Aims. To clarify the mid-term results of transposition osteotomy of the acetabulum (TOA), a type of spherical periacetabular osteotomy, combined with structural allograft bone grafting for severe hip dysplasia. Methods. We reviewed patients with severe hip dysplasia, defined as Severin IVb or V (lateral centre-edge angle (LCEA) < 0°), who underwent TOA with a structural bone allograft between 1998 and 2019. A medical chart review was conducted to extract demographic data, complications related to the osteotomy, and modified Harris Hip Score (mHHS). Radiological parameters of hip dysplasia were measured on pre- and postoperative radiographs. The cumulative probability of TOA failure (progression to Tönnis grade 3 or conversion to total hip arthroplasty) was estimated using the Kaplan–Meier product-limited method, and a multivariate Cox proportional hazard model was used to identify predictors for failure. Results. A total of 64 patients (76 hips) were included in this study. The median follow-up period was ten years (interquartile range (IQR) five to 14). The median mHHS improved from 67 (IQR 56 to 80) preoperatively to 96 (IQR 85 to 97) at the latest follow-up (p < 0.001). The radiological parameters improved postoperatively (p < 0.001), with the resulting parameters falling within the normal range in 42% to 95% of hips. The survival rate was 95% at ten years and 80% at 15 years. Preoperative Tönnis grade 2 was an independent risk factor for TOA failure. Conclusion. Our findings suggest that TOA with structural bone allografting is a viable surgical option for correcting severely dysplastic acetabulum in adolescents and young adults without advanced osteoarthritis, with favourable mid-term outcomes. Cite this article: Bone Joint J 2023;105-B(7):743–750

Aims. Periacetabular osteotomy (PAO) is the preferred treatment for symptomatic acetabular dysplasia in adolescents and young adults. There remains a lack of consensus regarding whether intra-articular procedures such as labral repair or improvement of femoral offset should be performed at the time of PAO or addressed subsequent to PAO if symptoms warrant. The purpose was to determine the rate of subsequent hip arthroscopy (HA) in a contemporary cohort of patients, who underwent PAO in isolation without any intra-articular procedures. Methods. From June 2012 to March 2022, 349 rectus-sparing PAOs were performed and followed for a minimum of one year (mean 6.2 years (1 to 11)). The mean age was 24 years (14 to 46) and 88.8% were female (n = 310). Patients were evaluated at final follow-up for patient-reported outcome measures (PROMs). Clinical records were reviewed for complications or subsequent surgery. Radiographs were reviewed for the following acetabular parameters: lateral centre-edge angle, anterior centre-edge angle, acetabular index, and the alpha-angle (AA). Patients were cross-referenced from the two largest hospital systems in our area to determine if subsequent HA was performed. Descriptive statistics were used to analyze risk factors for HA. Results. A total of 16 hips (15 patients; 4.6%) underwent subsequent HA with labral repair and femoral osteochondroplasty, the most common interventions. For those with a minimum of two years of follow-up, 5.3% (n = 14) underwent subsequent HA. No hips underwent total hip arthroplasty and one revision PAO was performed. Overall, 17 hips (4.9%) experienced a complication and 99 (26.9%) underwent hardware removal. All PROMs improved significantly postoperatively. Radiologically, 80% of hips (n = 279) reached the goal for acetabular correction (77% for acetbular index and 93% for LCEA), with no significant differences between those who underwent subsequent HA and those who did not. Conclusion. Rectus-sparing PAO is associated with a low rate of subsequent HA for intra-articular pathology at a mean of 6.2 years’ follow-up (1 to 11). Acetabular correction alone may be sufficient as the primary intervention for the majority of patients with symptomatic acetabular dysplasia. Cite this article: Bone Joint J 2024;106-B(5 Supple B):17–24

