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Geological and climatic changes, coupled with long-distance dispersals, have resulted in relatively recent origins and radiations of many New Zealand plant lineages. Several have extensive morphological but low genetic variation, rendering taxonomic resolution difficult. This study presents population-level phylogenies and networks for the New Zealand species of Plantago (Plantaginaceae) using DNA sequences from internal transcribed spacer (ITS) regions of the nuclear ribosomal genes. The data suggest that the two P. spathulata subspecies, and a 16-ploid entity (P. sp. 'Sylvester'), should be recognized at species rank. However, there was no evidence for divergence of: two P. raoulii forms; P. lanigera and P. novae-zelandiae; and two P. triandra subspecies. Several species and subspecies boundaries require revision with additional data (e.g. chromosome counts, morphological data, and additional DNA loci) needed. The high morphological variation but low sequence divergence found here could be caused by various factors, including incomplete speciation and/or hybridization. [ABSTRACT FROM AUTHOR]

Introduction: The key outcome of joint registries is revision events, which inform clinical practice and identify poor-performing implants. Registries record revision events and reasons, but accuracy may be limited by a lack of standardized definitions of revision. Our study aims to assess the accuracy and completeness of unicompartmental knee arthroplasty (UKA) revision and indications reported to the New Zealand Joint Registry (NZJR) with independent clinical review., Methods: Case record review of 2272 patients undergoing primary UKA at four large tertiary hospitals between 2000 and 2017 was performed, identifying 158 patients who underwent revision. Detailed review of clinical findings, radiographs and operative data was performed to identify revision cases and the reasons for revision using a standardized protocol. These were compared to NZJR data using chi-squared and Fisher exact tests., Results: The NZJR recorded 150 (95%) of all UKA revisions. Osteoarthritis progression was the most common reason on the systematic clinical review (35%), however, this was underreported to the registry (8%, P < 0.001). A larger proportion of revisions reported to the registry were for 'pain' (30% of cases vs. 5% on clinical review, P < 0.001). A reason for revision was not reported to the registry for 10% of cases., Conclusion: The NZJR had good capture of UKA revisions, but had significant differences in registry-reported revision reasons compared to our independent systematic clinical review. These included over-reporting of 'pain', under-reporting of osteoarthritis progression, and failing to identify a revision reason. Efforts to improve registry capture of revision reasons for UKA could be addressed through more standardized definitions of revision and tailored revision options for UKA on registry forms., (© 2024 Royal Australasian College of Surgeons.)

Hypothesis and Background: Recently, the indication of reverse total shoulder arthroplasty (RTSA) has expanded beyond rotator cuff arthropathy to include treatment of complex acute proximal humeral fracture (PHF). Limited previous studies have compared the long-term clinical and functional outcomes of patients undergoing RTSA for PHF vs. elective indications for degenerative conditions. The purpose of this study was to compare implant survivorship, reasons for revision and functional outcomes in patients undergoing RTSA for acute PHF with those undergoing elective RTSA in a population-based cohort study., Methods: Prospectively collected data from the New Zealand Joint Registry from 1999 to 2021 and identified 6862 patients who underwent RTSA. Patients were categorized by preoperative indication, including PHF (10.8%), rotator cuff arthropathy (RCA) (44.5%), osteoarthritis (OA) (34.1%), rheumatoid arthritis (RA) (5.5%), and old traumatic sequelae (5.1%). Revision-free implant survival and functional outcomes (Oxford Shoulder Scores [OSSs] at the 6-month, 5-year, and 10-year follow-ups) were adjusted by age, sex, American Society of Anesthesiologists class, and surgeon experience and compared., Results: Revision-free implant survival at 10 years for RTSA for PHF was 97.3%, compared with 96.1%, 93.7%, 92.8%, and 91.3% for OA, RCA, RA and traumatic sequelae, respectively. When compared with RTSA for PHF, the adjusted risk of revision was significantly higher for traumatic sequelae (hazard ratio = 2.3, P = .023) but not for other elective indications. The most common reason for revision in the PHF group was dislocation or instability (42.9%), which was similar to the OA (47.6%) and traumatic sequelae (33.3%) groups. At 6 months post-surgery, OSSs were significantly lower for the PHF group compared with the RCA, OA, and RA groups (31.1 vs. 35.6, 37.7, and 36.5, respectively, P < .001), and similar to traumatic sequelae (31.7, P = .431). At 5 years, OSSs were only significantly lower for PHF compared with OA (37.4 vs. 41.0, P < .001) and there was no difference between the PHF and other groups. At 10 years, there were no significant differences between groups., Conclusions: RTSA for PHF demonstrated reliable long-term survivorship and functional outcomes compared with elective indications. Despite lower functional outcomes in the early postoperative period for the PHF group, implant survivorship was similar in patients undergoing RTSA for the primary indication of acute PHF compared with RCA, OA, and RA and superior compared to the primary indication of traumatic sequelae., (Copyright © 2024 The Author(s). Published by Elsevier Inc. All rights reserved.)

Introduction: Arthroscopic procedures for osteoarthritis (OA), in particular arthroscopic meniscectomy, have poorer long-term clinical outcomes compared to those managed non-operatively. In addition, previous arthroscopy is associated with worse outcomes following subsequent total knee arthroplasty (TKA), however there is limited data on the impact on subsequent unicompartmental knee arthroplasty (UKA) outcomes. The aim of the study is to investigate whether patients who had arthroscopy prior to UKA have differences in survivorship or functional outcomes compared to those with no prior arthroscopy., Methods: All patients who received either a primary medial or lateral UKA at four large tertiary hospitals were included (n = 2,272). Patient data (age, sex, ethnicity, body mass index (BMI), American Society of Anesthesiologists (ASA) status and surgical data) was recorded following systematic review of all clinical notes and radiographs. Differences between survival curves were analysed using log-rank curves. Differences between categorical data was compared using Fisher's exact or Chi-squared tests, and differences between continuous variables were compared using t-tests., Results: There was no difference between the survival curves for UKA patients with previous arthroscopy compared to those with no previous arthroscopy (10 years: 91% UKA with previous arthroscopy vs. 92% no previous arthroscopy; 15 years: 78% previous arthroscopy vs. 86% no previous arthroscopy; p = 0.50). Oxford Knee Score (OKS) was comparable between patients who had previous arthroscopy and those who had no previous arthroscopy at 6 months (38.8 vs. 39.3, p = 0.45), 5 years (42.0 vs. 40.4, p = 0.11) and 10 years (40.8 vs. 40.2, p = 0.71)., Discussion: In this large patient cohort with comprehensive review of clinical data and outcomes, we found that prior arthroscopy did not affect survivorship or functional outcomes of UKA patients., (© 2024. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)

