barlow examination. LEVEL OF EVIDENCE: III; case-control study.

Small extracellular vesicles from mesenchymal stromal cells: the next therapeutic paradigm for musculoskeletal disorders.

Musculoskeletal disorders are one of the biggest contributors to morbidity and place an enormous burden on the health care system in an aging population. Owing to their immunomodulatory and regenerative properties, mesenchymal stromal/stem cells (MSCs) have demonstrated therapeutic efficacy for treatment of a wide variety of conditions, including musculoskeletal disorders. Although MSCs were originally thought to differentiate and replace injured/diseased tissues, it is now accepted that MSCs mediate tissue repair through secretion of trophic factors, particularly extracellular vesicles (EVs). Endowed with a diverse cargo of bioactive lipids, proteins, nucleic acids and metabolites, MSC-EVs have been shown to elicit diverse cellular responses and interact with many cell types needed in tissue repair. The present review aims to summarize the latest advances in the use of native MSC-EVs for musculoskeletal regeneration, examine the cargo molecules and mechanisms underlying their therapeutic effects, and discuss the progress and challenges in their translation to the clinic.

Lower re-rupture rates but higher complication rates following surgical versus conservative treatment of acute achilles tendon ruptures: a systematic review of overlapping meta-analyses.

PURPOSE: To systematically review and evaluate the current meta-analyses for the treatment of acute Achilles tendon rupture (AATR). This study can provide clinicians with a clear overview of the current literature to aid clinical decision-making and the optimal formulation of treatment plans for AATR. METHODS: Two independent reviewers searched PubMed and Embase on June 2, 2022 based on the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines. Assessment of evidence was twofold: level of evidence (LoE) and quality of evidence (QoE). LoE was evaluated using published criteria by The Journal of Bone and Joint Surgery and the QoE by the Assessing the Methodological Quality of Systematic Reviews (AMSTAR) scale. Pooled complication rates were highlighted for significance in favour of one treatment arm or no significance. RESULTS: There were 34 meta-analyses that met the eligibility criteria, with 28 studies of LoE 1, and the mean QoE was 9.8 ± 1.2. Significantly lower re-rupture rates were reported with surgical (2.3-5%) versus conservative treatment (3.9-13%), but conservative treatment was favoured in terms of lower complication rates. The re-rupture rates were not significantly different between percutaneous repair or minimally invasive surgery (MIS) compared to open repair, but MIS was favoured in terms of lower complication rates (7.5-10.4%). When comparing rehabilitation protocols following open repair (four studies), conservative treatment (nine studies), or combined (three studies), there was no significant difference in terms of re-rupture or obvious advantage in terms of lower complication rates between early versus later rehabilitation. CONCLUSION: This systematic review found that surgical treatment was significantly favoured over conservative treatment for re-rupture, but conservative treatment had lower complication rates other than re-rupture, notably for infections and sural nerve injury. Open repair had similar re-rupture rates to MIS, but lower complication rates; however, the rate of sural nerve injuries was lower in open repair. When comparing earlier versus later rehabilitation, there was no difference in re-rupture rates or obvious advantage in complications between open repair, conservative treatment, or when combined. The findings of this study will allow clinicians to effectively counsel their patients on the postoperative outcomes and complications associated with different treatment approaches for AATR. LEVEL OF EVIDENCE: IV.

Managing the Heterogeneity of Mesenchymal Stem Cells for Cartilage Regenerative Therapy: A Review.

Articular cartilage defects commonly result from trauma and are associated with significant morbidity. Since cartilage is an avascular, aneural, and alymphatic tissue with a poor intrinsic healing ability, the regeneration of functional hyaline cartilage remains a difficult clinical problem. Mesenchymal stem cells (MSCs) are multipotent cells with multilineage differentiation potential, including the ability to differentiate into chondrocytes. Due to their availability and ease of ex vivo expansion, clinicians are increasingly applying MSCs in the treatment of cartilage lesions. However, despite encouraging pre-clinical and clinical data, inconsistencies in MSC proliferative and chondrogenic potential depending on donor, tissue source, cell subset, culture conditions, and handling techniques remain a key barrier to widespread clinical application of MSC therapy in cartilage regeneration. In this review, we highlight the strategies to manage the heterogeneity of MSCs ex vivo for more effective cartilage repair, including reducing the MSC culture expansion period, and selecting MSCs with higher chondrogenic potential through specific genetic markers, surface markers, and biophysical attributes. The accomplishment of a less heterogeneous population of culture-expanded MSCs may improve the scalability, reproducibility, and standardisation of MSC therapy for clinical application in cartilage regeneration.

Results From a Randomized, Open-Label, Crossover Study Evaluating the Effect of the Aldosterone Synthase Inhibitor Baxdrostat on the Pharmacokinetics of Metformin in Healthy Human Subjects.