Aims. The purpose of this study was to evaluate the long-term outcome of adolescents with cerebral palsy who have undergone single-event multilevel surgery for a flexed-knee gait, followed into young adulthood using 3D motion analysis. Patients and Methods. A total of 59 young adults with spastic cerebral palsy, with a mean age of 26 years (. sd.  3), were enrolled into the study in which their gait was compared with an evaluation that had taken place a mean of 12 years (. sd.  2) previously. At their visits during adolescence, the children walked with excessive flexion of the knee at initial contact and surgical or therapeutic interventions were not controlled between visits. Results. Based on the change in flexed-knee gait over approximately ten years, improvements were seen in increased Gait Deviation Index (p < 0.001) and decreased flexion of the knee at initial contact (p < 0.001). Greater popliteal angle (p < 0.001), reduced Gross Motor Function Measure section D (p = 0.006), and reduced speed of gait (p = 0.007) suggested a mild decline in function. Quality-of-life measures showed that these patients fell within normal limits compared with typical young adults in areas other than physical function. Conclusion. While some small significant changes were noted, little clinically significant change was seen in function and gait, with gross motor function maintained between adolescence and young adulthood. Cite this article: Bone Joint J 2018;100-B:549–56

Aims. Giant cell tumour of bone (GCTB) is a locally aggressive lesion that is difficult to treat as salvaging the joint can be associated with a high rate of local recurrence (LR). We evaluated the risk factors for tumour relapse after treatment of a GCTB of the limbs. Methods. A total of 354 consecutive patients with a GCTB underwent joint salvage by curettage and reconstruction with bone graft and/or cement or en bloc resection. Patient, tumour, and treatment factors were analyzed for their impact on LR. Patients treated with denosumab were excluded. Results. There were 53 LRs (15%) at a mean 30.5 months (5 to 116). LR was higher after curettage (18.4%) than after resection (4.6%; p = 0.008). Neither pathological fracture (p = 0.240), Campanacci grade (p = 0.734), soft-tissue extension (p = 0.297), or tumour size (p = 0.872) affected the risk of recurrence. Joint salvage was possible in 74% of patients overall (262/354), and 98% after curettage alone (262/267). Of 49 patients with LR after curettage, 44 (90%) underwent repeated curettage and joint salvage. For patients treated by curettage, only age less than 30 years (p = 0.042) and location in the distal radius (p = 0.043) predicted higher LR. The rate of LR did not differ whether cement or bone graft was used (p = 0.753), but may have been reduced by the use of hydrogen peroxide (p = 0.069). Complications occurred in 15.3% of cases (54/354) and did not differ by treatment. Conclusion. Most patients with a GCTB can undergo successful joint salvage by aggressive curettage, even in the presence of a soft-tissue mass, pathological fracture, or a large lesion, with an 18.4% risk of local recurrence. However, 90% of local relapses after curettage can be treated by repeat joint salvage. Maximizing joint salvage is important to optimize long-term function since most patients with a GCTB are young adults. Younger patients and those with distal radius tumours treated with joint-sparing procedures have a higher rate of local relapse and may require more aggressive treatment and closer follow-up. Cite this article: Bone Joint J 2023;105-B(5):559–567

Objectives. Cellular movement and relocalisation are important for many physiologic properties. Local mesenchymal stem cells (MSCs) from injured tissues and circulating MSCs aid in fracture healing. Cytokines and chemokines such as Stromal cell-derived factor 1(SDF-1) and its receptor chemokine receptor type 4 (CXCR4) play important roles in maintaining mobilisation, trafficking and homing of stem cells from bone marrow to the site of injury. We investigated the differences in migration of MSCs from the femurs of young, adult and ovariectomised (OVX) rats and the effect of CXCR4 over-expression on their migration. Methods. MSCs from young, adult and OVX rats were put in a Boyden chamber to establish their migration towards SDF-1. This was compared with MSCs transfected with CXCR4, as well as MSCs differentiated to osteoblasts. Results. MSCs from OVX rats migrate significantly (p < 0.05) less towards SDF-1 (9%, . sd. 5%) compared with MSCs from adult (15%, . sd. 3%) and young rats (25%, . sd. 4%). Cells transfected with CXCR4 migrated significantly more towards SDF-1 compared with non-transfected cells, irrespective of whether these cells were from OVX (26.5%, . sd. 4%), young (47%, . sd. 17%) or adult (21%, . sd. 4%) rats. Transfected MSCs differentiated to osteoblasts express CXCR4 but do not migrate towards SDF-1. Conclusions. MSC migration is impaired by age and osteoporosis in rats, and this may be associated with a significant reduction in bone formation in osteoporotic patients. The migration of stem cells can be ameliorated by upregulating CXCR4 levels which could possibly enhance fracture healing in osteoporotic patients. Cite this article: A. Sanghani-Kerai, M. Coathup, S. Samazideh, P. Kalia, L. Di Silvio, B. Idowu, G. Blunn. Osteoporosis and ageing affects the migration of stem cells and this is ameliorated by transfection with CXCR4. Bone Joint Res 2017;6:–365. DOI: 10.1302/2046-3758.66.BJR-2016-0259.R1