Current in vitro models poorly represent the healthy or diseased tendon microenvironment, limiting the translation of the findings to clinics. The present work aims to establish a physiologically relevant in vitro tendon platform that mimics biophysical aspects of a healthy and tendinopathic tendon matrix using a decellularized bovine tendon and to characterize tendon cells cultured using this platform. Bovine tendons were subjected to various decellularization techniques, with the efficacy of decellularization determined histologically. The biomechanical and architectural properties of the decellularized tendons were characterized using an atomic force microscope. Tendinopathy-mimicking matrices were prepared by treating the decellularized tendons with collagenase for 3 h or collagenase-chondroitinase (CC) for 1 h. The tendon tissue collected from healthy and tendinopathic patients was characterized using an atomic force microscope and compared to that of decellularized matrices. Healthy human tendon-derived cells (hTDCs) from the hamstring tendon were cultured on the decellularized matrices for 24 or 48 h, with cell morphology characterized using f-actin staining and gene expression characterized using real-time PCR. Tendon matrices prepared by freeze-thawing and 48 h nuclease treatment were fully decellularized, and the aligned structure and tendon stiffness (1.46 MPa) were maintained. Collagenase treatment prepared matrices with a disorganized architecture and reduced stiffness (0.75 MPa), mimicking chronic tendinopathy. Treatment with CC prepared matrices with a disorganized architecture without altering stiffness, mimicking early tendinopathy (1.52 MPa). hTDCs on a healthy tendon matrix were elongated, and the scleraxis ( SCX ) expression was maintained. On tendinopathic matrices, hTDCs had altered morphological characteristics and lower SCX expression. The expression of genes related to actin polymerization, matrix degradation and remodeling, and immune cell invasion were higher in hTDCs on tendinopathic matrices. Overall, the present study developed a physiological in vitro system to mimic healthy tendons and early and late tendinopathy, and it can be used to better understand tendon cell characteristics in healthy and diseased states.

Introduction: Surgical options for patients with unicompartmental knee osteoarthritis include high tibial osteotomy (HTO) or unicompartmental knee arthroplasty (UKA). When managing younger patients with a higher chance of further surgery, the outcome of any subsequent conversion to total knee arthroplasty (TKA) also needs to be considered. The aim of this study was to compare implant survivorship and patient-reported outcomes for patients undergoing TKA after previous HTO or UKA, with comparisons for age, gender and comorbidities., Methods: Revision risk and 6-month Oxford Knee Scores (OKS) from the New Zealand Joint Registry were compared for patients who underwent TKA after HTO (HTO-TKA; n = 1556) or UKA (UKA-TKA; n = 965) between 1999 and 2019, with a comparison group of primary TKA (n = 110,948). Mean follow-up was 8.2 years., Results: Adjusted revision risk was similar for HTO-TKA and UKA-TKA groups (hazard ratio (HR) 1.04, p = 0.84); and risk for both groups were higher than primary TKA (HTO-TKA HR 1.45, p = 0.002; UKA-TKA HR 1.51, p = 0.01). Overall adjusted mean OKS at 6 months for HTO-TKA (36.2) was similar to primary TKA (36.8, p = 0.23); and both were higher than UKA-TKA (34.2, p < 0.001). For the youngest patient group (< 55 years), revision rates of UKA-TKA were two-fold higher than HTO-TKA (2.8 vs. 1.3 per 100 component yrs, p < 0.03). HTO-TKA had better OKS (37.5 vs. 34.1, p < 0.0001) for males. Mean OKS for UKA-TKA was lower than HTO-TKA for patients with ASA 1-2 (35.6 vs. 37.5, p < 0.01)., Conclusion: The findings from this study suggest that revision rate following TKA after HTO and UKA are similar. However, TKA after HTO have superior functional outcomes compared with TKA after UKA and are comparable to functional outcomes post primary TKA. The results support the use of HTO for young, male and less co-morbid patients., (© 2024. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)

Background: Published research suggests Indigenous peoples are less likely to receive analgesia in acute pain settings however there is limited data on the indigenous New Zealand Māori population. The aim of this exploratory pilot study was to compare management between Māori and non-Māori for acute fracture pain in a regional trauma centre., Methods: A retrospective review was undertaken for 120 patients with isolated tibial shaft fractures presenting at a tertiary level trauma center between 2015 and 2020. Outcome measures reflected the patient journey including type of analgesia charted pre-hospital, in the ED and on the ward., Results: Out of 104 matched patients, 48 (46%) were Māori and 65% were male. Fewer Māori received pre-hospital analgesia compared with non-Māori (odds ratio 0.29, p = 0.006). Pain scores were similar on arrival to ED (6.1 ± 3.5 versus 5.4 ± 2.7, p = 0.2). Once at hospital, there were similar rates of prescribed analgesia (paracetamol, NSAIDs, synthetics, or opioids) both in ED and the ward. Time to analgesia were also similar for both groups (72 ± 71 min versus 65 ± 63 min, P > 0.9)., Discussion: We found differences in pre-hospital administration of analgesia between Māori and non-Māori patients with tibial shaft fractures. However once in hospital although there was a trend towards lower prescribing for Māori, there were no significant differences. Exploring the reasons underpinning this difference and the development of robust analgesic guidelines for tibial shaft fractures may help in reducing this inequity in care, particularly in the pre-hospital setting., (© 2024 Royal Australasian College of Surgeons.)

Purpose: Osteoarthritis (OA) is associated with inflammation, and residual inflammation may influence outcomes following knee arthroplasty. This may be more relevant for patients undergoing unicompartmental knee arthroplasty (UKA) due to larger remaining areas of native tissue. This study aimed to: (1) characterise inflammatory profiles for medial UKA patients and (2) investigate whether inflammation markers are associated with post-operative outcomes., Methods: This prospective, observational study has national ethics approval. Bloods, synovial fluid, tibial plateaus and synovium were collected from medial UKA patients in between 1 January 2021 and 31 December 2021. Cytokine and chemokine concentrations in serum and synovial fluid (SF) were measured with multiplexed assays. Disease severity of cartilage and synovium was assessed using validated histological scores. Post-operative outcomes were measured with Oxford Knee Score (OKS), Forgotten Joint Score (FJS-12) and pain scores., Results: The study included 35 patients. SF VEGFA was negatively correlated with pre-operative pain at rest (r - 0.5, p = 0.007), and FJS-12 at six-week (r 0.44, p = 0.02), six-month (r 0.61, p < 0.01) and one-year follow-up (r 0.63, p = 0.03). Serum and SF IL-6 were positively correlated with OKS at early follow-up (serum 6 weeks, r 0.39, p = 0.03; 6 months, r 0.48, p < 0.01; SF 6 weeks, r 0.35, p = 0.04). At six weeks, increased synovitis was negatively correlated with improvements in pain at rest (r - 0.41, p = 0.03) and with mobilisation (r - 0.37, p = 0.047)., Conclusion: Lower levels of synovitis and higher levels of IL-6 and VEGFA were associated with better post-operative outcomes after UKA, which could be helpful for identifying UKA patients in clinical practice., Level of Evidence: Level IV case series., (© 2023. The Author(s).)

Background: The Oxford Knee Score (OKS) is used to measure knee arthroplasty outcomes; however, it is unclear which questions are more relevant. Our aims were to (1) identify which OKS question(s) were the strongest predictors of subsequent revision and (2) compare the predictive ability of the "pain" and "function" domains., Methods: All primary total knee arthroplasties (TKAs) and unicompartmental knee arthroplasties (UKAs) in the New Zealand Joint Registry between 1999 and 2019 with an OKS at 6 months (TKA n = 27,708; UKA n = 8,415), 5 years (TKA n = 11,519; UKA n = 3,365) or 10 years (TKA n = 6,311; UKA n = 1,744) were included. Prediction models were assessed using logistic regressions and receiver operating characteristic analyses., Results: A reduced model with 3 questions ("overall pain," "limping when walking," "knee giving way") showed better diagnostic ability than full OKS for predicting UKA revision at 6 months (area under the curve [AUC]: 0.80 versus 0.78; P < .01) and 5 years (0.81 versus 0.77; P = .02), and comparable diagnostic ability for predicting TKA revision at all time points (6 months, 0.77 versus 0.76; 5 years, 0.78 versus 0.75; 10 years, 0.76 versus 0.73; all not significant), and UKA revision at 10 years (0.80 versus 0.77; not significant). The pain domain had better diagnostic ability for predicting subsequent revision for both procedures at 5 and 10 years., Conclusion: Questions on "overall pain", "limping when walking", and "knee giving way" were the strongest predictors of subsequent revision. Attention to low scores from these questions during follow-up may allow for prompt identification of patients most at risk of revision., (Copyright © 2023 Elsevier Inc. All rights reserved.)