BACKGROUND: Due to the high comorbidity of diabetes and hypertension, co-administration of metformin with anti-hypertensive drugs is likely. Baxdrostat is an aldosterone synthase inhibitor in development for the potential treatment of hypertension. In vitro data indicated that baxdrostat inhibits the multidrug and toxin extrusion 1 (MATE1) and MATE2-K renal transporters. Metformin is a MATE substrate, so this study assessed potential effects of baxdrostat on the pharmacokinetics of metformin. METHODS: Twenty-seven healthy volunteers received 1000 mg metformin alone and 1000 mg metformin in the presence of 10 mg baxdrostat in a randomized, crossover manner. Each treatment was separated by 10 or more days. Blood and urine samples were collected over a 3-day period after each treatment to measure plasma and urine concentrations of metformin. Safety was assessed by adverse events (AEs), physical examinations, electrocardiograms, vital signs, and clinical laboratory evaluations. RESULTS: There were no deaths, serious AEs, discontinuations due to treatment-emergent AEs, or noteworthy increases in AEs with either treatment, indicating that metformin and baxdrostat were well-tolerated when co-administered. Baxdrostat did not significantly affect plasma concentrations or renal clearance of metformin. CONCLUSION: The results of this study suggest that diabetic patients with hypertension receiving both metformin and baxdrostat are unlikely to require dose adjustment. REGISTRATION: ClinicalTrials.gov identifier no. NCT05526690.

Perspective in Achieving Stratified Articular Cartilage Repair Using Zonal Chondrocytes.

Articular cartilage is composed of superficial, medial, and deep zones, which endow the tissue with biphasic mechanical properties to withstand shearing force and compressional loading. The tissue has very limited self-healing capacity once it is damaged due to its avascular nature. To prevent the early onset of osteoarthritis, surgical intervention is often needed to repair the injured cartilage. Current noncell-based and cell-based treatments focus on the regeneration of homogeneous cartilage to achieve bulk compressional properties without recapitulating the zonal matrix and mechanical properties, and often oversight in aiding cartilage integration between host and repair cartilage. It is hypothesized that achieving zonal architecture in articular cartilage tissue repair could improve the structural and mechanical integrity and thus the life span of the regenerated tissue. Engineering stratified cartilage constructs using zonal chondrocytes have been hypothesized to improve the functionality and life span of the regenerated tissues. However, stratified articular cartilage repair has yet to be realized to date due to the lack of an efficient zonal chondrocyte isolation method and an expansion platform that would allow both cell propagation and phenotype maintenance. Various attempts and challenges in achieving stratified articular cartilage repair in a clinical setting are evaluated. In this review, different perspectives on achieving stratified articular cartilage repair using zonal chondrocytes are described. The effectiveness of different zonal chondrocyte isolation and zonal chondrocyte phenotype maintenance methodologies during expansion are compared, with the focus on recent advancements in zonal chondrocyte isolation and expansion that could present a possible strategy to overcome the limitation of applying zonal chondrocytes to facilitate zonal architecture development in articular cartilage regeneration. Impact Statement The zonal properties of articular cartilage contribute to the biphasic mechanical properties of the tissues. Recapitulation of the zonal architecture in regenerated articular cartilage has been hypothesized to improve the mechanical integrity and life span of the regenerated tissue. This review provides a comprehensive discussion on the current state of research relevant to achieving stratified articular cartilage repair using zonal chondrocytes from different perspectives. This review further elaborates on a zonal chondrocyte production pipeline that can potentially overcome the current clinical challenges and future work needed to realize stratified zonal chondrocyte implantation in a clinical setting.

Results from a phase 1, randomized, double-blind, multiple ascending dose study characterizing the pharmacokinetics and demonstrating the safety and selectivity of the aldosterone synthase inhibitor baxdrostat in healthy volunteers.

Baxdrostat is a selective inhibitor of aldosterone synthase designed for the treatment of disorders associated with elevated aldosterone. This study evaluated the safety, pharmacokinetics, and pharmacodynamics of multiple ascending doses of baxdrostat in healthy volunteers. Subjects were randomized to receive oral baxdrostat (0.5, 1.5, 2.5, or 5.0 mg) or placebo once daily for 10 days and were placed on either a low-salt or normal-salt diet for the duration of the study. Blood samples were collected before and after dosing on days 1 and 10 to characterize pharmacokinetics and pharmacodynamics. Safety was assessed by adverse events, physical examinations, electrocardiograms, orthostatic vital signs, and clinical laboratory evaluations. Fifty-four subjects completed the study. There were no deaths or serious adverse events, and all treatment-emergent adverse events in subjects receiving baxdrostat were mild in severity. Plasma levels of baxdrostat increased proportionally with ascending doses, with peak concentrations observed within 4 h after dosing and a mean half-life of 26 to 31 h. A dose-dependent reduction of plasma aldosterone occurred with baxdrostat doses ≥1.5 mg, regardless of diet. Decreases in plasma aldosterone were sustained, with levels reduced by approximately 51 to 73% on day 10. Baxdrostat had no meaningful impact on plasma cortisol levels and resulted in mild dose-dependent decreases in plasma sodium levels and increases in potassium levels. Baxdrostat was safe and well tolerated with a half-life that supports once-daily dosing. The dose-dependent reduction in plasma aldosterone and lack of effect on cortisol demonstrate the selective blockade of aldosterone synthase.