Aims. Osteopetrosis (OP) is a rare hereditary disease that causes reduced bone resorption and increased bone density as a result of osteoclastic function defect. Our aim is to review the difficulties, mid-term follow-up results, and literature encountered during the treatment of OP. Methods. This is a retrospective and observational study containing data from nine patients with a mean age of 14.1 years (9 to 25; three female, six male) with OP who were treated in our hospital between April 2008 and October 2018 with 20 surgical procedures due to 17 different fractures. Patient data included age, sex, operating time, length of stay, genetic type of the disease, previous surgery, fractures, complications, and comorbidity. Results. The mean follow-up period was 92.5 months (25 to 140). Bony union was observed in all of our patients. Osteomyelitis developed in two patients with femoral shaft fractures, and two patients had peri-implant stress fractures. Conclusion. Treatment of fractures in OP patients is difficult, healing is protracted, and the risk of postoperative infection is high. In children and young adults with OP who have open medullary canal and the epiphyses are not closed, fractures can be treated with surgical techniques such as intramedullary titanium elastic nail (TENS) technique or fixation with Kirschner (K)-wire. Cite this article: Bone Joint J 2020;102-B(8):1082–1087

Aims. The aim of this study was to report the long-term results of rotational acetabular osteotomy (RAO) for symptomatic hip dysplasia in patients aged younger than 21 years at the time of surgery. Patients and Methods. We evaluated 31 patients (37 hips) aged younger than 21 years at the time of surgery retrospectively. There were 29 female and two male patients. Their mean age at the time of surgery was 17.4 years (12 to 21). The mean follow-up was 17.9 years (7 to 30). The RAO was combined with a varus or valgus femoral osteotomy or a greater trochanteric displacement in eight hips, as instability or congruence of the hip could not be corrected adequately using RAO alone. Results. The mean Merle d’Aubigné clinical score improved significantly from 15.4 to 17.2 (p < 0.0001). The mean centre-edge (CE) angle improved from -2.6° to 26°, the mean acetabular roof angle improved from 3.0° to 5.2°, and the mean head lateralization index improved from 0.68 to 0.62. Progression of radiological osteoarthritis (OA) was seen in seven hips, but no patient underwent total hip arthroplasty. Conclusion. RAO is an effective form of correction for a severely dysplastic hip in adolescent and young adult patients. Cite this article: Bone Joint J 2019;101-B:390–395

Objectives. This study aimed to assess the effect of age and osteoporosis on the proliferative and differentiating capacity of bone-marrow-derived mesenchymal stem cells (MSCs) in female rats. We also discuss the role of these factors on expression and migration of cells along the C-X-C chemokine receptor type 4 (CXCR-4) / stromal derived factor 1 (SDF-1) axis. Methods. Mesenchymal stem cells were harvested from the femora of young, adult, and osteopenic Wistar rats. Cluster of differentiation (CD) marker and CXCR-4 expression was measured using flow cytometry. Cellular proliferation was measured using Alamar Blue, osteogenic differentiation was measured using alkaline phosphatase expression and alizarin red production, and adipogenic differentiation was measured using Oil red O. Cells were incubated in Boyden chambers to quantify their migration towards SDF-1. Data was analyzed using a Student’s t-test, where p-values < 0.05 were considered significant. Results. CD marker expression and proliferation of the MSCs from the three groups was not significantly different. The young MSCs demonstrated significantly increased differentiation into bone and fat and superior migration towards SDF-1. The migration of SDF-1 doubled with young rats compared with the adult rats (p = 0.023) and it was four times higher when compared with cells isolated from ovariectomized (OVX) osteopenic rats (p = 0.013). Conclusion. Young rat MSCs are significantly more responsive to osteogenic differentiation, and, contrary to other studies, also demonstrated increased adipogenic differentiation compared with cells from adult and ostopenic rats. Young-rat-derived cells also showed superior migration towards SDF-1 compared with MSCs from OVX and adult control rats. Cite this article: A. Sanghani-Kerai, L. Osagie-Clouard, G. Blunn, M. Coathup. The influence of age and osteoporosis on bone marrow stem cells from rats. Bone Joint Res 2018;7:289–297. DOI: 10.1302/2046-3758.74.BJR-2017-0302.R1