Background: Long-term survivorship and accurate characterization of revision reasons in unicompartmental knee arthroplasty (UKA) are limited by a lack of long-term data and standardized definitions of revision. The aim of this study was to identify survivorship, risk factors, and reasons for revision in a large cohort of medial UKAs with long-term follow-up (up to 20 years)., Methods: Patient, implant, and revision details for 2,015 primary medial UKAs (mean follow-up, 8 years) were recorded following systematic clinical and radiographic review. Survivorship and risk of revision were analyzed using Cox proportional hazards. Reasons for revision were analyzed using competing-risk analysis., Results: Implant survivorship at 15 years was 92% for cemented fixed-bearing (cemFB), 91% for uncemented mobile-bearing (uncemMB), and 80% for cemented mobile-bearing (cemMB) UKAs (p = 0.02). When compared with cemFB, the risk of revision was higher for cemMB implants (hazard ratio [HR] = 1.9, 95% confidence interval [CI] = 1.1 to 3.2; p = 0.03). At 15 years, cemented implants had a higher cumulative frequency of revision due to aseptic loosening (3% to 4%, versus 0.4% for uncemented; p < 0.01), cemMB implants had a higher cumulative frequency of revision due to osteoarthritis progression (9% versus 2% to 3% for cemFB/uncemMB; p < 0.05), and uncemMB implants had a higher cumulative frequency of revision due to bearing dislocation (4% versus 2% for cemMB; p = 0.02). Compared with the oldest patients (≥70 years), younger patients had a higher risk of revision (<60 years: HR = 1.9, 95% CI = 1.2 to 3.0; 60 to 69 years: HR = 1.6, 95% CI = 1.0 to 2.4; p < 0.05 for both). At 15 years, there was a higher cumulative frequency of revision for aseptic loosening in these younger groups (3.2% and 3.5% versus 2.7% for ≥70 years; p < 0.05)., Conclusions: Implant design and patient age were risk factors for revision of medial UKA. The findings from this study suggest that surgeons should consider using cemFB or uncemMB designs because of their superior long-term implant survivorship compared with cemMB designs. Additionally, for younger patients (<70 years), uncemMB designs had a lower risk of aseptic loosening than cemFB designs at the expense of a risk of bearing dislocation., Level of Evidence: Prognostic Level III . See Instructions for Authors for a complete description of levels of evidence., Competing Interests: Disclosure: The Disclosure of Potential Conflicts of Interest forms are provided with the online version of the article ( http://links.lww.com/JBJS/H435 )., (Copyright © 2023 by The Journal of Bone and Joint Surgery, Incorporated.)

Purpose: UKA has higher revision risk, particularly for lower volume surgeons. While robotic-arm assisted systems allow for increased accuracy, introduction of new systems has been associated with learning curves. The aim of this study was to determine the learning curve of a UKA robotic-arm assisted system. The hypothesis was that this may affect operative times, patient outcomes, limb alignment, and component placement., Methods: Between 2017 and 2021, five surgeons performed 152 consecutive robotic-arm assisted primary medial UKA, and measurements of interest were recorded. Patient outcomes were measured with Oxford Knee Score, EuroQol-5D, and Forgotten Joint Score at 6 weeks, 1 year, and 2 years. Surgeons were grouped into 'low' and 'high' usage groups based on total UKA (manual and robotic) performed per year., Results: A learning curve of 11 cases was found with operative time (p < 0.01), femoral rotation (p = 0.02), and insert sizing (p = 0.03), which highlighted areas that require care during the learning phase. Despite decreased 6-week EQ-5D-5L VAS in the proficiency group (77 cf. 85, p < 0.01), no difference was found with implant survival (98.2%) between phases (p = 0.15), or between 'high' and 'low' usage surgeons (p = 0.23) at 36 months. This suggested that the learning curve did not lead to early adverse effects in this patient cohort., Conclusion: Introduction of a UKA robotic-arm assisted system showed learning curves for operative times and insert sizing but not for implant survival at early follow-up. The short learning curve regardless of UKA usage indicated that robotic-arm assisted UKA may be particularly useful for low-usage surgeons., Level of Evidence: Level III, Retrospective cohort study., (© 2021. The Author(s) under exclusive licence to European Society of Sports Traumatology, Knee Surgery, Arthroscopy (ESSKA).)

Unicompartmental knee arthroplasty (UKA) has higher revision rates than total knee arthroplasty (TKA). As revision of UKA may be less technically demanding than revision TKA, UKA patients with poor functional outcomes may be more likely to be offered revision than TKA patients with similar outcomes. The aim of this study was to compare clinical thresholds for revisions between TKA and UKA using revision incidence and patient-reported outcomes, in a large, matched cohort at early, mid-, and late-term follow-up. Analyses were performed on propensity score-matched patient cohorts of TKAs and UKAs (2:1) registered in the New Zealand Joint Registry between 1 January 1999 and 31 December 2019 with an Oxford Knee Score (OKS) response at six months (n, TKA: 16,774; UKA: 8,387), five years (TKA: 6,718; UKA: 3,359), or ten years (TKA: 3,486; UKA: 1,743). Associations between OKS and revision within two years following the score were examined. Thresholds were compared using receiver operating characteristic analysis. Reasons for aseptic revision were compared using cumulative incidence with competing risk. Fewer TKA patients with 'poor' outcomes (≤ 25) subsequently underwent revision compared with UKA at six months (5.1% vs 19.6%; p < 0.001), five years (4.3% vs 12.5%; p < 0.001), and ten years (6.4% vs 15.0%; p = 0.024). Compared with TKA, the relative risk for UKA was 2.5-times higher for 'unknown' reasons, bearing dislocations, and disease progression. Compared with TKA, more UKA patients with poor outcomes underwent revision from early to long-term follow-up, and were more likely to undergo revision for 'unknown' reasons, which suggest a lower clinical threshold for UKA. For UKA, revision risk was higher for bearing dislocations and disease progression. There is supporting evidence that the higher revision UKA rates are associated with lower clinical thresholds for revision and additional modes of failure., Competing Interests: None declared., (© 2023 The British Editorial Society of Bone & Joint Surgery.)