Both Medialization and Anteromedialization Tibial Tubercle Osteotomies are Effective Surgical Management for Skeletally Mature Patients with Patellofemoral Instability when Combined with Medial Patellofemoral Ligament Reconstruction.

The study aimed to compare the midterm outcomes of medialization and anteromedialization tibial tubercle osteotomies when used in the management of recurrent patellofemoral instability. The hypothesis is that both techniques would result in significant improvement for patellofemoral instability, but anteromedialization would result in a lower incidence of early osteoarthritis. In the cohort study, all skeletally mature patients aged 18 years old or younger who underwent tibial tubercle osteotomy for recurrent patellofemoral instability within a 10-year period in a single institution were included. All patients underwent either medialization or anteromedialization tibial tubercle osteotomy. The preoperative and postoperative outcomes of the tibial tubercle osteotomies were compared. All patients included in the study had a minimum of 5-year follow-up duration before the conclusion of the study. There was no statistically significant difference in the rates of preoperative and postoperative patellofemoral dislocation when either technique was employed (p = 0.999). Additionally, both the preoperative and postoperative Kujala scores were similar (p = 0.166 and p = 0.554, respectively). The knees did not have a statistically significant difference in their patellar tilt angles and tibial tubercle-trochlear groove distances preoperatively or postoperatively when either technique was used (p = 0.165 and 0.149, respectively). There was also no incidence of osteoarthritis identified in either of the groups (p = 0.999). Both anteriorization and anteromedialization tibial tubercle osteotomies were effective surgical management for patellofemoral instability when combined with medial patellofemoral ligament reconstruction. There were no significant differences in clinical, functional, and radiological outcomes when either medialization or anteromedialization tibial tubercle osteotomy was performed.

Do meniscal repairs with meniscus cyst do better than meniscectomy?-a systematic review of meniscal cyst treatment.

Background: This systematic review aims to determine the best modality for the management of meniscal cysts and its associated meniscus tear; whether the meniscal cyst treated via arthroscopy or open methods and whether meniscal debridement or repair achieves better results. Methods: This systematic review was performed using PRISMA guidelines. A literature search of PubMed, EMBASE and Cochrane was carried out in July 2020 using the search terms 'meniscal cyst' and 'treatment'. All clinic studies that included filters for papers in the last 20 years, English language, and meniscal cysts found in humans were included. Studies that contained case reports, were in any language other than English, and with subjects that were not humans were excluded. The methodology quality assessment was performed through the modified Coleman methodology score (CMS). Results: A total of 166 results were obtained from PubMed, Cochrane library and EMBASE. Of them, 12 duplicates were identified across the databases and removed from consideration. Six papers were found relevant from EMBASE in which 1 was eventually included in this paper. In total, 12 papers were used in this study. The weighted mean age of the patients was 35.1 years, with total of 523 meniscal cysts, of which 488 of these cysts are associated with meniscal tears (93.31%). The studies included performed cystectomies and/or decompression of meniscal cysts while some left the meniscal cyst alone and dealt with the meniscal lesion instead. All clinical scores showed significant improvement following surgical procedures. Conclusions: Both arthroscopic and open methods can be used for meniscal cysts treatment. Open cystectomy rather than decompression seemed to confer lower risk of cyst recurrences and complications. It is inconclusive to whether meniscal repair or meniscus debridement influenced recurrence and outcome scores. A recommendation for meniscus repair cannot be made due to insufficient high-quality level I or II trials.

Clinical Outcomes of Patients with C3G or IC-MPGN Treated with the Factor D Inhibitor Danicopan: Final Results from Two Phase 2 Studies.