Aims. Despite advances in the treatment of paediatric hip disease, adolescent and young adult patients can develop early onset end-stage osteoarthritis. The aims of this study were to address the indications and medium-term outcomes for total hip arthroplasty (THA) with ceramic bearings for teenage patients. Methods. Surgery was performed by a single surgeon working in the paediatric orthopaedic unit of a tertiary referral hospital. Databases were interrogated from 2003 to 2017 for all teenage patients undergoing THA with a minimum 2.3 year follow-up. Data capture included patient demographics, the underlying hip pathology, number of previous surgeries, and THA prostheses used. Institutional ethical approval was granted to contact patients for prospective clinical outcomes and obtain up-to-date radiographs. In total, 60 primary hips were implanted in 51 patients (35 female, 16 male) with nine bilateral cases. The mean age was 16.7 years (12 to 19) and mean follow-up was 9.3 years (2.3 to 16.8). Results. The most common indication for teenage hip arthroplasty was avascular necrosis secondary to slipped upper femoral epiphysis (31%; n = 16). Overall, 64% of patients (n = 33) had undergone multiple previous operations. The survival at follow-up was 97%; two patients required revision for aseptic loosening (one femoral stem, one acetabular component). Both patients had fused hips noted at the time of arthroplasty. A further two patients had radiolucent lines but were asymptomatic. At latest follow-up the mean Oxford Hip Score was 44 (31 to 48) and a Visual Analogue Scale measurement of 1.5, indicating satisfactory function. Conclusion. Operating on this cohort can be complicated by multiple previous surgeries and distorted anatomy, which in some cases require custom-made prostheses. We have demonstrated a good outcome with low revision rate in this complex group of patients. Cite this article: Bone Joint J 2020;102-B(11):1491–1496

Objectives. It has been hypothesized that patellofemoral pain, a common knee condition in adolescents and young adults, may be a precursor of degenerative joint changes and may ultimately lead to patellofemoral osteoarthritis. Since both conditions share several mechanical disease characteristics, such as altered contact area between the femur and patella and increased joint stress, we investigated whether these conditions share similar and different shape characteristics of the patella compared with normal controls. Methods. This cross-sectional study compared three different study populations: 32 patellofemoral pain subjects (mean age, 32 years (22 to 45); 72% female); 56 isolated radiological patellofemoral osteoarthritis subjects (mean age, 54 years (44 to 58); 89% female); and 80 healthy control subjects (mean age, 52 years (44 to 58); 74% female). Measurements included questionnaires, and lateral and skyline radiographs of the knee. Two separate 30-point 2D statistical shape models of the patella were created from the lateral and skyline radiographs. A general linear model was used to test for differences in standardized shape modes (a specific shape variant of the patella) between patellofemoral osteoarthritis, patellofemoral pain, and controls, using Bonferroni correction and adjustment for body mass index and gender. Results. Five shape modes showed statistically significant differences between groups: skyline modes 1 (p < 0.001), 8 (p = 0.004), and 10 (p < 0.001); and lateral modes 5 (p = 0.002) and 7 (p = 0.002). Skyline mode 8 and lateral mode 5 were similar for patellofemoral osteoarthritis and patellofemoral pain populations, while being statistically significant different from the control group. Conclusion. Our results indicate that patellofemoral pain and patellofemoral osteoarthritis share similar shape characteristics, which are different from control subjects. These findings support the proposed continuum disease model of patellofemoral pain predisposing to the development of patellofemoral osteoarthritis. Cite this article: J. F. A. Eijkenboom, J. H. Waarsing, E. H. G. Oei, S. M. A. Bierma-Zeinstra, M. van Middelkoop. Is patellofemoral pain a precursor to osteoarthritis? Patellofemoral osteoarthritis and patellofemoral pain patients share aberrant patellar shape compared with healthy controls. Bone Joint Res 2018;7:541–547. DOI: 10.1302/2046-3758.79.BJR-2018-0112.R1