Background: Self-reported outcome measures are increasingly being collected for healthcare evaluation therefore it is prudent to understand their associations with patient outcomes. Our aims were to investigate: (1) if Oxford Knee Score (OKS) is associated with impending revision at long-term (5 and 10 years) follow-up, and (2) if decreased OKS at subsequent follow-ups is associated with higher risk of revision., Patients and Methods: All total knee (TKAs) and unicompartmental knee arthroplasties (UKAs) between 1999 and 2019 in the New Zealand Joint Registry with an OKS at 6 months (TKA n = 27 708, UKA n = 8415), 5 years (TKA n = 11 519, UKA n = 3365) or 10 years (TKA n = 6311, UKA n = 1744) were included. Logistic regression determined associations of the OKS with revision within 2 years of each score. Change in OKS between timepoints were compared with revision risk., Results: For every one-unit increase in OKS, the odds of TKA and UKA revision decreased by 10% and 11% at 6 months, 10% and 12% at 5 years and 9% and 5% at 10 years. For both procedures a decrease of seven or more OKS points from previous follow-up was associated with higher risk of revision (5 years: TKA 4.7% versus 0.5%, UKA 8.7% versus 0.9%; 10 years: TKA 4.4% versus 0.7%, UKA 11.3% versus 1.5%; all P < 0.01)., Conclusion: The OKS had a strong negative association with risk of impending TKA and UKA revision from early to long-term (10+ years) follow-up. A decrease of seven or more points when compared with the previous follow-up was also associated with higher revision risk., (© 2023 The Authors. ANZ Journal of Surgery published by John Wiley & Sons Australia, Ltd on behalf of Royal Australasian College of Surgeons.)

Background: Total knee arthroplasty (TKA) is an effective procedure for patients with a variety of knee conditions. The main cause of aseptic TKA failure is implant loosening, which has been linked to poor cement mantle quality. Cementless components were introduced to offer better longer-term biological fixation through osseointegration; however, early designs led to increased rate of revision due to a lack of initial press-fit and bony ingrowth. Newer highly porous metal designs may alleviate this issue but randomised data of fully uncemented TKA (tibial, femoral, patella) is lacking. The aim of the Knee-Fix study is to investigate the long-term implant survival and patient outcomes of fully uncemented compared with cemented fixation in TKA. Our study hypothesis was that uncemented TKA would be as clinically reliable and durable as the gold-standard cemented TKA., Methods: The Knee-Fix study is a two-arm, single-blinded, non-inferiority randomised controlled trial with 160 patients in each arm and follow-up at 6 weeks, 6 months, 12 months, 24 months, 5 years and 10 years. The primary outcome of interest is implant fixation, which will be measured by assessment of postoperative progressive radiolucencies with the Knee Society Total Knee Arthroplasty Roentgenographic Evaluation and Scoring System. Secondary outcome measures are patient-reported outcomes, measured using Oxford Knee Score (OKS), International Knee Society System (IKSS), Forgotten Joint Score-12 (FJS-12), EuroQol (EQ-5D-5L), VAS Pain, Patient Satisfaction Score and Net Promoter Score., Discussion: While cemented fixation remains the gold standard, a growing proportion of TKA are now implanted cementless. Highly porous metal cementless components for TKA can offer several benefits including potentially improved biological fixation; however, long-term outcomes need further investigation. This prospective study will help discern long-term differences between the two techniques., Trial Registration: Australian New Zealand Clinical Trials Registry ACTRN12616001624471 . Registered trial name: Knee-Fix study (Cemented vs Uncemented Total Knee Replacement). Registered on 24 November 2016., (© 2022. The Author(s).)

Purpose: The introduction of robotics for total knee arthroplasty (TKA) into the operating theatre is often associated with a learning curve and is potentially associated with additional complications. The purpose of this study was to determine the learning curve of robotic-assisted (RA) TKA within a multi-surgeon team., Methods: This prospective cohort study included 83 consecutive conventional jig-based TKAs compared with 53 RA TKAs using the Robotic Surgical Assistant (ROSA) system (Zimmer Biomet, Warsaw, Indiana, USA) for knee osteoarthritis performed by three high-volume (> 100 TKA per year) orthopaedic surgeons. Baseline characteristics including age, BMI, sex and pre-operative Kellgren-Lawrence graded and Hip-Knee-Ankle Axis were well-matched between the conventional and RA TKA groups. Cumulative summation (CUSUM) analysis was used to assess learning curves for operative times for each surgeon. Peri-operative and delayed complications (infection, periprosthetic fracture, thromboembolism, and compromised wound healing) and revisions were reviewed., Results: The CUSUM analysis for operative time demonstrated an inflexion point after 5, 6 and 15 cases for each of the three surgeons, or 8.7 cases on average. There were no significant differences (p = 0.53) in operative times between the RA TKA learning (before inflexion point) and proficiency (after inflexion point) phases. Similarly, the operative times of the RA TKA group did not differ significantly (p = 0.92) from the conventional TKA group. There was no discernible learning curve for the accuracy of component planning using the RA TKA system. The average length of post-operative follow-up was 21.3 ± 9.0 months. There was one revision for instability in the conventional TKA group and none in the RA TKA group. There were no significant difference (p > 0.99) in post-operative complication rates between the conventional TKA and RA TKA groups., Conclusions: The introduction of the RA TKA system was associated with a learning curve for operative time of 8.7 cases. Operative times between the RA TKA and conventional TKA group were similar. The short learning curve implies this RA TKA system can be adopted relatively quickly into a surgical team with minimal risks to patients., (© 2022. The Author(s).)

Background: Robotic-arm assisted systems are increasingly used for knee arthroplasty, however introduction of new systems can involve a learning curve. We aimed to define the learning curve in terms of operative time and component placement/sizing of a robotic system for total knee arthroplasty (TKA) in a team of experienced surgeons, and to investigate mid-term patient outcomes., Methods: A total of 101 consecutive patients underwent primary robotic-arm assisted TKA by three surgeons (mean 2 year follow-up). Operative times, component placement, implant sizing and reoperations were recorded. Cumulative Summation (CUSUM) was used to analyse learning curves. Patient outcomes were compared between learning and proficiency phases., Results: The learning curve was 16 cases, with a 12-min increase in operative time (P < 0.01). Once proficiency was achieved, the greatest time reductions were seen for navigation registration (P = 0.003) and bone preparation (P < 0.0001). A learning curve was found with polyethylene (PE) insert sizing (P = 0.01). No differences were found between learning and proficiency groups in terms of implant survival (100% and 97%, respectively, NS) or patient-reported outcome measures at 2 years (NS)., Conclusion: Introduction of a robotic-arm assisted system for TKA led to increased operative times for navigation registration and bone preparation, and a learning curve with PE insert sizing. No difference in patient outcomes between learning and proficiency groups at 2 years was found. These findings can inform surgeons' expectations when starting to use robotic-assisted systems., (© 2022 The Authors. ANZ Journal of Surgery published by John Wiley & Sons Australia, Ltd on behalf of Royal Australasian College of Surgeons.)

