Reliability of Tibial Tubercle-Trochlear Groove Distance for Assessing Tibial Tubercle Lateralization: A Study Comparing Different Anatomic References.

Background: The tibial tubercle-trochlear groove (TT-TG) distance is a measurement used to quantitatively assess tibial tubercle lateralization (TTL), and it has important reference value for the treatment of patellar dislocation (PD). However, TT-TG distance accuracy has been questioned, so many new parameters have been proposed. Purpose: To compare which of the TT-TG, tibial tubercle-midepicondyle (TT-ME), tibial tubercle-Roman arch (TT-RA), tibial tubercle-tibial intercondylar midpoint (TT-TIM), and tibial tubercle-mid inter-epicondyle trochlea intersection (TT-MIELTI) distances better reflect TTL in patients with PD. Study Design: Cohort study (diagnosis); Level of evidence, 3. Methods: A total of 96 patients who had undergone surgery for PD and 96 patients without PD (controls) were included in the study. The patients had all undergone computed tomography examination. The TT-TG, TT-ME, TT-RA, TT-TIM, TT-MIELTI distances and the TTL distance were measured independently by 2 surgeons in a blinded and randomized fashion. The t test was used to detect whether the parameters were significantly different between the 2 groups. The TTL distance was used as a reference value for lateralization of tibial tubercle. Pearson correlation coefficients were calculated to determine correlations between the defined measurements. Results: The intra- and interobserver reliability of the defined measurements was excellent. All parameters except for TT-TIM distance were significantly larger in the PD group than the control group (P < .01 for all). There was a moderate correlation (r = 0.601) between the TT-TG distance and TTL, and other parameters were less correlated with TTL. Conclusion: Among 5 the parameters tested, the TT-TG distance still had the highest correlation with TTL and was able to reflect TTL better in patients with PD. The role of TT-TIM distance in the assessment of PD needs further study.

Effect of antipsychotics and mood stabilisers on metabolism in bipolar disorder: a network meta-analysis of randomised-controlled trials.

Background: Antipsychotics and mood stabilisers are gathering attention for the disturbance of metabolism. This network meta-analysis aims to evaluate and rank the metabolic effects of the commonly used antipsychotics and mood stabilisers in treating bipolar disorder (BD). Methods: Registries including PubMed, Embase, Cochrane Library, Web of Science, Ovid, and Google Scholar were searched before February 15th, 2024, for randomised controlled trials (RCTs) applying antipsychotics or mood stabilisers for BD treatment. The observed outcomes were twelve metabolic indicators. The data were extracted by two reviewers independently, and confirmed by another four reviewers and a corresponding author. The above six reviewers all participated in data analyses. Data extraction was based on PRISMA guidelines, and quality assessment was conducted according to the Cochrane Handbook. Use a random effects model for data pooling. The PROSPERO registration number is CRD42023466669. Findings: Together, 5421 records were identified, and 41 publications with 11,678 complete-trial participants were confirmed eligible. After eliminating possible sensitivity, risperidone ranked 1st in elevating fasting serum glucose (SUCRA = 90.7%) and serum insulin (SUCRA = 96.6%). Lurasidone was most likely to elevate HbA1c (SUCRA = 82.1%). Olanzapine ranked 1st in elevating serum TC (SUCRA = 93.3%), TG (SUCRA = 89.6%), and LDL (SUCRA = 94.7%). Lamotrigine ranked 1st in reducing HDL (SUCRA = 82.6%). Amisulpride ranked 1st in elevating body weight (SUCRA = 100.0%). For subgroup analyses, quetiapine is more likely to affect indicators of glucose metabolism among male adult patients with bipolar mania, while long-term lurasidone tended to affect glucose metabolism among female patients with bipolar depression. Among patients under 18, divalproex tended to affect glucose metabolism, with lithium affecting lipid metabolism. In addition, most observed antipsychotics performed higher response and remission rates than placebo, and displayed a similar dropout rate with placebo, while no between-group significance of rate was observed among mood stabilisers. Interpretation: Our findings suggest that overall, antipsychotics are effective in treating BD, while they are also more likely to disturb metabolism than mood stabilisers. Attention should be paid to individual applicability in clinical practice. The results put forward evidence-based information and clinical inspiration for drug compatibility and further research of the BD mechanism. Funding: The National Key Research and Development Program of China (2023YFC2506200), and the Research Project of Jinan Microecological Biomedicine Shandong Laboratory (No. JNL-2023001B).

Efficacy and tolerability of FDA-approved atypical antipsychotics for the treatment of bipolar depression: a systematic review and network meta-analysis.

