Highlights d A selective, orally bioavailable Menin-MLL inhibitor, VTP50469, is developed d Displacement of Menin from chromatin leads to loss of MLL from specific loci d Treatment with VTP50469 leads to suppression of a subset of MLL fusion target genes d Treatment with VTP50469 improves survival in PDX models of MLL-r ALL

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Summary Obesity-related osteoarthritis (OA) is a complex, multifactorial condition that can cause significant impact on patients’ quality of life. Whilst chronic inflammation, adipocytokines and metabolic factors are considered to be important pathogenic factors in obesity related OA, there has been limited investigation into the biomechanical impact of obesity on OA development. This review aims to demonstrate that mechanical factors are the major pathological cause of obesity-related OA. The effect of obesity on pathological changes to the osteochondral unit and surrounding connective tissues in OA is summarized, as well as the impact of obesity-related excessive and abnormal joint loading, concomitant joint malalignment and muscle weakness. An integrated therapeutic strategy based on this multi-factorial presentation is presented, to assist in the management of obesity related OA. The translational potential of this article Despite the high prevalence of obesity-related OA, there is no specific guideline available for obesity-related OA management. In this review, we demonstrated the pathological changes of obesity-related OA and summarized the impact of biomechanical factors by proposing a hypothetical model of obesity-related OA change. Therapeutic strategies based on adjusting abnormal mechanical effects are presented to assist in the management of obesity-related OA.

The assessment of cartilage repair has largely been limited to macroscopic observation, magnetic resonance imaging (MRI), or destructive biopsy. The aims of this study were to establish an ovine model of articular cartilage injury repair and to examine the efficacy of nondestructive techniques for assessing cartilage regeneration by matrix-induced autologous chondrocyte implantation (MACI). The development of nondestructive assessment techniques facilitates the monitoring of repair treatments in both experimental animal models and human clinical subjects. Defects (Ø 6 mm) were created on the trochlea and medial femoral condyle of 21 sheep randomized into untreated controls or one of two treatment arms: MACI or collagen-only membrane. Each group was divided into 8-, 10-, and 12-week time points. Repair outcomes were examined using laser scanning confocal arthroscopy (LSCA), MRI, histology, macroscopic ICRS grading, and biomechanical compression analysis. Interobserver analysis of the randomized blinded scoring of LSCA images validated our scoring protocol. Pearson correlation analysis demonstrated the correlation between LSCA, MRI, and ICRS grading. Testing of overall treatment effect independent of time point revealed significant differences between MACI and control groups for all sites and assessment modalities (Asym Sig < 0.05), except condyle histology. Biomechanical analysis suggests that while MACI tissue may resemble native tissue histologically in the early stages of remodeling, the biomechanical properties remain inferior at least in the short term. This study demonstrates the potential of a multisite sheep model of articular cartilage defect repair and its assessment via nondestructive methods. ß

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Aims Instability continues to be a troublesome complication after total hip arthroplasty (THA). Patient-related risk factors associated with a higher dislocation risk include the preoperative diagnosis, an age of 75 years or older, high body mass index (BMI), a history of alcohol abuse, and neurodegenerative diseases. The goal of this study was to assess the dislocation rate, radiographic outcomes, and complications of patients stratified as high-risk for dislocation who received a dual mobility (DM) bearing in a primary THA at a minimum follow-up of two years. Materials and Methods We performed a retrospective review of a consecutive series of DM THA performed between 2010 and 2014 at our institution (Hospital for Special Surgery, New York, New York) by a single, high-volume orthopaedic surgeon employing a single prosthesis design (Anatomic Dual Mobility (ADM) Stryker, Mahwah, New Jersey). Patient medical records and radiographs were reviewed to confirm the type of implant used, to identify any preoperative risk factors for dislocation, and any complications. Radiographic analysis was performed to assess for signs of osteolysis or remodelling of the acetabulum. Results There were 151 patients who met the classification of high-risk according to the inclusion criteria and received DM THA during the study period. Mean age was 82 years old (73 to 95) and 114 patients (77.5%) were female. Mean follow-up was 3.6 years (1.9 to 6.1), with five patients lost to follow-up and one patient who died (for a reason unrelated to the index procedure). One patient (0.66%) sustained an intraprosthetic dislocation; there were no other dislocations. Conclusion At mid-term follow-up, the use of a DM bearing for primary THA in patients at high risk of dislocation provided a stable reconstruction option with excellent radiographic results. Longer follow-up is needed to confirm the durability of these reconstructions.

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Aims A proximal femur fracture (PFF) is a common orthopaedic presentation, with an incidence of over 25,000 cases reported in the Australian and New Zealand Hip Fracture Registry (ANZHFR) in 2018. Hip fractures are known to have high mortality. The purpose of this study was to determine the utility of the Clinical Frailty Scale (CFS) in predicting 30-day and one-year mortality after a PFF in older patients. Methods A retrospective review of all fragility hip fractures who met the inclusion/exclusion criteria of the ANZHFR between 2017 and 2018 was undertaken at a single large volume tertiary hospital. There were 509 patients included in the study with one-year follow-up obtained in 502 cases. The CFS was applied retrospectively to patients according to their documented pre-morbid function and patients were stratified into five groups according to their frailty score. The groups were compared using t-test, analysis of variance (ANOVA), and the chi-squared test. The discriminative ability of the CFS to predict mortality was then compared with American Society of Anaesthesiologists (ASA) classification and the patient’s chronological age. Results A total of 38 patients were deceased at 30 days and 135 patients at one year. The 30-day mortality rate increased from 1.3% (CFS 1 to 3; 1/80) to 14.6% (CFS ≥ 7; 22/151), and the one-year mortality increased from 3.8% (CFS 1 to 3; 3/80) to 41.7% (CFS ≥ 7; 63/151). The CFS was demonstrated superior discriminative ability in predicting mortality after PFF (area under the curve (AUC) 0.699; 95% confidence interval (CI) 0.651 to 0.747) when compared with the ASA (AUC 0.634; 95% CI 0.576 to 0.691) and chronological age groups (AUC 0.585; 95% CI 0.523 to 0.648). Conclusion The CFS demonstrated utility in predicting mortality after PFF fracture. The CFS can be easily performed by non-geriatricians and may help to reduce age related bias influencing surgical decision making. Cite this article: Bone Joint Open 2020;1-8:443–449.