Importance: Lateral unicompartmental knee arthroplasty (UKA) is a surgical option for patients with isolated lateral osteoarthritis however, the procedure has higher revision rates than medial UKA. The reason for this remains unclear; therefore, a better understanding of the indications for lateral UKA revision is needed., Aim: The primary aim of this systematic review was to identify revision indications for lateral UKA. Secondary aims were to further investigate if revision indications were influenced by implant design and time from surgery., Evidence Review: A systematic literature review was performed according to the PRISMA 2020 guidelines. Search was performed in January 2022 in MedLine, EMBASE, CINAHL and the Cochrane Library using the keywords "knee arthroplasty", "unicompartmental", "reoperation", synonyms and abbreviations. Articles published in 2000-2021 that were at least level III retrospective cohort studies with at least 10 lateral UKAs and reported all failure modes were included. Risk of bias was assessed using the ROBINS-I tool. Revision indications, patient characteristics, study design, implant types and time to failure were extracted from the selected studies. Collated data were tabulated and differences were tested using Chi-square or Fisher's exact test., Findings: A total of 29 cohort and 4 registry studies that included 7,668 UKAs met the inclusion criteria. Studies were judged as having moderate or severe risk of bias; this was associated with the retrospective nature of studies required to investigate long-term outcomes of knee arthroplasty. The main indications for lateral UKA revision were OA progression (35%), aseptic loosening (17%) and bearing dislocation (14%). The incidence of revision was similar for mobile-bearing implants (7.6%) and fixed-bearing (6.4%). For mobile-bearing implants, there was introduction of bearing dislocations as an additional mode of failure (24% cf. 0%, p < 0.001). For fixed-bearing implants, the incidence of revision was higher for all-poly-ethylene (13.9%) than metal-backed (1.8%) tibial components. Early lateral UKA failures were associated with bearing dislocations (sequential decrease from 69% under 6 months to 0% 10+ years, p < 0.001), whereas late failures were associated with OA progression (sequential increase from 0% under 6 months to 100% > 10+ years, p < 0.01). Compared with medial UKA, OA progression (41% cf. 30%, p = 0.004), malalignment (2.7% cf. 0.8%, p = 0.02), instability (4% cf. 1%, p = 0.02) and bearing dislocations (20% cf. 10%, p < 0.001) were more common for lateral UKA., Conclusions and Relevance: OA progression, aseptic loosening and bearing dislocation were the three main revision indications for lateral UKA. Compared to medial UKA, OA progression, malalignment, instability and bearing dislocations were more common revision indications for lateral UKA. Higher survivorship of metal-backed fixed-bearing implants was found. The findings suggest that the outcomes of lateral UKA may be improved with more optimal alignment, gap balancing and patient selection., Level of Evidence: Level III systematic review., (Copyright © 2022 The Author(s). Published by Elsevier Inc. All rights reserved.)

Purpose: Surgeons with higher medial unicompartmental knee arthroplasty (UKA) usage have lower UKA revision rates. However, an increase in UKA usage may cause a decrease of total knee arthroplasty (TKA) usage. The purpose of this study was to investigate the influence of UKA usage on revision rates and patient-reported outcomes (PROMs) of UKA, TKA, and combined UKA + TKA results., Methods: Using the New Zealand Registry Database, surgeons were divided into six groups based on their medial UKA usage: < 1%, 1-5%, 5-10%, 10-20%, 20-30% and > 30%. A comparison of UKA, TKA and UKA + TKA revision rates and PROMs using the Oxford Knee Score (OKS) was performed., Results: A total of 91,895 knee arthroplasties were identified, of which 8,271 were UKA (9.0%). Surgeons with higher UKA usage had lower UKA revision rates, but higher TKA revision rates. The lowest TKA and combined UKA + TKA revision rates were observed for surgeons performing 1-5% UKA, compared to the highest TKA and UKA + TKA revision rates which were seen for surgeons using > 30% UKA (p < 0.001 TKA; p < 0.001 UKA + TKA). No clinically important differences in UKA + TKA OKS scores were seen between UKA usage groups at 6 months, 5 years, or 10 years., Conclusion: Surgeons with higher medial UKA usage have lower UKA revision rates; however, this comes at the cost of a higher combined UKA + TKA revision rate that is proportionate to the UKA usage. There was no difference in TKA + UKA OKS scores between UKA usage groups. A small increase in TKA revision rate was observed for high-volume UKA users (> 30%), when compared to other UKA usage clusters. A significant decrease in UKA revision rate observed in high-volume UKA surgeons offsets the slight increase in TKA revision rate, suggesting that UKA should be performed by specialist UKA surgeons., Level of Evidence: III, Retrospective therapeutic study., (© 2021. The Author(s).)

Background: Improving the functional outcome following total knee arthroplasty (TKA) by using different alignment techniques remains controversial. The surgical techniques and technologies used so far to obtain these alignments have all suffered from inaccuracies. The use of robotic technology to plan and execute the bony resection provides increased accuracy for these various alignment techniques and may determine which will deliver superior function. Functional alignment (FA) is a newer surgical technique that aims to position the prosthesis with respect to each patients' specific bony anatomy whilst minimising disruption to the soft tissue envelope. This trial aims to compare the patient and surgical outcomes of FA to the current gold standard surgical technique, mechanical alignment (MA), under randomised and blinded conditions., Methods: Patients with symptomatic knee osteoarthritis will be prospectively recruited. Following informed consent, 240 patients will be randomised to either a MA surgical technique (the control group) or a FA surgical technique (the intervention group) at a ratio of 4:1 using a random number generator. All patients will undergo computer tomography (CT) based robotic arm-assisted surgery to execute planned implant positioning and alignment with high levels of accuracy. The primary outcome is the forgotten joint score (FJS) at 2 years post-operation. Secondary outcome measures include patient reported outcome measures of post-operative rehabilitation, pain, function and satisfaction, as well as limb alignment, implant revisions and adverse events. Intention-to-treat and per-protocol population analysis will also be conducted. Standardisation of the surgical system and care pathways will minimise variation and assist in both patient and physiotherapist blinding. Ethical approval was obtained from the Northern B Health and Disability Ethics Committee (20/NTB/10)., Discussion: Currently, MA remains the gold standard in knee replacement due to proven outcomes and excellent long-term survivorship. There are many alternative alignment techniques in the literature, all with the goal of improving patient outcomes. This study is unique in that it leverages an advanced analytics tool to assist the surgeon in achieving balance. Both alignment techniques will be executed with high precision using the CT-based robotic arm-assisted surgery system which will minimise surgical variation. This trial design will help determine if FA delivers superior outcomes for patients., Trial Registration: Australia and New Zealand Clinical Trials Registry (ANZCTR), ACTRN12620000009910 . Registered on 9 January 2020., Clinicaltrials: gov, NCT04600583 . Registered on 29 September 2020., (© 2022. The Author(s).)

Aims: Unicompartmental knee arthroplasty (UKA) has a higher risk of revision than total knee arthroplasty (TKA), particularly for younger patients. The outcome of knee arthroplasty is typically defined as implant survival or revision incidence after a defined number of years. This can be difficult for patients to conceptualize. We aimed to calculate the 'lifetime risk' of revision for UKA as a more meaningful estimate of risk projection over a patient's remaining lifetime, and to compare this to TKA., Methods: Incidence of revision and mortality for all primary UKAs performed from 1999 to 2019 (n = 13,481) was obtained from the New Zealand Joint Registry (NZJR). Lifetime risk of revision was calculated for patients and stratified by age, sex, and American Society of Anesthesiologists (ASA) grade., Results: The lifetime risk of revision was highest in the youngest age group (46 to 50 years; 40.4%) and decreased sequentially to the oldest (86 to 90 years; 3.7%). Across all age groups, lifetime risk of revision was higher for females (ranging from 4.3% to 43.4% vs males 2.9% to 37.4%) and patients with a higher ASA grade (ASA 3 to 4, ranging from 8.8% to 41.2% vs ASA 1 1.8% to 29.8%). The lifetime risk of revision for UKA was double that of TKA across all age groups (ranging from 3.7% to 40.4% for UKA, and 1.6% to 22.4% for TKA). The higher risk of revision in younger patients was associated with aseptic loosening in both sexes and pain in females. Periprosthetic joint infection (PJI) accounted for 4% of all UKA revisions, in contrast with 27% for TKA; the risk of PJI was higher for males than females for both procedures., Conclusion: Lifetime risk of revision may be a more meaningful measure of arthroplasty outcomes than implant survival at defined time periods. This study highlights the higher lifetime risk of UKA revision for younger patients, females, and those with a higher ASA grade, which can aid with patient counselling prior to UKA. Cite this article: Bone Joint J  2022;104-B(6):672-679.