We employed a Bayesian network meta-analysis for comparison of the efficacy and tolerability of US Food and Drug Administration (FDA)-approved atypical antipsychotics (AAPs) for the treatment of bipolar patients with depressive episodes. Sixteen randomized controlled trials with 7234 patients treated by one of the five AAPs (cariprazine, lumateperone, lurasidone, olanzapine, and quetiapine) were included. For the response rate (defined as an improvement of ≥50% from baseline on the Montgomery-Åsberg Depression Rating Scale [MADRS]), all AAPs were more efficacious than placebo. For the remission rate (defined as the endpoint of MADRS ≤12 or ≤ 10), cariprazine, lurasidone, olanzapine, and quetiapine had higher remission rates than placebo. In terms of tolerability, olanzapine was unexpectedly associated with lower odds of all-cause discontinuation in comparison with placebo, whereas quetiapine was associated with higher odds of discontinuation due to adverse events than placebo. Compared with placebo, lumateperone, olanzapine, and quetiapine showed higher odds of somnolence. Lumateperone had a lower rate of ≥ weight gain of 7% than placebo and other treatments. Olanzapine was associated with a significant increase from baseline in total cholesterol and triglycerides than placebo. These findings inform individualized prescriptions of AAPs for treating bipolar depression in clinical practice.

The influence of varus and valgus deviation on the contact area of patellofemoral joint in healthy knees.

OBJECT: Varus-valgus lower alignment is a risk factor for patellofemoral osteoarthritis, but malalignment alone affect not only the tibiofemoral joint but also the patellofemoral joint. The aim of the present study was to analyse the contact area of patellofemoral joint in varus alignment and valgus alignment of healthy subjects using magnetic resonance imaging. METHODS: Twenty-six healthy subjects with valgus lower limb alignment (Group I, n = 26) and twenty-six volunteers with varus lower limb alignment (Group II, n = 26) was performed. An MRI scan was used to capture and measure the patellofemoral joint articular cartilage contact area at different degrees of knee flexion (20°, 40°,60°) in passive movement. All subjects were categorized on the basis of the global limb alignment and mechanical alignment of the femur and tibia. Varus alignment is hip-knee-ankle angle ≥ 3°; and valgus alignment is hip-knee-ankle angle ≥ - 3°. To obtain medial facet contact area and lateral facet contact area for each slice, the length of each respective line of contact was multiplied by the 5 mm slice thickness. RESULTS: The overall joint contact area increased from 168.0 ± 20.5 mm2 at 20° knee flexion to 334.4 ± 30.5 mm2 at 60° knee flexion in group (I) The overall joint contact area increased from 178.0 ± 18.9 mm2 at 20° knee flexion to 328.9 ± 27.2 mm2 at 60° knee flexion in group (II) There was a significant difference in lateral facet contact area between group I and group II at 40° of knee flexion. There was significantly different in medial facet contact area between group I and group II at 20° and 40° of knee flexion. CONCLUSIONS: Throughout the knee movement, the contact area on the lateral facet of the patellofemoral joint was greater in the valgus group. In the early phase of knee flexion, the contact area of the medial patellofemoral joint was larger in the varus group. Lower alignment is an important factor in patellofemoral joint degeneration.

Predicting the Probability of Recurrence Based on Individualized Risk Factors After Primary Lateral Patellar Dislocation Treated Nonoperatively.

PURPOSE: To develop a comprehensive and effective personalized scoring system on the basis of demographic and clinical characteristics for predicting recurrence probability in patients with primary lateral patellar dislocation (LPD). METHODS: Participants included 261 primary patients with LPD with 2-year minimum follow-up from our hospital across 2013 to 2020. Demographic and clinical characteristics were collected retrospectively. The backward stepwise method was performed to identify independent predictors and construct a nomogram to predict the probability of recurrence. The predictive performance was assessed by receiver operating characteristic curves, calibration plots, and decision curve analysis. RESULTS: After variables selection, 6 independent predictors of recurrence (skeletal maturity, trochlear dysplasia, tibial tuberosity-trochlear groove distance, mechanical axis deviation, Insall-Salvati index, and patellar tilt) were enrolled in our model. Validation of this nomogram in both training and validation cohort revealed powerful predictive ability, with an area under the curve of 0.962 and 0.977, respectively. The nomogram also showed great calibration and good clinical practicability. CONCLUSIONS: Our study presented a nomogram that incorporates 6 independent risk factors (skeletal maturity, trochlear dysplasia, tibial tuberosity-trochlear groove distance, mechanical axis deviation, Insall-Salvati index, and patellar tilt), which can be conveniently used to accurately predicts the risk of recurrence after primary LPD in individual cases. LEVEL OF EVIDENCE: Level III, retrospective comparative prognostic study.

Contact area and pressure changes of patellofemoral joint during stair ascent and stair descent.

