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The Bone & Joint Journal
Vol. 98-B, Issue 7 | Pages 984 - 989
1 Jul 2016
Zijlmans JL Buis DR Verbaan D Vandertop WP

Aims. Our aim was to perform a systematic review of the literature to assess the incidence of post-operative epidural haematomas and wound infections after one-, or two-level, non-complex, lumbar surgery for degenerative disease in patients with, or without post-operative wound drainage. Patients and Methods. Studies were identified from PubMed and EMBASE, up to and including 27 August 2015, for papers describing one- or two-level lumbar discectomy and/or laminectomy for degenerative disease in adults which reported any form of subcutaneous or subfascial drainage. Results. Eight papers describing 1333 patients were included. Clinically relevant post-operative epidural haematomas occurred in two (0.15%), and wound infections in ten (0.75%) patients. Epidural haematomas occurred in two (0.47%) patients who had wound drainage (n = 423) and in none of those without wound drainage (n = 910). Wound infections occurred in two (0.47%) patients with wound drainage and in eight (0.88%) patients without wound drainage. Conclusion. These data suggest that the routine use of a wound drain in non-complex lumbar surgery does not prevent post-operative epidural haematomas and that the absence of a drain does not lead to a significant change in the incidence of wound infection. Cite this article: Bone Joint J 2016;98-B:984–9


The Bone & Joint Journal
Vol. 97-B, Issue 1 | Pages 50 - 55
1 Jan 2015
Zuiderbaan HA Khamaisy S Thein R Nawabi DH Pearle AD

Progressive degenerative changes in the medial compartment of the knee following lateral unicompartmental arthroplasty (UKA) remains a leading indication for revision surgery. The purpose of this study is to evaluate changes in the congruence and joint space width (JSW) of the medial compartment following lateral UKA. The congruence of the medial compartment of 53 knees (24 men, 23 women, mean age 13.1 years; . sd. 62.1) following lateral UKA was evaluated pre-operatively and six weeks post-operatively, and compared with 41 normal knees (26 men, 15 women, mean age 33.7 years;. sd . 6.4), using an Interactive closest point algorithm which calculated the congruence index (CI) by performing a rigid transformation that best aligns the digitised tibial and femoral surfaces. Inner, middle and outer JSWs were measured by sub-dividing the medial compartment into four quarters on pre- and post-operative, weight bearing tunnel view radiographs. The mean CI of knees following lateral UKA significantly improved from 0.92 . (sd . 0.06) pre-operatively to 0.96 . (sd . 0.02) (p < 0.001) six weeks post-operatively. The mean CI of the healthy control group was 0.99 sd 0.01. Post-operatively, the mean inner JSW increased (p = 0.006) and the outer decreased (p = 0.002). The JSW was restored post-operatively as no significant differences were noted in all three locations compared with the control group (inner JSW p = 0.43; middle JSW p = 0.019, outer JSW p = 0.51). . Our data suggest that a well conducted lateral UKA may improve the congruence and normalise the JSW of the medial compartment, potentially preventing progression of degenerative change. . Cite this article: Bone Joint J 2015;97-B:50–5


Bone & Joint Research
Vol. 9, Issue 9 | Pages 613 - 622
1 Sep 2020
Perucca Orfei C Lovati AB Lugano G Viganò M Bottagisio M D’Arrigo D Sansone V Setti S de Girolamo L

Aims. In the context of tendon degenerative disorders, the need for innovative conservative treatments that can improve the intrinsic healing potential of tendon tissue is progressively increasing. In this study, the role of pulsed electromagnetic fields (PEMFs) in improving the tendon healing process was evaluated in a rat model of collagenase-induced Achilles tendinopathy. Methods. A total of 68 Sprague Dawley rats received a single injection of type I collagenase in Achilles tendons to induce the tendinopathy and then were daily exposed to PEMFs (1.5 mT and 75 Hz) for up to 14 days - starting 1, 7, or 15 days after the injection - to identify the best treatment option with respect to the phase of the disease. Then, 7 and 14 days of PEMF exposure were compared to identify the most effective protocol. Results. The daily exposure to PEMFs generally provided an improvement in the fibre organization, a decrease in cell density, vascularity, and fat deposition, and a restoration of the physiological cell morphology compared to untreated tendons. These improvements were more evident when the tendons were exposed to PEMFs during the mid-acute phase of the pathology (7 days after induction) rather than during the early (1 day after induction) or the late acute phase (15 days after induction). Moreover, the exposure to PEMFs for 14 days during the mid-acute phase was more effective than for 7 days. Conclusion. PEMFs exerted a positive role in the tendon healing process, thus representing a promising conservative treatment for tendinopathy, although further investigations regarding the clinical evaluation are needed. Cite this article: Bone Joint Res 2020;9(9):613–622