Introduction: Unicompartmental knee arthroplasty (UKA) has advantages over total knee arthroplasty including fewer complications and faster recovery; however, UKAs also have higher revision rates. Understanding reasons for UKA failure may, therefore, allow for optimized clinical outcomes. We aimed to identify failure modes for medial UKAs, and to examine differences by implant bearing, cement use and time., Materials and Methods: A systematic review was conducted by searching MedLine, EMBASE, CINAHL and Cochrane databases from 2000 to 2020. Studies were selected if they included ≥ 250 participants, ≥ 10 failures and reported all failure modes of medial UKA performed for osteoarthritis (OA)., Results: A total of 24 cohort and 2 registry-based studies (levels II and III) were selected. The most common failure modes were aseptic loosening (24%) and OA progression (30%). Earliest failures (< 6 months) were due to infection (40%), bearing dislocation (20%), and fracture (20%); mid-term failures (> 2 years to 5 years) were due to OA progression (33%), aseptic loosening (17%) and pain (21%); and late-term (> 10 years) failures were mostly due to OA progression (56%). Rates of failure from wear were higher with fixed-bearing prostheses (5% cf. 0.3%), whereas rates of bearing dislocations were higher with mobile-bearing prostheses (14% cf. 0%). With cemented components, there was a high rate of failure due to aseptic loosening (27%), which was reduced with uncemented components (4%)., Conclusions: UKA failure modes differ depending on implant design, cement use and time from surgery. There should be careful consideration of implant options and patient selection for UKA., (© 2021. The Author(s), under exclusive licence to Springer-Verlag GmbH, DE part of Springer Nature.)

The incidence of obesity in women of reproductive age has significantly increased over the past 100 years. There is a well-established connection between maternal obesity during pregnancy and an increased risk of developing non-communicable cardiometabolic diseases in her offspring. This mini-review focuses on evidence examining the effect of maternal high-fat diet (HFD) on skeletal development and bone health in later life in offspring. The majority of rodent studies indicate that maternal HFD generally negatively affects both embryonic bone development and bone volume in adult animals. Details surrounding the mechanisms of action that drive changes in the skeleton in offspring remain unclear, although numerous studies suggest that some effects are sex-specific. Human studies in this area are limited but also suggest that HFD during pregnancy may impair bone formation and increase fracture risk during childhood. Given the consequences of low bone mass and deranged bone microarchitecture for offspring, advances in our understanding of the developmental origins of bone health is critical in the battle against osteoporosis., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2021 Buckels, Bolam, Tay and Matthews.)

Background: Acute rheumatic fever (ARF) is a serious sequela of Group A Streptococcus (GAS) infection associated with significant global mortality. Pathogenesis remains poorly understood, with the current prevailing hypothesis based on molecular mimicry and the notion that antibodies generated in response to GAS infection cross-react with cardiac proteins such as myosin. Contemporary investigations of the broader autoantibody response in ARF are needed to both inform pathogenesis models and identify new biomarkers for the disease., Methods: This study has utilised a multi-platform approach to profile circulating autoantibodies in ARF. Sera from patients with ARF, matched healthy controls and patients with uncomplicated GAS pharyngitis were initially analysed for autoreactivity using high content protein arrays (Protoarray, 9000 autoantigens), and further explored using a second protein array platform (HuProt Array, 16,000 autoantigens) and 2-D gel electrophoresis of heart tissue combined with mass spectrometry. Selected autoantigens were orthogonally validated using conventional immunoassays with sera from an ARF case-control study (n=79 cases and n=89 matched healthy controls) and a related study of GAS pharyngitis (n=39) conducted in New Zealand., Results: Global analysis of the protein array data showed an increase in total autoantigen reactivity in ARF patients compared with controls, as well as marked heterogeneity in the autoantibody profiles between ARF patients. Autoantigens previously implicated in ARF pathogenesis, such as myosin and collagens were detected, as were novel candidates. Disease pathway analysis revealed several autoantigens within pathways linked to arthritic and myocardial disease. Orthogonal validation of three novel autoantigens (PTPN2, DMD and ANXA6) showed significant elevation of serum antibodies in ARF (p < 0.05), and further highlighted heterogeneity with patients reactive to different combinations of the three antigens., Conclusions: The broad yet heterogenous elevation of autoantibodies observed suggests epitope spreading, and an expansion of the autoantibody repertoire, likely plays a key role in ARF pathogenesis and disease progression. Multiple autoantigens may be needed as diagnostic biomarkers to capture this heterogeneity., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2021 McGregor, Tay, Carlton, Hanson-Manful, Raynes, Forsyth, Brewster, Middleditch, Bennett, Martin, Wilson, Atatoa Carr, Baker and Moreland.)

Pili of Group A Streptococcus (GAS) are surface-exposed structures involved in adhesion and colonisation of the host during infection. The major protein component of the GAS pilus is the T-antigen, which multimerises to form the pilus shaft. There are currently no licenced vaccines against GAS infections and the T-antigen represents an attractive target for vaccination. We have generated a multivalent vaccine called TeeVax1, a recombinant protein that consists of a fusion of six T-antigen domains. Vaccination with TeeVax1 produces opsonophagocytic antibodies in rabbits and confers protective efficacy in mice against invasive disease. Two further recombinant proteins, TeeVax2 and TeeVax3 were constructed to cover 12 additional T-antigens. Combining TeeVax1-3 produced a robust antibody response in rabbits that was cross-reactive to a full panel of 21 T-antigens, expected to provide over 95% vaccine coverage. These results demonstrate the potential for a T-antigen-based vaccine to prevent GAS infections.

Acute rheumatic fever (ARF) and chronic rheumatic heart disease (RHD) are autoimmune sequelae of a Group A streptococcal infection with significant global mortality and poorly understood pathogenesis. Immunoglobulin and complement deposition were observed in ARF/RHD valve tissue over 50 years ago, yet contemporary investigations have been lacking. This study applied systems immunology to investigate the relationships between the complement system and immunoglobulin in ARF. Patients were stratified by C-reactive protein (CRP) concentration into high (≥10 μg mL -1 ) and low (<10 μg mL -1 ) groups to distinguish those with clinically significant inflammatory processes from those with abating inflammation. The circulating concentrations of 17 complement factors and six immunoglobulin isotypes and subclasses were measured in ARF patients and highly matched healthy controls using multiplex bead-based immunoassays. An integrative statistical approach combining feature selection and principal component analysis revealed a linked IgG3-C4 response in ARF patients with high CRP that was absent in controls. Strikingly, both IgG3 and C4 were elevated above clinical reference ranges, suggesting these features are a marker of ARF-associated inflammation. Humoral immunity in response to M protein, an antigen implicated in ARF pathogenesis, was completely polarized to IgG3 in the patient group. Furthermore, the anti-M-protein IgG3 response was correlated with circulating IgG3 concentration, highlighting a potential role for this potent immunoglobulin subclass in disease. In conclusion, a linked IgG3-C4 response appears important in the initial, inflammatory stage of ARF and may have immediate utility as a clinical biomarker given the lack of specific diagnostic tests currently available., (© 2019 Australian and New Zealand Society for Immunology Inc.)