PURPOSE: To investigate the differences of patellofemoral joint pressure and contact area between the process of stair ascent and stair descent. METHODS: The finite element models of 9 volunteers without disorders of knee (9 males) to estimate patellar cartilage pressure during the stair ascent and the stair descent. Simulations took into account cartilage morphology from magnetic resonance imaging, joint posture from weight-bearing magnetic resonance imaging, and ligament model. The three-dimension models of the patella, femur and tibia were developed with the medical image processing software, Mimics 11.1. The ligament was established by truss element of the non-linear FE solver. The equivalent gravity direction (-z direction) load was applied to the whole end of femur (femoral head) according to the body weight of the volunteers, and the force of patella was observed. A paired-samples t-test or Wilcoxon rank sum test to make comparisons between stair ascent and stair descent. Statistical analyses were performed using SPSS 22.0 using a P value of 0.05 to indicate significance. RESULTS: During the stair descent (knee flexion at 30°), the contact pressure of the patella was 2.59 ± 0.06Mpa. The contact pressure of femoral trochlea cartilage was 2.57 ± 0.06Mpa. During the stair ascent (knee flexion at 60°), the contact pressure with patellar cartilage was 2.82 ± 0.08Mpa. The contact pressure of the femoral trochlea cartilage was 3.03 ± 0.11Mpa. The contact area between patellar cartilage and femoral trochlea cartilage was 249.27 ± 1.35mm2 during the stair descent, which was less than 434.32 ± 1.70mm2 during the stair ascent. The area of high pressure was located in the lateral area of patella during stair descent and the area of high pressure was scattered during stair ascent. CONCLUSION: There are small change in the cartilage contact pressure between stair ascent and stair descent, indicating that the joint adjusts the contact pressure by increasing the contact area.

Association Between Femoral Anteversion and Distal Femoral Morphology in Patients With Patellar Dislocation and Trochlear Dysplasia.

Background: Increased femoral anteversion (FA) is reportedly associated with patellar dislocation (PD) and trochlear dysplasia (TD), and the increase in FA may occur at different segments of the femur. In addition, TD is associated with dysplasia of the posterior femoral condyle. Among patients with PD, whether FA is greater with or without TD remains unclear. Purpose: To explore differences in FA and torsion distribution at different femoral sections among patients with PD and TD, patients with PD and no TD, and sex- and age-matched controls and to investigate the association between FA and distal femoral morphology. Study Design: Cross-sectional study; Level of evidence, 3. Methods: This study involved 132 knees: 44 knees with PD and TD, 44 knees with PD but no TD, and 44 control knees. FA, proximal torsion (PT), middle torsion (MT), distal torsion (DT), and distal femoral morphology were measured. Differences were investigated by 1-way analysis of variance. Pearson correlation analysis was conducted to explore the association between FA and each parameter. Results: FA was significantly larger in the PD with TD group (25.4° ± 4.7°) than in the other groups (controls: 18.9° ± 5.6°; PD without TD: 19.9° ± 4.8°) (P < .01). DT was significantly larger in the PD with TD group (15.8° ± 2.9°) than in the other groups (controls: 9.0° ± 4.3°; PD without TD: 8.8° ± 3.9°) (P < .01). In all 3 groups, FA was strongly positively correlated with DT (control, PD without TD, and PD with TD, respectively: r = 0.76, 0.80, and 0.88; P < .01), strongly positively correlated with the posteromedial condylar length (r = 0.48, 0.48, and 0.70; P < .01) and negatively correlated with the posterolateral condylar length (r = -0.30, -0.35, and -0.78, respectively; P < .05). Conclusion: The increased FA in knees with TD was due mainly to DT rather than PT or MT, which may provide a reference for choosing the optimal position for femoral derotation osteotomy.

Platelet-Derived Exosomes Alleviate Knee Osteoarthritis by Attenuating Cartilage Degeneration and Subchondral Bone Loss.