Patellar instability most frequently presents during adolescence. Congenital and infantile dislocation of the patella is a distinct entity from adolescent instability and measurable abnormalities may be present at birth. In the normal patellofemoral joint an increase in quadriceps angle and patellar height are matched by an increase in trochlear depth as the joint matures. Adolescent instability may herald a lifelong condition leading to chronic disability and arthritis. Restoring normal anatomy by trochleoplasty, tibial tubercle transfer or medial patellofemoral ligament (MPFL) reconstruction in the young adult prevents further instability. Although these techniques are proven in the young adult, they may cause growth arrest and deformity where the physis is open. A vigorous non-operative strategy may permit delay of surgery until growth is complete. Where non-operative treatment has failed a modified MPFL reconstruction may be performed to maintain stability until physeal closure permits anatomical reconstruction. If significant growth remains an extraosseous reconstruction of the MPFL may impart the lowest risk to the physis. If minor growth remains image intensifier guided placement of femoral intraosseous fixation may impart a small, but acceptable, risk to the physis. This paper presents and discusses the literature relating to adolescent instability and provides a framework for management of these patients. Cite this article: Bone Joint J 2017;99-B:159–70

We have compared the findings of MRI with those of hip arthroscopy in 23 hips in young adults with hip pain. Large deep cartilage deficiencies on the acetabulum or femoral head, the percentage of femoral head cover, and the presence of marginal osteophytes seen on MRI correlated well with those seen at arthroscopy, but chondral softening, fibrillation, or partial-thickness defects less than 1 cm in diameter were less consistently detected by MRI. Osteochondral loose bodies and labral tears were not well demonstrated by MRI, but were readily identified and treated at arthroscopy. Arthroscopy of the hip is a useful investigation for hip pain in young adults especially when standard non-invasive MRI fails to provide a clear diagnosis

We have divided Severin group-V severely dysplastic hips with a false into three subtypes, based on the height and shape of the socket. We performed rotational acetabular osteotomy (RAO) in 19 hips in 17 young adults with a type-1 ‘low’ false acetabulum which had direct contact with the true acetabulum. This is a periacetabular osteotomy which gives acetabular coverage with articular cartilage and produces a nearly normal position of the head. Concomitant osteotomies of the proximal femur were carried out in 11 hips. We reviewed the patients clinically and radiologically at a mean of ten years (6 to 18) after operation. Of the 19 hips, 15 showed very good or good results. This operation is indicated in young adults with a dysplastic hip and a type-1 low false acetabulum. Subclassification of Severin group V is a convenient way of defining those patients who would benefit from the procedure

Young adults with hip pain secondary to femoroacetabular impingement (FAI) are rapidly being recognised as an important cohort of orthopaedic patients. Interest in FAI has intensified over the last decade since its recognition as a precursor to arthritis of the hip and the number of publications related to the topic has increased exponentially in the last decade. Although not all patients with abnormal hip morphology develop osteoarthritis (OA), those with FAI-related joint damage rapidly develop premature OA. There are no explicit diagnostic criteria or definitive indications for surgical intervention in FAI. Surgery for symptomatic FAI appears to be most effective in younger individuals who have not yet developed irreversible OA. The difficulty in predicting prognosis in FAI means that avoiding unnecessary surgery in asymptomatic individuals, while undertaking intervention in those that are likely to develop premature OA poses a considerable dilemma. FAI treatment in the past has focused on open procedures that carry a potential risk of complications. Recent developments in hip arthroscopy have facilitated a minimally invasive approach to the management of FAI with few complications in expert hands. Acetabular labral preservation and repair appears to provide superior results when compared with debridement alone. Arthroscopic correction of structural abnormalities is increasingly becoming the standard treatment for FAI, however there is a paucity of high-level evidence comparing open and arthroscopic techniques in patients with similar FAI morphology and degree of associated articular cartilage damage. Further research is needed to develop an understanding of the natural course of FAI, the definitive indications for surgery and the long-term outcomes. Cite this article: Bone Joint J 2013;95-B, Supple A:26–30