The Bone & Joint Journal
Vol. 101-B, Issue 12 | Pages 1512 - 1519
1 Dec 2019
Klug A Konrad F Gramlich Y Hoffmann R Schmidt-Horlohé K

Aims. The aim of this study was to evaluate the outcome of Monteggia-like lesions at midterm follow-up and to determine whether the surgical treatment of the radial head influences the clinical and radiological results. Patients and Methods. A total of 78 patients with a Monteggia-like lesion, including 44 women and 34 men with a mean age of 54.7 years (19 to 80), were available for assessment after a mean 4.6 years (2 to 9.2). The outcome was assessed using the Mayo Elbow Performance Score (MEPS), Oxford Elbow Score (OES), Mayo Modified Wrist Score (MMWS), and The Disabilities of the Arm, Shoulder and Hand (DASH) score. Radiographs were analyzed for all patients. A total of 12 Mason type I, 16 type II, and 36 type III fractures were included. Surgical treatment consisted of screw fixation for all type II and reconstructable type III fractures, while radial head arthroplasty (RHA) or excision was performed if reconstruction was not possible. Results. The mean MEPS was 88.9 (40 to 100), mean OES was 40.1 (25 to 48), mean MMWS was 88.1 (50 to 100), mean DASH score was 14.7 (0 to 60.2), and mean movement was 114° (. sd. 27) in extension/flexion and 155° (. sd. 37) in pronation/supination. Mason III fractures, particularly those with an associated coronoid fracture treated with RHA, had a significantly poorer outcome. Suboptimal results were also identified in patients who had degenerative changes or heterotopic ossification on their latest radiograph. In contrast, all patients with successful radial head reconstruction or excision had a good outcome. Conclusion. Good outcomes can be achieved in Monteggia-like lesions with Mason II and III fractures, when reconstruction is possible. Otherwise, RHA is a reliable option with satisfactory outcomes, especially in patients with ligamenteous instability. Whether the radial head should be excised remains debatable, although good results were achieved in patients with ligamentous stability and in those with complications after RHA. Cite this article: Bone Joint J 2019;101-B:1512–1519


The Bone & Joint Journal
Vol. 100-B, Issue 2 | Pages 197 - 204
1 Feb 2018
Gaspar MP Pham PP Pankiw CD Jacoby SM Shin EK Osterman AL Kane PM

Aims. The aims of this study were to compare the mid-term outcomes of patients with late-stage arthritis of the wrist treated with proximal row carpectomy (PRC) and dorsal capsular interposition (DCI) arthroplasty with a matched cohort treated with routine PRC alone. Patients and Methods. A total of 25 arthritic wrists (24 patients) with pre-existing degenerative changes of the proximal capitate and/or the lunate fossa of the radius were treated with PRC + DCI over a ten-year period. This group of patients were matched 1:2 with a group of 50 wrists (48 patients) without degenerative changes in the capitate or lunate fossa that were treated with a routine PRC alone during the same period. The mean age of the patients at the time of surgery was 56.8 years (25 to 81), and the demographics and baseline range of movement of the wrist, grip strength, Quick Disabilities of the Arm, Shoulder, and Hand (QuickDASH) score, and Patient-Rated Wrist Evaluation (PRWE) score were similar in both groups. . Results. At a mean follow-up of 5.9 years (1.8 to 11.8), significant improvements in mean grip strength, the flexion-extension arc of movement of the wrist, QuickDASH, and PRWE scores were seen in both groups. There was no diifference between the groups for any of the outcomes. One patient in the PRC + DCI group required additional surgery for a deep infection, while two in the PRC group had complications (one wound dehiscence requiring revision closure, one transient radial sensory neuritis). One patient in each group required total arthrodesis of the wrist for progressive degenerative radiocarpal changes. A total of 70 patients (93%) were satisfied with the outcomes. Conclusion. PRC with DCI is an effective form of treatment for late-stage arthritis of the wrist involving the capitolunate joint, with mid-term outcomes that are similar to those in patients without degenerative changes affecting the capitate or lunate fossa who are treated with a routine PRC alone. Cite this article: Bone Joint J 2018;100-B:197–204