BACKGROUND: Osteoarthritis (OA) is the most prevalent chronic degenerative joint disease among the aged population. However, current treatments for OA are limited to alleviating symptoms, with no therapies that prevent and regenerate cartilage deterioration. PURPOSE: To assess the effects of platelet-derived exosomes (Plt-exos) on OA and then to explore the potential molecular mechanism. STUDY DESIGN: Controlled laboratory study. METHODS: Exosomes derived from human apheresis platelets were isolated and identified. The effects of Plt-exos in protecting chondrocytes under interleukin 1ß stimulation were evaluated by analyzing the proliferation and migration in human primary chondrocytes. RNA sequencing was later performed in vitro for primary chondrocytes to reveal the underlying mechanisms of Plt-exo treatment. Anterior cruciate ligament transection was used to construct an OA mice model, and intra-articular injection of Plt-exos was given once a week for 6 weeks. Mice were sacrificed 4 weeks after the last injection. Histologic and immunohistochemistry staining and micro-computed tomography analysis were performed to assess alterations of articular cartilage and subchondral bone. RESULTS: Plt-exos significantly promoted proliferation and migration of chondrocytes within a dose-dependent manner, as well as dramatically promoted cartilage regeneration and attenuated abnormal tibial subchondral bone remodeling, thus slowing the progression of OA. After being treated with Plt-exos, 1797 genes were differentially expressed in chondrocytes (923 upregulated and 874 downregulated genes). Functional enrichment results and hub genes were mainly involved in anti-inflammatory effects, mediating cell adhesion, stimulating cartilage repair, promoting anabolism, and inhibiting catabolism. CONCLUSION: Our results demonstrated that Plt-exos promoted chondrocyte proliferation and migration in vitro, as well as attenuated cartilage degeneration, improved the microarchitecture of subchondral bone, and retarded OA progression in vivo. CLINICAL RELEVANCE: Our study illustrated that the administered Plt-exos could alleviate knee OA by attenuating cartilage degeneration and subchondral bone loss, possibly serving as a novel promising treatment for OA in the future.

Sclerostin antibody promotes bone formation through the Wnt/ß-catenin signaling pathway in femoral trochlear after patellar instability.

PURPOSE: The molecular mechanism of patellar instability (PI) remains unknown. The purpose of this study was to explore the function of SOST/sclerostin in PI and examine the effect of sclerostin antibody (Scl-Ab). MATERIALS AND METHODS: We randomly divided 60 male 3-week-old C57Bl/6 mice into four groups: sham, PI, Scl-Ab intraperitoneal injection (Scl-Ab IP), Scl-Ab intraarticular injection (Scl-Ab IA). PI was established in the latter three groups. The Scl-Ab IP/IA groups were administered with an intraperitoneal/intraarticular Scl-Ab injection (100 mg/kg, 20 µl), respectively, at 5-day intervals. Distal femurs were collected 30 days after the surgery. The SOST/sclerostin, ß-catenin, ALP, OPG and RANKL expression in distal femur were determined. Trochlear morphology and structural parameters of the trabecular and cortical bone compartments were determined by micro-CT. Further sub-regional analysis was performed. HE staining and Masson's trichrome staining were performed to evaluate cartilage changes. RESULTS: PI increased the expression of SOST/sclerostin and RANKL, and decreased ß-catenin, ALP and OPG levels, while Scl-Ab IP reversed these changes. Scl-Ab IP brought trochlear morphology closer to normality. Additionally, Scl-Ab IP significantly improved most of the bone parameters. Importantly, both PI and Scl-Ab IP acted mainly on trabecular bone. Histological analysis showed that Scl-Ab IP protected cartilage from degeneration. However, Scl-Ab IA did not protect against bone loss or cartilage degradation. CONCLUSIONS: SOST/sclerostin plays an important role in PI and systemic Scl-Ab use promotes bone formation through the Wnt/ß-catenin signaling pathway in the femoral trochlear after PI.

Isolated medial patellofemoral ligament reconstruction is valid to stabilize patellofemoral joint but uncertain to reduce patellar height in setting of lateral patellar dislocation and patella alta.

INTRODUCTION: Medial patellofemoral ligament reconstruction (MPFLR) is the most commonly used surgical treatment for patients with lateral patellar dislocation (LPD). It is still poorly understood whether or not MPFLR has a contributory effect on decreasing patellar height. MATERIALS AND METHODS: Forty-five patients who underwent isolated MPFLR for LPD and patella alta were evaluated with a mean follow-up period of 24 months (22-25 months). Knee joint functions were evaluated by Banff patellofemoral instability instrument (BPII) 2.0 scores and Kujala scores. Patellofemoral engagement and stability were assessed by the patella tilt angle (PTA) and patellar congruence angle (PCA) measured by CT scans, and the patellar-glide test. Patellar height was calculated on lateral radiographs according to three methods: Caton-Deschamps ratios (CDR), Insall-Salvati ratios (ISR), and Blackburne-Peel ratios (BPR). A threshold value of p < 0.05 denoted a statistically significant difference. RESULTS: Significant improvements were found in both BPII 2.0 scores, which increased from 41.7 to 77.8 (p < 0.001) and Kujala scores, which increased from 49.2 to 85.5 (p < 0.001). Post-operative PTAs and PCA decreased from 19.6 ± 8.8 to - 3.4 ± 6.2, and from 24.6 ± 7.3 to 13.1 ± 3.8 degrees respectively (p < 0.001). No patients showed lateral translation more than grade II in the patellar-glide test. Regarding patellar height, a tiny reduction (Δ = 0.02, Δ max = 0.09) was discovered in using CDR (p = 0.027), rather than ISR or BPR. All measurements of radiographic indices had an excellent intra- and inter-rater reliability (ICC > 0.75). CONCLUSIONS: Isolated anatomic MPFLR is sufficient to achieve good clinical outcomes, as well as patellofemoral stability and high rates of return-to-sport. However, it is unclear if the reconstructed MPFL has a contributory effect on reducing patellar height.