Neglected fractures of the femoral neck, common in young adults in underdeveloped countries, may be complicated by nonunion or avascular necrosis (AVN). We treated 52 cases by open reduction, fixation by compression screw and a free fibular graft. The mean delay between injury and operation was 5.1 months. Of 40 fractures assessed at a mean of 58.8 months (24 to 153), 38 were found to be united and two, owing to surgical errors, were not. Seven of eight heads which were avascular before operation revascularised without collapse, while seven others developed AVN after the procedure. At the last follow-up considerable collapse was apparent in five femoral heads, and 11 hips had developed coxa vara. The fibular graft had fractured in four cases. The hip had been penetrated by the screw in six cases and by the graft in three. Hip function was excellent in seven patients, good in 21 and fair in seven. Five patients had poor results. Incorporation of the fibular graft was seen after four years: in many cases the graft had been almost completely resorbed. We recommend this procedure for the treatment of neglected fractures of the neck of the femur in young adults to reduce resorption of the neck, AVN and nonunion

The August 2024 Hip & Pelvis Roundup³⁶⁰ looks at: Understanding perceived leg length discrepancy post-total hip arthroplasty: the role of pelvic obliquity; Influence of femoral stem design on revision rates in total hip arthroplasty; Outcomes of arthroscopic labral treatment of femoroacetabular impingement in adolescents; Characteristics and quality of online searches for direct anterior versus posterior approach for total hip arthroplasty; Rapid return to braking after anterior and posterior approach total hip arthroplasty; How much protection does a collar provide?; Timing matters: reducing infection risk in total hip arthroplasty with corticosteroid injection intervals; Identifying pain recovery patterns in total hip arthroplasty using PROMIS data.

Aims

The aim of this study was to determine the clinical outcomes and factors contributing to failure of transposition osteotomy of the acetabulum (TOA), a type of spherical periacetabular osteotomy, for advanced osteoarthritis secondary to hip dysplasia.

Implantation of autologous chondrocytes and matrix autologous chondrocytes are techniques of cartilage repair used in the young adult knee which require harvesting of healthy cartilage and which may cause iatrogenic damage to the joint. This study explores alternative sources of autologous cells. Chondrocytes obtained from autologous bone-marrow-derived cells and those from the damaged cartilage within the lesion itself are shown to be viable alternatives to harvest-derived cells. A sufficient number and quality of cells were obtained by the new techniques and may be suitable for autologous chondrocyte and matrix autologous chondrocyte implantation

Juvenile idiopathic arthritis (JIA) is a chronic disease of childhood; it causes joint damage which may require surgical intervention, often in the young adult. The aim of this study was to describe the long-term outcome and survival of hip replacement in a group of adult patients with JIA and to determine predictors of survival for the prosthesis. In this retrospective comparative study patients were identified from the database of a regional specialist adult JIA clinic. This documented a series of 47 hip replacements performed in 25 adult patients with JIA. Surgery was performed at a mean age of 27 years (11 to 47), with a mean follow-up of 19 years (2 to 36). The mean Western Ontario and McMaster Universities osteoarthritis index questionnaire (WOMAC) score at the last follow-up was 53 (19 to 96) and the mean Health Assessment Questionnaire score was 2.25 (0 to 3). The mean pain component of the WOMAC score (60 (20 to 100)) was significantly higher than the mean functional component score (46 (0 to 97)) (p = 0.02). Kaplan-Meier survival analysis revealed a survival probability of 46.6% (95% confidence interval 37.5 to 55.7) at 19 years, with a trend towards enhanced survival with the use of a cemented acetabular component and a cementless femoral component. This was not, however, statistically significant (acetabular component, p = 0.76, femoral component, p = 0.45). Cox’s proportional hazards regression analysis showed an implant survival rate of 54.9% at 19 years at the mean of covariates. Survival of the prosthesis was significantly poorer (p = 0.001) in patients who had been taking long-term corticosteroids and significantly better (p = 0.02) in patients on methotrexate

The June 2023 Spine Roundup³⁶⁰ looks at: Characteristics and comparative study of thoracolumbar spine injury and dislocation fracture due to tertiary trauma; Sublingual sufentanil for postoperative pain management after lumbar spinal fusion surgery; Minimally invasive bipolar technique for adult neuromuscular scoliosis; Predictive factors for degenerative lumbar spinal stenosis; Lumbosacral transitional vertebrae and lumbar fusion surgery at level L4/5; Does recall of preoperative scores contaminate trial outcomes? A randomized controlled trial; Vancomycin in fibrin glue for prevention of SSI; Perioperative nutritional supplementation decreases wound healing complications following elective lumbar spine surgery: a randomized controlled trial.