The Journal of Bone & Joint Surgery British Volume
Vol. 91-B, Issue 10 | Pages 1341 - 1346
1 Oct 2009
Rosenblatt Y Young C MacDermid JC King GJW

Between 1995 and 2006, five intra-articular osteotomies of the head of the radius were performed in patients with symptomatic healed displaced articular fractures. Pre-operatively, all patients complained of persistent painful clicking on movement. Only patients with mild or no degenerative changes of the radial head and capitellum were considered for osteotomy. The operations were performed at a mean of 8.2 months (4 to 13) after injury and the patients were reviewed at a mean of 5.5 years (15 months to 12 years) after the osteotomy. The average Mayo Elbow Performance Index Score improved significantly from 74 before to 88 after operation, with four patients rated as good or excellent (p < 0.05). The subjective patient satisfaction score was 8.4 on a ten-point scale. All osteotomies healed and there were no complications. In this small series intra-articular osteotomy of the head of the radius was a safe and effective treatment for symptomatic intra-articular malunion without advanced degenerative changes


The Journal of Bone & Joint Surgery British Volume
Vol. 93-B, Issue 8 | Pages 1027 - 1032
1 Aug 2011
Schilders E Dimitrakopoulou A Bismil Q Marchant P Cooke C

Labral tears are commonly associated with femoroacetabular impingement. We reviewed 151 patients (156 hips) with femoroacetabular impingement and labral tears who had been treated arthroscopically. These were subdivided into those who had undergone a labral repair (group 1) and those who had undergone resection of the labrum (group 2). In order to ensure the groups were suitably matched for comparison of treatment effects, patients with advanced degenerative changes (Tönnis grade > 2, lateral sourcil height < 2 mm and Outerbridge grade 4 changes in the weight-bearing area of the femoral head) were excluded, leaving 96 patients (101 hips) in the study. At a mean follow-up of 2.44 years (2 to 4), the mean modified Harris hip score in the labral repair group (group 1, 69 hips) improved from 60.2 (24 to 85) pre-operatively to 93.6 (55 to 100), and in the labral resection group (group 2, 32 hips) from 62.8 (29 to 96) pre-operatively to 88.8 (35 to 100). The mean modified Harris hip score in the labral repair group was 7.3 points greater than in the resection group (p = 0.036, 95% confidence interval 0.51 to 14.09). Labral detachments were found more frequently in the labral repair group and labral flap tears in the resection group. No patient in our study group required a subsequent hip replacement during the period of follow-up. This study shows that patients without advanced degenerative changes in the hip can achieve significant improvement in their symptoms after arthroscopic treatment of femoroacetabular impingement. Where appropriate, labral repair provides a superior result to labral resection


The Bone & Joint Journal
Vol. 106-B, Issue 8 | Pages 775 - 782
1 Aug 2024
Wagner M Schaller L Endstrasser F Vavron P Braito M Schmaranzer E Schmaranzer F Brunner A

Aims

Hip arthroscopy has gained prominence as a primary surgical intervention for symptomatic femoroacetabular impingement (FAI). This study aimed to identify radiological features, and their combinations, that predict the outcome of hip arthroscopy for FAI.

Methods

A prognostic cross-sectional cohort study was conducted involving patients from a single centre who underwent hip arthroscopy between January 2013 and April 2021. Radiological metrics measured on conventional radiographs and magnetic resonance arthrography were systematically assessed. The study analyzed the relationship between these metrics and complication rates, revision rates, and patient-reported outcomes.


The Bone & Joint Journal
Vol. 106-B, Issue 5 Supple B | Pages 32 - 39
1 May 2024
Briem T Stephan A Stadelmann VA Fischer MA Pfirrmann CWA Rüdiger HA Leunig M

Aims

The purpose of this study was to evaluate the mid-term outcomes of autologous matrix-induced chondrogenesis (AMIC) for the treatment of larger cartilage lesions and deformity correction in hips suffering from symptomatic femoroacetabular impingement (FAI).