High-affinity monoclonal antibodies are valuable tools for studying the humoral immune response to Group A Streptococcus (GAS) antigens. This protocol describes a method for the selection of monoclonal antibody fragments that bind to GAS antigens using either naïve or immune repertoires displayed on the surface of M13 bacteriophage. Clones that specifically bind to GAS antigens are enriched for during the biopanning process, in which antibody-phage clones bind to an immobilized GAS antigen and are then washed, eluted, and amplified for subsequent rounds of selection. After the final round of biopanning, individual clones are screened by phage enzyme-linked immunosorbent assay (ELISA), and unique clones are identified by DNA fingerprinting and sequencing. The isolated monoclonal antibodies can be used to explore antibody-antigen interactions in molecular detail and provide insight into the protective mechanisms from GAS infection.

Gene expression involves the transcription and splicing of nascent transcripts through the removal of introns. In Drosophila, a double-stranded RNA binding protein Disco-interacting protein 1 (DIP1) targets INE-1 stable intronic sequence RNAs (sisRNAs) for degradation after splicing. How nascent transcripts that also contain INE-1 sequences escape degradation remains unknown. Here we observe that these nascent transcripts can also be bound by DIP1 but the Drosophila homolog of SON (Dsn) protects them from unproductive degradation in ovaries. Dsn localizes to the satellite body where active decay of INE-1 sisRNAs by DIP1 occurs. Dsn is a repressor of DIP1 posttranslational modifications (primarily sumoylation) that are assumed to be required for efficient DIP1 activity. Moreover, the pre-mRNA destabilization caused by Dsn depletion is rescued in DIP1 or Sumo heterozygous mutants, suggesting that Dsn is a negative regulator of DIP1. Our results reveal that under normal circumstances nascent transcripts are susceptible to DIP1-mediated degradation, however intronic sequences are protected by Dsn until intron excision has taken place., Competing Interests: The authors have declared that no competing interests exist.

Background: Augmenting repairs with extracellular matrix-based scaffolds is a common option for rotator cuff tears. In this study, a new collagen scaffold was assessed for its efficacy in augmenting rotator cuff repair., Methods: The collagen scaffold was assessed in vitro for cytocompatibility and retention of tenocyte phenotype using alamarBlue assays, fluorescent imaging, and real-time polymerase chain reaction. Immunogenicity was assessed in vitro by the activation of human monocytes. In vivo, by use of a modified rat rotator cuff defect model, supraspinatus tendon repairs were carried out in 40 animals. Overlay augmentation with the collagen scaffold was compared with unaugmented repairs. At 6 and 12 weeks postoperatively, the repairs were tested biomechanically to evaluate repair strength, as well as histologically to assess quality of healing., Results: The collagen scaffold supported human tendon-derived cell growth in vitro, with cells demonstrating proliferation and appearing morphologically tenocytic over the experimental period. No immunogenic responses were provoked compared with suture material control. In vivo, augmentation with the scaffold improved the histologic scores at 12 weeks (8.4 of 15 vs 6.4 of 15, P = .032). However, no significant difference was detected with mechanical testing., Conclusion: The new collagen scaffold was supportive of cell growth in vitro and generated a minimal acute inflammatory response. In vivo, we observed an improvement in the histologic appearance of the repair at 12 weeks. However, a meaningful increase in biomechanical strength was not achieved. Further modification and improvement of the scaffold are required prior to consideration for clinical use., (Copyright © 2018 Journal of Shoulder and Elbow Surgery Board of Trustees. Published by Elsevier Inc. All rights reserved.)

Background: Bone erosion is a frequent complication of gout and is strongly associated with tophi, which are lesions comprising inflammatory cells surrounding collections of monosodium urate (MSU) crystals. Osteocytes are important cellular mediators of bone remodeling. The aim of this study was to investigate the direct effects of MSU crystals and indirect effects of MSU crystal-induced inflammation on osteocytes., Methods: For direct assays, MSU crystals were added to MLO-Y4 osteocyte cell line cultures or primary mouse osteocyte cultures. For indirect assays, the RAW264.7 macrophage cell line was cultured with or without MSU crystals, and conditioned medium from these cultures was added to MLO-Y4 cells. MLO-Y4 cell viability was assessed using alamarBlue® and LIVE/DEAD® assays, and MLO-Y4 cell gene expression and protein expression were assessed by real-time polymerase chain reaction (PCR) and enzyme-linked immunosorbent assay (ELISA), respectively. Histological analysis was used to examine the relationship between MSU crystals, inflammatory cells, and osteocytes in human joints affected by tophaceous gout., Results: In direct assays, MSU crystals reduced MLO-Y4 cell and primary mouse osteocyte viability but did not alter MLO-Y4 cell gene expression. In contrast, conditioned medium from MSU crystal-stimulated RAW264.7 macrophages did not affect MLO-Y4 cell viability but significantly increased MLO-Y4 cell expression of osteocyte-related factors including E11, connexin 43, and RANKL, and inflammatory mediators such as interleukin (IL)-6, IL-11, tumor necrosis factor (TNF)-α and cyclooxygenase-2 (COX-2). Inhibition of COX-2 in MLO-Y4 cells significantly reduced the indirect effects of MSU crystals. In histological analysis, CD68 + macrophages and MSU crystals were identified in close proximity to osteocytes within bone. COX-2 expression was also observed in tophaceous joint samples., Conclusions: MSU crystals directly inhibit osteocyte viability and, through interactions with macrophages, indirectly promote a shift in osteocyte function that favors bone resorption and inflammation. These interactions may contribute to disordered bone remodeling in gout.

Study Design: In vitro Study., Objective: To evaluate the effect that factors released from human posterior spinal bone dust have on primary human osteoblast growth and maturation., Summary of Background Data: Bone dust, created during spinal fusion surgeries, has the potential to be used as an autologous bone graft by providing a source of viable autologous osteoblasts and mesenchymal stem cells with osteogenic potential. Till date, no information is available on whether bone dust also provides a source of anabolic factors with the potential to enhance osteoblast proliferation and maturation, which would enhance its therapeutic potential., Methods: Bone dust was collected from consenting patients undergoing elective posterior spinal fusion surgeries, and primary human osteoblasts were cultured from patients undergoing elective hip or knee arthroplasty. Growth factors and cytokines released by bone dust were quantified using enzyme-linked immunosorbent assay. Primary human osteoblast proliferation and gene expression in response to bone dust were assessed using H-thymidine incorporation and real-time polymerase chain reaction, respectively., Results: Human bone dust released anabolic cytokines (IL-1β and IL-6) and growth factors (TGF-β, VEGF, FGF-Basic, and PDGF-BB) in increasing concentrations over a 7-day period. In vitro, the anabolic factors released by bone dust increased osteoblast proliferation by 7-fold, compared with osteoblasts cultured alone. In addition, the factors released from bone dust up-regulated a number of osteoblastic genes integral to osteoblast differentiation, maturation, and angiogenesis., Conclusion: This study is the first to demonstrate that human posterior spinal bone dust released anabolic factors that potently enhance osteoblast proliferation and the expression of genes that favor bone healing and bone union. As bone dust is anabolic and its harvest is fast, simple, and safe to perform, spinal surgeons should be encouraged to 'recycle' bone dust and harness the regenerative potential of this free autologous bone graft., Level of Evidence: N/A.