Combined HASPIN and mTOR inhibition is synergistic against KRAS-driven carcinomas.

BACKGROUND: Oncogenic mutations in the KRAS gene are very common in human cancers, resulting in cells with well-characterized selective advantages. For more than three decades, the development of effective therapeutics to inhibit KRAS-driven tumorigenesis has proved a formidable challenge and KRAS was considered 'undruggable'. Therefore, multi-targeted therapy may provide a reasonable strategy for the effective treatment of KRAS-driven cancers. Here, we assess the efficacy and mechanistic rationale for combining HASPIN and mTOR inhibition as a potential therapy for cancers carrying KRAS mutations. METHODS: We investigated the synergistic effect of a combination of mTOR and HASPIN inhibitors on cell viability, cell cycle, cell apoptosis, DNA damage, and mitotic catastrophe using a panel of human KRAS-mutant and wild-type tumor cell lines. Subsequently, the human transplant models were used to test the therapeutic efficacy and pharmacodynamic effects of the dual therapy. RESULTS: We demonstrated that the combination of mTOR and HASPIN inhibitors induced potent synergistic cytotoxic effects in KRAS-mutant cell lines and delayed the growth of human tumor xenograft. Mechanistically, we showed that inhibiting of mTOR potentiates HASPIN inhibition by preventing the phosphorylation of H3 histones, exacerbating mitotic catastrophe and DNA damage in tumor cell lines with KRAS mutations, and this effect is due in part to a reduction in VRK1. CONCLUSIONS: These findings indicate that increased DNA damage and mitotic catastrophe are the basis for the effective synergistic effect observed with mTOR and HASPIN inhibition, and support the clinical evaluation of this dual therapy in patients with KRAS-mutant tumors.

A plasmonic AgNP decorated heterostructure substrate for synergetic surface-enhanced Raman scattering identification and quantification of pesticide residues in real samples.

Rapid and on-site Raman spectroscopic identification and quantification of pesticide residues have been restricted to the low instrumental sensitivity of a portable Raman instrument, and no ideal platforms have been reported for analyzing pesticides on real sample surfaces. An efficient method to improve the detection sensitivity is to fabricate a highly sensitive surface-enhanced Raman scattering (SERS) substrate. Here, we present a MOF-derived ZnO@TiO2 heterostructure combined with plasmonic AgNPs as a SERS sensor to achieve synergetic EM and CM enhancement, exhibiting high sensitivity, excellent signal reproducibility (RSD < 5.9%) and superior stability for analysis of model molecules. The SERS sensor achieved a low detection concentration of 10-8 M for both CV and R6G molecular solutions on a portable Raman device. As a proof of concept, we modelled a pesticide residue on real samples of dendrobium leaves. Thiram, triazophos and fonofos solutions were selected as analytes for mimicking the function of on-site analysis. The SERS analytical platform showed not only high sensitivity for single- and multi-component identification, but also quantitative detection of pesticide residues on dendrobium leaves. These preliminary investigations indicate that this SERS analytical platform will allow the development and potential applications in rapid and on-site pesticide analysis.

Anatomical Components Associated With Increased Tibial Tuberosity-Trochlear Groove Distance.

Background: Increased tibial tuberosity-trochlear groove (TT-TG) distance is an important indicator of medial tibial tubercle transfer in the surgical management of lateral patellar dislocation (LPD). Changes to TT-TG distance are determined by a combination of several anatomical factors. Purpose: To (1) determine the anatomical components related to increased TT-TG distance and (2) quantify the contribution of each to identify the most prominent component. Study Design: Case-control study; Level of evidence, 3. Methods: Included were 80 patients with recurrent LPD and 80 age- and body mass index-matched controls. The 2 groups were compared in TT-TG distance and its related anatomical components: tibial tubercle lateralization (TTL), trochlear groove medialization, femoral anteversion, tibiofemoral rotation (TFR), tibial torsion, and mechanical axis deviation (MAD). The Pearson correlation coefficient (r) was calculated to evaluate the association between increased TT-TG distance and its anatomical parameters, and factors that met the inclusion criteria of P < .05 and r ≥ 0.30 were analyzed via stepwise multivariable linear regression analysis to predict TT-TG distance. Results: The LPD and control groups differed significantly in TT-TG distance, TTL, TFR, and MAD (P < .001 for all). Increased TT-TG distance was significantly positively correlated with TTL (r = 0.376; P < .001), femoral anteversion (r = 0.166; P = .036), TFR (r = 0.574; P < .001), and MAD (r = 0.415; P < .001), and it was signficantly negatively correlated with trochlear groove medialization (r = -0.178; P = .024). The stepwise multivariable analysis revealed that higher TTL, excessive knee external rotation, and excessive knee valgus were statistically significant predictors of greater TT-TG distance (P < .001 for all). The standardized estimates that were used for evaluating the predictive values were larger for TFR compared with those for TTL and MAD. Conclusion: TTL, TFR, and MAD were the main independent anatomical components associated with increased TT-TG distance, with the most prominent component being TFR. The association of TT-TG distance to each component analyzed in our study may help guide surgical planning.