Methods

This single-centre study focused on a cohort of 24 patients with cam- or pincer-type FAI, full-thickness femoral or acetabular chondral lesions, or osteochondral lesions ≥ 2 cm2, who underwent surgical hip dislocation for FAI correction in combination with AMIC between March 2009 and February 2016. Baseline data were retrospectively obtained from patient files. Mid-term outcomes were prospectively collected at a follow-up in 2020: cartilage repair tissue quality was evaluated by MRI using the Magnetic Resonance Observation of Cartilage Repair Tissue (MOCART) score. Patient-reported outcome measures (PROMs) included the Oxford Hip Score (OHS) and Core Outcome Measure Index (COMI). Clinical examination included range of motion, impingement tests, and pain.


Bone & Joint Open
Vol. 5, Issue 7 | Pages 543 - 549
3 Jul 2024
Davies AR Sabharwal S Reilly P Sankey RA Griffiths D Archer S

Aims

Shoulder arthroplasty is effective in the management of end-stage glenohumeral joint arthritis. However, it is major surgery and patients must balance multiple factors when considering the procedure. An understanding of patients’ decision-making processes may facilitate greater support of those considering shoulder arthroplasty and inform the outcomes of future research.

Methods

Participants were recruited from waiting lists of three consultant upper limb surgeons across two NHS hospitals. Semi-structured interviews were conducted with 12 participants who were awaiting elective shoulder arthroplasty. Transcribed interviews were analyzed using a grounded theory approach. Systematic coding was performed; initial codes were categorized and further developed into summary narratives through a process of discussion and refinement. Data collection and analyses continued until thematic saturation was reached.


The Journal of Bone & Joint Surgery British Volume
Vol. 93-B, Issue 5 | Pages 650 - 657
1 May 2011
Hasegawa K Shimoda H Kitahara K Sasaki K Homma T

We examined the reliability of radiological findings in predicting segmental instability in 112 patients (56 men, 56 women) with a mean age of 66.5 years (27 to 84) who had degenerative disease of the lumbar spine. They underwent intra-operative biomechanical evaluation using a new measurement system. Biomechanical instability was defined as a segment with a neutral zone > 2 mm/N. Risk factor analysis to predict instability was performed on radiographs (range of segmental movement, disc height), MRI (Thompson grade, Modic type), and on the axial CT appearance of the facet (type, opening, vacuum and the presence of osteophytes, subchondral erosion, cysts and sclerosis) using multivariate logistic regression analysis with a forward stepwise procedure. The facet type was classified as sagittally orientated, coronally orientated, anisotropic or wrapped. Stepwise multivariate regression analysis revealed that facet opening was the strongest predictor for instability (odds ratio 5.022, p = 0.009) followed by spondylolisthesis, MRI grade and subchondral sclerosis. Forward stepwise multivariate logistic regression indicated that spondylolisthesis, MRI grade, facet opening and subchondral sclerosis of the facet were risk factors. Symptoms evaluated by the Short-Form 36 and visual analogue scale showed that patients with an unstable segment were in significantly more pain than those without. Furthermore, the surgical procedures determined using the intra-operative measurement system were effective, suggesting that segmental instability influences the symptoms of lumbar degenerative disease


Bone & Joint Research
Vol. 13, Issue 6 | Pages 279 - 293
7 Jun 2024
Morris JL Letson HL McEwen PC Dobson GP

Aims

Adenosine, lidocaine, and Mg2+ (ALM) therapy exerts differential immuno-inflammatory responses in males and females early after anterior cruciate ligament (ACL) reconstruction (ACLR). Our aim was to investigate sex-specific effects of ALM therapy on joint tissue repair and recovery 28 days after surgery.

Methods

Male (n = 21) and female (n = 21) adult Sprague-Dawley rats were randomly divided into ALM or Saline control treatment groups. Three days after ACL rupture, animals underwent ACLR. An ALM or saline intravenous infusion was commenced prior to skin incision, and continued for one hour. An intra-articular bolus of ALM or saline was also administered prior to skin closure. Animals were monitored to 28 days, and joint function, pain, inflammatory markers, histopathology, and tissue repair markers were assessed.