Introduction: Numerous observational studies have reported that serum urate concentration positively correlates with bone density and reduced risk of fractures. The aim of this study was to examine whether soluble urate directly influences bone remodelling., Methods: In laboratory studies, the in vitro effects of soluble urate were examined in osteoclast, osteoblast and osteocyte assays at a range of urate concentrations consistent with those typically observed in humans (up to 0.70 mmol/L). The clinical relevance of the in vitro assay findings was assessed using serial procollagen-1 N-terminal propeptide (P1NP) and Month 12 bone density data from a randomised controlled trial of allopurinol dose escalation in people with gout., Results: Addition of urate in the RAW264.7 cell osteoclastogenesis assay led to small increases in osteoclast formation (ANOVA p = 0.018), but no significant difference in bone resorption. No significant effects on osteoclast number or activity were observed in primary cell osteoclastogenesis or resorption assays. Addition of urate did not alter viability or function in MC3T3-E1 pre-osteoblast, primary human osteoblast, or MLO-Y4 osteocyte assays. In the clinical trial analysis, reducing serum urate over a 12 month period by allopurinol dose escalation did not lead to significant changes in P1NP or differences in bone mineral density., Conclusion: Addition of soluble urate at physiological concentrations does not influence bone remodelling in vitro. These data, together with clinical trial data showing no effect of urate-lowering on P1NP or bone density, do not support a direct role for urate in influencing bone remodelling.

Stable intronic sequence RNAs (sisRNAs) are by-products of splicing and regulate gene expression. How sisRNAs are regulated is unclear. Here we report that a double-stranded RNA binding protein, Disco-interacting protein 1 (DIP1) regulates sisRNAs in Drosophila. DIP1 negatively regulates the abundance of sisR-1 and INE-1 sisRNAs. Fine-tuning of sisR-1 by DIP1 is important to maintain female germline stem cell homeostasis by modulating germline stem cell differentiation and niche adhesion. Drosophila DIP1 localizes to a nuclear body (satellite body) and associates with the fourth chromosome, which contains a very high density of INE-1 transposable element sequences that are processed into sisRNAs. DIP1 presumably acts outside the satellite bodies to regulate sisR-1, which is not on the fourth chromosome. Thus, our study identifies DIP1 as a sisRNA regulatory protein that controls germline stem cell self-renewal in Drosophila.Stable intronic sequence RNAs (sisRNAs) are by-products of splicing from introns with roles in embryonic development in Drosophila. Here, the authors show that the RNA binding protein DIP1 regulates sisRNAs in Drosophila, which is necessary for germline stem cell homeostasis.

Introduction: Recently, bone-active factors such as parathyroid hormone and lactoferrin, have been used in pre-clinical models to promote tendon healing. How-ever, there is limited understanding of how these boneactive factors may affect the cells of the ten-don themselves. Here, we present an in vitro study assessing the effects of parathyroid hor-mone and lactoferrin on primary tendon cells (tenocytes), and compare their responses to the tenogenic factors, PDGF, IGF-1 and TGF-β., Materials and Methods: Tenocyte proliferation and collagen production were assessed by alamarBlue® and Sirius red as-says, respectively. To assess tenocyte trans-differentiation, changes in the expression of genes important in tenocyte, chondrocyte and osteoblast biology were determined using real-time PCR., Results: Parathyroid hormone and lactoferrin had no effect on tenocyte growth or collagen production, with minimal changes in gene expression and no detrimental effects observed to suggest trans-differentiation away from tendon cell behaviour. Tenogenic factors PDGF, IGF-1 and TGF all increasetenocyte collagen production, however, the gene expression data suggests that PDGF promotes severe de-differentiation of the tenocytes., Discussion: Our findings suggest that using parathyroid hormone or lactoferrin as a singular factor to promote tendon healing may not be of benefit, but for use in tendon-bone healing there would be no detrimental effect on the tendon itself., Competing Interests: Conflicts of Interest The Authors declare that there is no conflict of interest.

Maternally inherited noncoding RNAs (ncRNAs) can regulate zygotic gene expression across generations [1-4]. Recently, many stable intronic sequence RNAs (sisRNAs), which are byproducts of pre-mRNA splicing, were found to be maternally deposited and persist till zygotic transcription in Xenopus and Drosophila [5-7]. In various organisms, sisRNAs can be in linear or circular conformations, and they have been suggested to regulate host gene expression [5-10]. It is unknown whether maternally deposited sisRNAs can regulate zygotic gene expression in the embryos. Here, we show that a maternally inherited sisRNA (sisR-4) from the deadpan locus is important for embryonic development in Drosophila. Mothers, but not fathers, mutant for sisR-4 produce embryos that fail to hatch. During embryogenesis, sisR-4 promotes transcription of its host gene (deadpan), which is essential for development. Interestingly, sisR-4 functions by activating an enhancer present in the intron where sisR-4 is encoded. We propose that a maternal sisRNA triggers expression of its host gene via a positive feedback loop during embryogenesis., (Copyright © 2017 Elsevier Ltd. All rights reserved.)

Nilotinib and imatinib are tyrosine kinase inhibitors (TKIs) used in the treatment of chronic myeloid leukemia (CML) and gastrointestinal stromal tumors (GIST). In vitro, imatinib and nilotinib inhibit osteoclastogenesis, and in patients they reduce levels of bone resorption. One of the mechanisms that might underlie these effects is an increase in the production of osteoprotegerin (OPG). In the current work we report that platelet-derived growth factor receptor beta (PDGFRβ) signaling regulates OPG production in vitro. In addition, we have shown that TKIs have effects on RANKL signaling through inhibition of the PDGFRβ and other target receptors. These findings have implications for our understanding of the mechanisms by which TKIs affect osteoclastogenesis, and the role of PDGFRβ signaling in regulating osteoclastogenesis. Further studies are indicated to confirm the clinical effects of PDGFRβ-inhibitors and to elaborate the intracellular pathways that underpin these effects., Competing Interests: The authors have declared that no competing interests exist.

Upon splicing, introns are rapidly degraded. Hence, RNAs derived from introns are commonly deemed as junk sequences. However, the discoveries of intronic-derived small nucleolar RNAs (snoRNAs), small Cajal body associated RNAs (scaRNAs) and microRNAs (miRNAs) suggested otherwise. These non-coding RNAs are shown to play various roles in gene regulation. In this review, we highlight another class of intron-derived RNAs known as stable intronic sequence RNAs (sisRNAs). sisRNAs have been observed since the 1980 s; however, we are only beginning to understand their biological significance. Recent studies have shown or suggested that sisRNAs regulate their own host's gene expression, function as molecular sinks or sponges, and regulate protein translation. We propose that sisRNAs function as an additional layer of gene regulation in the cells.

Stable intronic sequence RNAs (sisRNAs) have been found in Xenopus tropicalis, human cell lines, and Epstein-Barr virus; however, the biological significance of sisRNAs remains poorly understood. We identify sisRNAs in Drosophila melanogaster by deep sequencing, reverse transcription polymerase chain reaction, and Northern blotting. We characterize a sisRNA (sisR-1) from the regena (rga) locus and show that it can be processed from the precursor messenger RNA (pre-mRNA). We also document a cis-natural antisense transcript (ASTR) from the rga locus, which is highly expressed in early embryos. During embryogenesis, ASTR promotes robust rga pre-mRNA expression. Interestingly, sisR-1 represses ASTR, with consequential effects on rga pre-mRNA expression. Our results suggest a model in which sisR-1 modulates its host gene expression by repressing ASTR during embryogenesis. We propose that sisR-1 belongs to a class of sisRNAs with probable regulatory activities in Drosophila., (© 2015 Pek et al.)