Changes in Patellar Morphology Following Soft Tissue Surgical Correction of Recurrent Patellar Dislocation in Children with Low-Grade Trochlear Dysplasia.

OBJECTIVE: To investigate the changes in patellar morphology following soft tissue surgical correction of recurrent patellar dislocation in children with low-grade trochlear dysplasia. METHODS: The prospective cohort study was performed between November 2007 and December 2012. Finally, 25 cases, with the mean age of 8.4 years (range from 7 to 10 years), were admitted to the study. All patients were diagnosed as bilateral recurrent patellar dislocation associated with femoral trochlear dysplasia. The knee that suffered injury or was dislocated was treated with medial patellar retinacular plasty (surgery group). The contralateral knee, which served as a control, was treated conservatively (conservative group). Axial CT scans were undertaken in all patients to assess the patellar morphological characteristics. RESULTS: The mean follow-up time was 60.8 months (range 48 to 75 months). Preoperatively, there were no statistically significant differences between the patellar morphology in the two groups (P > 0.05). Many radiological parameters of patellar morphology were significantly different between the two groups at the final follow-up, including well-known parameters, such as the mean patellar width (surgery group, 40.58 mm [SD 1.26]; conservative group, 36.41 mm [SD 1.17]; P < 0.05), the mean patellar thickness (surgery group, 11.59 mm [SD 0.74]; conservative group, 9.38 mm [SD 0.56]; P < 0.05) and the mean Wiberg index (surgery group, 0.54 [SD 0.06]; conservative group, 0.72 [SD 0.08]; P < 0.05). There are also little-known parameters, such as the ratio of length of lateral patella to medial patella (surgery group, 1.26 [SD 0.17]; conservative group, 1.69 [SD 0.21]; P < 0.05), which was a measurement of facet asymmetry. However, the Wiberg angle was not significantly different between the two groups (surgery group, 128.63° [SD 9.05]; conservative group, 125.47° [SD 13.96°]; P > 0.05) at the final follow-up. No complications were found. CONCLUSIONS: The patellar morphology can be significantly improved by early soft tissue surgical correction in children with patellar instability associated with low-grade femoral trochlear dysplasia.

RNA-seq based integrative analysis of potential crucial genes and pathways associated with patellar instability.

Patellar instability (PI) is a common knee injury in adolescents, but the crucial biomarkers and molecular mechanisms associated with it remain unclear. We established a PI mouse model and investigated PI-related changes in gene expression by RNA sequencing (RNA-seq). Differentially expressed gene (DEG) analysis and enrichment analysis were performed to identify crucial genes and pathways associated with PI. Subsequently, a protein-protein interaction, DEG-miRNA, DEG-transcription factors, and DEG-drug interaction networks were constructed to reveal hub genes, molecular mechanism, and potential drugs for PI. Finally, the reliability of the sequencing results was confirmed by real-time quantitative polymerase chain reaction (RT-qPCR) and immunohistochemistry. Upon comparison with the control group, 69 genes were differently expressed in PI, including 17 upregulated and 52 downregulated ones. The DEGs were significantly enriched in Janus kinase (JAK)/signal transducer and activator of transcription (STAT) signaling pathway and immune responses. The protein-protein interaction network identified ten PI-related hub genes, all of which are involved in the JAK/STAT signaling pathway or inflammation-related pathways. DEG-miRNA and DEG-transcription factor networks offered new insights for regulating DEGs post-transcriptionally. We also determined potential therapeutic drugs or molecular compounds that could restore dysregulated expression of DEGs via the DGIdb database. RT-qPCR results were consistent with the RNA-seq, confirming the reliability of the sequencing data. Immunohistochemistry results suggested that JAK1 and STAT3 expression was increased in PI. Our study explored the potential molecular mechanisms in PI, provided promising biomarkers and suggested a molecular basis for therapeutic targets for this condition.