The Bone & Joint Journal
Vol. 105-B, Issue 1 | Pages 64 - 71
1 Jan 2023
Danielsen E Gulati S Salvesen Ø Ingebrigtsen T Nygaard ØP Solberg TK

Aims

The number of patients undergoing surgery for degenerative cervical radiculopathy has increased. In many countries, public hospitals have limited capacity. This has resulted in long waiting times for elective treatment and a need for supplementary private healthcare. It is uncertain whether the management of patients and the outcome of treatment are equivalent in public and private hospitals. The aim of this study was to compare the management and patient-reported outcomes among patients who underwent surgery for degenerative cervical radiculopathy in public and private hospitals in Norway, and to assess whether the effectiveness of the treatment was equivalent.

Methods

This was a comparative study using prospectively collected data from the Norwegian Registry for Spine Surgery. A total of 4,750 consecutive patients who underwent surgery for degenerative cervical radiculopathy and were followed for 12 months were included. Case-mix adjustment between those managed in public and private hospitals was performed using propensity score matching. The primary outcome measure was the change in the Neck Disability Index (NDI) between baseline and 12 months postoperatively. A mean difference in improvement of the NDI score between public and private hospitals of ≤ 15 points was considered equivalent. Secondary outcome measures were a numerical rating scale for neck and arm pain and the EuroQol five-dimension three-level health questionnaire. The duration of surgery, length of hospital stay, and complications were also recorded.


Bone & Joint Research
Vol. 13, Issue 2 | Pages 52 - 65
1 Feb 2024
Yao C Sun J Luo W Chen H Chen T Chen C Zhang B Zhang Y

Aims

To investigate the effects of senescent osteocytes on bone homeostasis in the progress of age-related osteoporosis and explore the underlying mechanism.

Methods

In a series of in vitro experiments, we used tert-Butyl hydroperoxide (TBHP) to induce senescence of MLO-Y4 cells successfully, and collected conditioned medium (CM) and senescent MLO-Y4 cell-derived exosomes, which were then applied to MC3T3-E1 cells, separately, to evaluate their effects on osteogenic differentiation. Furthermore, we identified differentially expressed microRNAs (miRNAs) between exosomes from senescent and normal MLO-Y4 cells by high-throughput RNA sequencing. Based on the key miRNAs that were discovered, the underlying mechanism by which senescent osteocytes regulate osteogenic differentiation was explored. Lastly, in the in vivo experiments, the effects of senescent MLO-Y4 cell-derived exosomes on age-related bone loss were evaluated in male SAMP6 mice, which excluded the effects of oestrogen, and the underlying mechanism was confirmed.


Bone & Joint 360
Vol. 12, Issue 2 | Pages 24 - 28
1 Apr 2023

The April 2023 Wrist & Hand Roundup360 looks at: MRI-based classification for acute scaphoid injuries: the OxSMART; Deep learning for detection of scaphoid fractures?; Ulnar shortening osteotomy in adolescents; Cost-utility analysis of thumb carpometacarpal resection arthroplasty; Arthritis of the wrist following scaphoid fracture nonunion; Extensor hood injuries in elite boxers; Risk factors for reoperation after flexor tendon repair; Nonoperative versus operative treatment for displaced finger metacarpal shaft fractures.


The Bone & Joint Journal
Vol. 106-B, Issue 4 | Pages 380 - 386
1 Apr 2024
Cho J Lee S Kim D Oh W Koh I Chun Y Choi Y

Aims

The study aimed to assess the clinical outcomes of arthroscopic debridement and partial excision in patients with traumatic central tears of the triangular fibrocartilage complex (TFCC), and to identify prognostic factors associated with unfavourable clinical outcomes.

Methods

A retrospective analysis was conducted on patients arthroscopically diagnosed with Palmer 1 A lesions who underwent arthroscopic debridement and partial excision from March 2009 to February 2021, with a minimum follow-up of 24 months. Patients were assessed using the Disabilities of the Arm, Shoulder and Hand (DASH) questionnaire, Mayo Wrist Score (MWS), and visual analogue scale (VAS) for pain. The poor outcome group was defined as patients whose preoperative and last follow-up clinical score difference was less than the minimal clinically important difference of the DASH score (10.83). Baseline characteristics, arthroscopic findings, and radiological factors (ulnar variance, MRI, or arthrography) were evaluated to predict poor clinical outcomes.