INTRODUCTION: C3 glomerulopathy (C3G) is an ultrarare, chronic and progressive nephropathy mediated by dysregulation of the alternative pathway of complement (AP), with poor prognosis and limited treatment options. Targeted inhibition of proximal AP through factor D (FD) blockade represents a rational treatment approach. We present two phase 2 proof-of-concept clinical studies of the orally active FD inhibitor danicopan in patients with C3G and immune complex-mediated membranoproliferative glomerulonephritis (IC-MPGN) (NCT03369236 and NCT03459443). METHODS: A double-blind, placebo-controlled study in patients with C3G and a single-arm, open-label study in patients with C3G or IC-MPGN treated with danicopan are reported. The studies evaluated pharmacokinetic/pharmacodynamic (PK/PD), efficacy, and safety outcomes. The co-primary endpoints were change from baseline in composite biopsy score and the proportion of patients with a 30% reduction in proteinuria relative to baseline at 6 or 12 months. RESULTS: Optimal systemic concentrations of danicopan were not achieved for complete and sustained inhibition of AP, although there was evidence that blockade of FD reduced AP activity shortly after drug administration. Consequently, limited clinical response was observed in key efficacy endpoints. While stable disease or improvement from baseline was seen in some patients, response was not consistent. The data confirmed the favorable safety profile of danicopan. CONCLUSION: While demonstrating a favorable safety profile, danicopan resulted in incomplete and inadequately sustained inhibition of AP, probably due to limitations in its PK/PD profile in C3G, leading to lack of efficacy. Complete and sustained AP inhibition is required for a clinical response in patients with C3G.

Limited evidence of adjuvant biologics with bone marrow stimulation for the treatment of osteochondral lesion of the talus: a systematic review.

PURPOSE: To evaluate the complication rates, continuous functional outcome scores, and return to play data following bone marrow stimulation (BMS) versus biologics ± BMS for the treatment of osteochondral lesion of the talus (OLT). METHODS: A systematic review was performed. The PubMed and Embase databases were searched using specific search terms and eligibility criteria according to the PRISMA guidelines. The level of evidence was assessed using published criteria by The Journal of Bone & Joint Surgery, and the quality of evidence using the Modified Coleman Methodology Score. Continuous variables were presented as mean ± standard deviation and categorical variables as frequencies (percentages). RESULTS: BMS versus BMS + hyaluronic acid (HA): no complications in either treatment arm were reported. The mean American Orthopaedic Foot and Ankle Society score was 43.5 to 67.3 points and 44.0 to 72.4 points, respectively. The mean 10 mm Visual Analogue Scale pain score was 7.7 to 3.8 points and 7.5 to 2.5 points, respectively. BMS versus BMS + concentrated bone marrow aspirate (CBMA): the pooled overall complication rate was 17/64 (26.6%) versus 11/71 (15.5%), respectively (non-significant). The pool revision rate was 15/64 (23.4%) versus 6/71 (8.5%), respectively (p = 0.016). There has been a notable poor reporting of complication rates for the use of ADSC and PRP as adjuvant biological therapies to BMS for the treatment of OLT. CONCLUSION: There was an overall limited comparative clinical evidence of adjuvant biologics with BMS versus BMS alone for the treatment of OLT. BMS + HA and BMS + CBMA can provide superior outcomes, albeit the currently limited evidence. Further studies are warranted to establish the true clinical superiority of the various biologics ± BMS versus BMS alone. These studies must also compare the various biologics against one another to determine, if any, the optimal biologic for OLT. Clinicians should counsel patients accordingly on these findings as required. LEVEL OF EVIDENCE: Level III.

Predictive Scoring for Recurrent Patellar Instability After a First-time Patellar Dislocation.

PURPOSE: Patellofemoral instability is a common acute knee injury seen in the pediatric population. First-time patellar dislocations usually undergo conservative management, but ~15% to 80% of patients experience recurrent instability. This study aims to develop a prediction model using radiographic parameters of the patellofemoral joint seen on computed tomography scans in different degrees of knee flexion, to determine the risk of recurrence after the first episode of patellofemoral instability. METHODS: A 12-year retrospective case-control study was performed. All patients in a single institution aged 18 years or younger who had a computed tomography patellar tracking scan performed for patellar instability were included. Predictors included in the score were determined through backward logistic regression and compared using receiver operating characteristic curve analysis. RESULTS: This study revealed that recurrent dislocation in first-time patellofemoral dislocation could be accurately predicted using the prediction score that consisted of age, tibial tubercle-trochlear groove distance and congruence angle at 10- and 20-degree flexion. The sensitivity of the score was 100% and specificity was 73.3%. Three diagnostic zones were identified and used to categorize patients into low-, intermediate-, and high-probability groups. CONCLUSION: This study presented a scoring system that incorporated radiographic knee kinematics in the risk assessment for recurrent patellofemoral instability for patient stratification. The scoring system could guide the decision for early surgical intervention after the first-episode patellofemoral dislocation for patients at high risk of recurrent patellofemoral dislocation.