The tibial tubercle-posterior cruciate ligament (TT-PCL) distance does not truly reflect the lateralization of the tibial tubercle.

PURPOSE: The role of the tibial tubercle-posterior cruciate ligament (TT-PCL) and tibial tubercle-trochlear groove (TT-TG) in recurrent patellar instability (RPI) remains unclear. This study aims to confirm the validity of the TT-TG and TT-PCL in predicting RPI and to verify whether the TT-PCL can truly reflect the lateralization of the tibial tubercle. METHODS: A total of 50 patients with RPI and 50 controls were recruited and underwent magnetic resonance imaging examinations. The TT-TG, TT-PCL, and tibial tubercle lateralization (TTL) were measured independently by two authors in a blinded and randomized fashion. T-test was used for parametric variances and the Mann-Whitney U and Chi-square tests were used for non-parametric variances. Pearson's product moment correlation coefficients were calculated to determine correlations between the defined measurements. The intraclass correlation coefficient was used to assess the reliability of the measurements. RESULTS: All defined measurements showed excellent intra- and inter-observer reliability. The TT-TG distance, TT-PCL distance, and TTL were significantly greater in the PI group than in the control group. The AUC was highest for the TT-TG distance compared with that for the TT-PCL distance, and TTL were 0.798, 0.764, and 0.769, with the calculated cut-off value of 12.5 mm, 16.5 mm, and 66.1 percentages. There was a moderate correlation (r = 0.595) between the TT-TG distance and TTL, and a weak correlation (r = 0.430) between the TT-PCL distance and TTL. CONCLUSION: Both the TT-TG distance and TT-PCL distance can be measured with excellent reliability on magnetic resonance imaging. The TT-TG distance, rather than the TT-PCL distance, has a better performance in predicting RPI. Most interestingly, the TT-PCL distance cannot reflect the real lateralization of TT. This study provides new information to evaluate TTL in patients with RPI. LEVEL OF EVIDENCE: III.

Can Traditional Straight-leg Swaddling Influence Developmental Dysplasia of the Femoral Trochlea? An In Vivo Study in Rats.

BACKGROUND: It has been reported that trochlear dysplasia occurs very early in development, and environmental factors like swaddling may cause developmental dysplasia of the hip, which is associated with a shallower trochlear groove. However, to our knowledge, there are no definitive studies about the relationship between trochlear dysplasia and traditional straight-leg swaddling. QUESTIONS/PURPOSES: Using a rat model of femoral trochlear dysplasia, we asked: Does straight-leg swaddling for 1 and 2 weeks in newborn Wistar rats alter the femoral trochlea with respect to (1) gross morphology, (2) histologic appearance, as well as (3) trochlear sulcus angle, width, and depth? METHODS: Eighty-four newborn Wistar rats (44 females and 40 males) were divided into two equal groups: 42 in the unswaddled group and 42 in the swaddled group; each group was comprised of 22 females and 20 males. In the swaddled group, the rats were wrapped in surgical tape to maintain hip and knee extension to simulate traditional human straight-leg swaddling. To determine whether longer periods of swaddling were associated with more severe trochlear dysplasia, 21 rats in each group were euthanized at 1 and 2 weeks, respectively, and the gross morphology of the femoral trochlea was observed by one observer blinded to condition. Then hematoxylin and eosin staining of the femoral trochlea was performed and the distribution and number of the chondrocytes of the trochlear groove were viewed through a microscope. The trochlear sulcus angles, depth, and width were measured by an experienced technician blinded to condition. RESULTS: By observing the gross morphology, we found that the trochlear groove in the swaddled group became qualitatively flatter compared with the unswaddled group at 1 week, and at 2 weeks, the trochlear groove became much shallower. At 1 and 2 weeks, histologic examinations showed obvious qualitative changes in the distribution and number of chondrocytes of the trochlear groove in the swaddled than in the unswaddled groups. In the swaddled group, trochlear dysplasia was more common at 2 weeks, occurring in 62% (26 of 42 [16 of 22 females and 10 of 22 males]) versus 33% (14 of 42 [8 of 22 females and 6 of 20 males]) at 1 week. At 1 week, the swaddled group showed more trochlear dysplasia compared with the unswaddled group as measured by angle of the trochlear groove (137° ± 6° versus 132°± 3.6°, mean difference 5° [95% confidence interval 2.9° to 7.2°]; p < 0.001), depth of the trochlear grove (0.28 ± 0.04 mm versus 0.31 ± 0.02 mm, mean difference 0.03 mm [95% CI 0.01 to 0.04]; p < 0.001). At 2 weeks, the swaddled group showed more severe trochlear dysplasia than at 1 week compared with the unswaddled group as measured by the angle of the trochlear groove (135° ± 6.0° versus 128° ± 4.8°, mean difference 7° [95% CI 5.7° to 10.4°]; p < 0.001), depth of the trochlear grove (0.32 ± 0.04 mm versus 0.36 ± 0.02 mm, mean difference 0.04 mm [95% CI 0.03 to 0.06]; p < 0.001). There was no difference in the width of the trochlear sulcus between the swaddled and the unswaddled groups at 1 week (1.29 ± 0.14 mm versus 1.30 ± 0.12 mm, mean difference 0.01 mm [95% CI -0.05 to 0.07]; p = 0.73) and 2 weeks (1.55 ± 0.12 mm versus 1.56 ± 0.12 mm, mean difference 0.01 mm [95% CI -0.05 to 0.07]; p = 0.70). CONCLUSION: Our results indicate that traditional straight-leg swaddling could induce trochlear dysplasia in this model of newborn rats. With an increased swaddling time of 2 weeks, more severe trochlear dysplasia appeared in the swaddled group. CLINICAL RELEVANCE: Our findings suggest that traditional straight-leg swaddling may impair trochlear development in the human neonate and lead to trochlear dysplasia in infants. We believe our animal model will be useful in future work to observe and study the change of cartilage and subchondral bone in each stage of the development of trochlear dysplasia and the change of mechanotransduction-associated proteins (such as, TRPV4/ Piezo1 and CollagenⅡ) in cartilage and subchondral osteocytes. It will also be helpful to further investigate the mechanism of developmental femoral trochlea dysplasia caused by biomechanical changes.