The Journal of Bone & Joint Surgery British Volume
Vol. 87-B, Issue 11 | Pages 1483 - 1487
1 Nov 2005
Hart AJ Buscombe J Malone A Dowd GSE

We used single-photon emission computed tomography (SPECT) to determine the long-term risk of degenerative change after reconstruction of the anterior cruciate ligament (ACL). Our study population was a prospective series of 31 patients with a mean age at injury of 27.8 years (18 to 47) and a mean follow-up of ten years (9 to 13) after bone-patellar tendon-bone reconstruction of the ACL. The contralateral normal knee was used as a control. All knees were clinically stable with high clinical scores (mean Lysholm score, 93; mean Tegner activity score, 6). Fifteen patients had undergone a partial meniscectomy and ACL reconstruction at or before reconstruction of their ACL. In the group with an intact meniscus, clinical symptoms of osteoarthritis (OA) were found in only one patient (7%), who was also the only patient with marked isotope uptake on the SPECT scan compatible with OA. In the group which underwent a partial meniscectomy, clinical symptoms of OA were found in two patients (13%), who were among five (31%) with isotope uptake compatible with OA. Only one patient (7%) in this group had evidence of advanced OA on plain radiographs. The risk of developing OA after ACL reconstruction in this series is very low and lower than published figures for untreated ACL-deficient knees. There is a significant increase (p < 0.05) in degenerative change in patients who had a reconstruction of their ACL and a partial meniscectomy compared with those who had a reconstruction of their ACL alone


The Bone & Joint Journal
Vol. 105-B, Issue 4 | Pages 422 - 430
15 Mar 2023
Riksaasen AS Kaur S Solberg TK Austevoll I Brox J Dolatowski FC Hellum C Kolstad F Lonne G Nygaard ØP Ingebrigtsen T

Aims

Repeated lumbar spine surgery has been associated with inferior clinical outcomes. This study aimed to examine and quantify the impact of this association in a national clinical register cohort.

Methods

This is a population-based study from the Norwegian Registry for Spine surgery (NORspine). We included 26,723 consecutive cases operated for lumbar spinal stenosis or lumbar disc herniation from January 2007 to December 2018. The primary outcome was the Oswestry Disability Index (ODI), presented as the proportions reaching a patient-acceptable symptom state (PASS; defined as an ODI raw score ≤ 22) and ODI raw and change scores at 12-month follow-up. Secondary outcomes were the Global Perceived Effect scale, the numerical rating scale for pain, the EuroQoL five-dimensions health questionnaire, occurrence of perioperative complications and wound infections, and working capability. Binary logistic regression analysis was conducted to examine how the number of previous operations influenced the odds of not reaching a PASS.


The Bone & Joint Journal
Vol. 105-B, Issue 5 | Pages 496 - 503
1 May 2023
Mills ES Talehakimi A Urness M Wang JC Piple AS Chung BC Tezuka T Heckmann ND

Aims

It has been well documented in the arthroplasty literature that lumbar degenerative disc disease (DDD) contributes to abnormal spinopelvic motion. However, the relationship between the severity or pattern of hip osteoarthritis (OA) as measured on an anteroposterior (AP) pelvic view and spinopelvic biomechanics has not been well investigated. Therefore, the aim of the study is to examine the association between the severity and pattern of hip OA and spinopelvic motion.

Methods

A retrospective chart review was conducted to identify patients undergoing primary total hip arthroplasty (THA). Plain AP pelvic radiographs were reviewed to document the morphological characteristic of osteoarthritic hips. Lateral spine-pelvis-hip sitting and standing plain radiographs were used to measure sacral slope (SS) and pelvic femoral angle (PFA) in each position. Lumbar disc spaces were measured to determine the presence of DDD. The difference between sitting and standing SS and PFA were calculated to quantify spinopelvic motion (ΔSS) and hip motion (ΔPFA), respectively. Univariate analysis and Pearson correlation were used to identify morphological hip characteristics associated with changes in spinopelvic motion.


Bone & Joint 360
Vol. 11, Issue 6 | Pages 20 - 21
1 Dec 2022

The December 2022 Sports Roundup360 looks at: Anterior cruciate ligament (ACL) repair with dynamic intraligamentary stabilization or anterior ACL at five years?; Femoroacetabular impingement in mild osteoarthritis: is hip arthroscopy the answer?; Steroids in Achilles tendinopathy: A randomized trial.