Bromodomain-containing protein 9 is a prognostic biomarker associated with immune infiltrates and promotes tumor malignancy through activating notch signaling pathway in negative HIF-2α clear cell renal cell carcinoma.

HIF-2α selective inhibitor showed successful efficacy in sensitive clear cell renal cell carcinoma (ccRCC) presenting higher levels of HIF-2α compared to resistant tumors with low level of HIF-2α (negative HIF-2α ccRCC). Currently, negative HIF-2α ccRCC lacks truly effective therapeutic agents to improve the outcomes. Bromodomain-containing protein 9 (BRD9) plays a critical role in human hepatocellular carcinoma, squamous cell lung cancer, acute myeloid leukemia, and so on. However, expression and biological role of BRD9 in negative HIF-2α ccRCC is poorly understood. Clinically, we demonstrated that expression of BRD9 in negative HIF-2α ccRCC tissues was higher than that in positive HIF-2α ccRCC. Moreover, high BRD9 expression was correlated with unfavorable clinicopathological features and predicted the poor overall survival of negative HIF-2α ccRCC patients. Functionally, BRD9 knockout resulted in reduced proliferation, migration and invasion of negative HIF-2α ccRCC cells (Caki-2). In addition, BRD9 was related to the TIIC infiltration level in negative HIF-2α ccRCC tissues. Mechanistically, Gene set enrichment analysis (GSEA) showed that BRD9 was closely related to Notch signaling pathway. BRD9 knockout resulted in reduced mRNA level of Hes1 and Notch1 in negative HIF-2α ccRCC in vitro. The overexpression of NICD (Notch intracellular domain) enhanced malignant behaviors of Caki-2 cells with BRD9 knockout. And Notch inhibition led to attenuation of cell growth and reduced migration and invasion in Caki-2 cells. Overall, our results identified that BRD9 promotes the proliferation, migration and invasion of negative HIF-2α ccRCC cells by targeting Notch signaling pathway and serve as a promising biomarker for negative HIF-2α ccRCC.

Bioisosteric replacements of the indole moiety for the development of a potent and selective PI3Kδ inhibitor: Design, synthesis and biological evaluation.

Based on indole scaffold, a potent and selective phosphoinositide 3-kinase delta (PI3Kδ) inhibitor, namely FD223, was developed by the bioisosteric replacement drug discovery approach and studied for the treatment of acute myeloid leukemia (AML). In vitro studies revealed that FD223 displays high potency (IC50 = 1 nM) and selectivity (29-51 fold over other PI3K isoforms) against PI3Kδ, and exhibits efficient inhibition of the proliferation of AML cell lines (MOLM-16, HL-60, EOL-1 and KG-1) by suppressing p-AKT Ser473 thus causing G1 phase arrest during the cell cycle. Further given the favorable pharmacokinetic (PK) profiles of FD223, in vivo studies were evaluated using xenograft model in nude mice, confirming its significant antitumor efficacy meanwhile with no observable toxicity. All these results are comparable to the positive group of Idelalisib (CAL-101), indicating that FD223 has potential for further development as a promising PI3Kδ inhibitor for the treatment of leukemia such as AML.