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Abstract
Introduction Knee osteotomy combined with meniscal allograft transplantation (MAT) showed promising results to treat unicompartmental knee osteoarthritis (OA) secondary to meniscal deficiency and knee malalignment. However, there is still no high-level evidence to demonstrate whether the combination of these two treatments is superior to osteotomy alone.
Methods and analysis 52 patients with unicompartmental knee OA Kellgren-Lawrence grade ≤3 secondary to meniscal deficiency and knee malalignment (aged 20–60 years) are randomised to undergo knee osteotomy associated with MAT or knee osteotomy alone in a 1:1 ratio. The primary outcome is the International Knee Documentation Committee (IKDC) subjective score at 12 months. The secondary outcomes are the IKDC subjective score at 1, 3 and 6 months, the Western Ontario and McMaster Universities Osteoarthritis Index score, the Knee Injury and Osteoarthritis Outcome Score, the Visual Analogue Scale, the EuroQol Visual Analogue Scale, the Tegner Activity Level Scale, objective parameters (transpatellar circumference, suprapatellar circumference and range of motion), patient expectation on treatment efficacy and patient satisfaction at 1, 3, 6 and 12 months. Radiographs are performed at baseline and at 1-, 6- and 12-month follow-ups and magnetic resonance evaluations at baseline and at 12 months. Biomechanical assessment is performed through gait analysis before surgery and at 12 months, investigating motion data, biomechanical parameters and muscle activation through electromyography. In addition, to detect early joint environment changes and potential MAT effects in protecting the articular surface providing a better knee homeostasis, biological markers of cartilage turnover and inflammation obtained from synovial fluid, serum and urine are evaluated at baseline and at 24 hours, 1-, 3-, 6- and 12-month follow-ups.
Ethics and dissemination The study protocol has been approved by Emilia Romagna’s Ethics Committee (CE-AVEC), Bologna, Italy. Written informed consent is obtained from all participants. Findings of this study will be disseminated through peer-reviewed publications and conference presentations.
Protocol version March 2023.
Trial registration number NCT05840887.
- Knee
- Randomised Controlled Trial
- Patient Reported Outcome Measures
- Gait Analysis
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STRENGTHS AND LIMITATIONS OF THIS STUDY
This is a prospective, randomised, double-blind, controlled trial performed in a highly specialised orthopaedic centre for the treatment of knee osteoarthritis (OA), meniscal deficiency and knee malalignment.
Patients are prospectively analysed combining patient-reported outcome measures with objective clinical parameters and imaging evaluations using radiographs and magnetic resonance.
Patients are assessed with both gait analysis and serum, urine, and synovial biomarkers evaluations to identify biomechanical and biological changes after the surgical procedures.
The uncontrolled pain medication use by patients (although being discouraged) could influence the primary outcome and could be not properly evaluated and analysed, which can be a relevant limitation of the study.
The 1-year follow-up can be considered a relatively short timeframe limiting the assessment of the progression of knee OA and the benefits provided by the addition of meniscal allograft transplantation to knee osteotomy in delaying the progression of knee OA.
Introduction
Knee osteoarthritis (OA) is one of the most common causes of joint pain and physical disability, with a considerable socioeconomic impact.1–3 OA knees often present a more severe involvement of one joint compartment (unicompartmental OA), especially in younger patients due to mechanical problems such as lower limb malalignment and/or meniscal deficiency.4 5 Both lower limb malalignment and previous meniscectomy can induce an overload on the affected knee compartment, favouring an early onset and faster progression of cartilage degeneration.6–9 The treatment is challenging as it is aimed not only at pain improvement and function recovery but also at proper load redistribution. Knee arthroplasty offers satisfactory results in the elderlies, but younger and active patients can experience a worse outcome with the risk of requiring revision arthroplasty, high morbidity and poorer results.10–12 Knee osteotomy is appropriate to treat the affected compartment by correcting the malalignment, although it leaves a damaged compartment and results can be only partially satisfactory in these young and demanding active patients.13 14 In this scenario, an approach combining knee osteotomy and meniscal allograft transplantation (MAT) to address meniscus deficiency could improve the treatment results.
MAT is considered a suitable option to replace the residual meniscus,15 and it has been proposed as a possible solution to improve the results of knee osteotomy by properly restoring weight distribution on the articular surface in patients with lower limb malalignment as well as meniscal deficiency.16 17 Previous studies showed that MAT can replicate the shock-absorbing function of the normal meniscus, improving both symptoms and knee function.18–23 There are preliminary data suggesting the safety and efficacy of knee osteotomy and MAT-combined procedures in unicompartmental OA patients.14 However, the evidence on the real benefit of this treatment strategy is rather anecdotal, and no high-level studies investigated the clinical, biomechanical and biological advantages offered by the combined approach compared with knee osteotomy alone in patients with lower limb malalignment and meniscal deficiency. A randomised controlled trial (RCT) directly investigating the added benefit of MAT to the improvement offered by osteotomy would offer clear indications for promoting this combined treatment approach in the clinical practice to address patients with symptomatic unicompartmental knee OA in malaligned limbs and meniscus deficiency.
Objectives and trial design
A double-blinded RCT has been designed to compare the clinical outcome of the combination of knee osteotomy and MAT (treatment group) versus knee osteotomy alone (control group) to address patients with unicompartmental knee OA associated with meniscal deficiency and lower limb malalignment, with a 1:1 allocation ratio. As secondary goals, this study aims at demonstrating whether the addition of MAT to osteotomy is able to improve biomechanical, biological and imaging parameters, offering protective effects on the articular surface and on the joint environment.
Methods and analysis
Study setting
The study is a single-centre, double-blind RCT, with all activities related to the study performed at a single site (IRCCS Istituto Ortopedico Rizzoli, Bologna, Italy). This trial protocol has been produced according to the Standard Protocol Items: Recommendations for Interventional Trials (SPIRIT) reporting guidelines.24
Patient and public involvement
Patients contributed to raise the research questions by prompting clinicians to find solutions to their knee pain in the presence of malalignment and meniscal deficiency. Patients were not involved in planning the design of the study and outcome measures, which were decided according to the field scientific standards.
Eligibility criteria
Patients are recruited according to the following criteria.
Inclusion criteria
Men or women aged between 20 and 60 years;
Symptomatic tibiofemoral unicompartmental OA (Visual Analogue Scale (VAS) for pain ≥3 and OA grade ≤3 according to the Kellgren-Lawrence classification) unresponsive to non-operative treatment (oral medication, physiotherapy or injective treatments);
Surgical indication of corrective osteotomy (lower limb axial malalignment >5°);
Meniscal deficiency (total or subtotal meniscectomy) in the compartment affected by overload;
Ability and consent to participate to clinical and imaging follow-ups;
Informed consent signed.
Exclusion criteria
Patients mentally incapacitated;
Patients with active malignancy;
Patients suffering from rheumatic diseases or arthritis secondary to other inflammatory diseases;
HIV infection, viral hepatitis, chondrocalcinosis;
Patients suffering from uncontrolled diabetes or thyroid disorders;
Patients with a history of alcohol or drug abuse;
Body mass index >40 kg/m2;
Pregnancy, breastfeeding or intention to start pregnancy during the study;
Patients who underwent knee surgery in the previous 12 months.
Intervention
Patients are treated by two orthopaedic surgeons with established experience in cartilage preservation procedures including knee osteotomy and MAT, with more than 100 treatments per year considering MAT and osteotomies. The treatment is performed in a single step in the operating room with patients in a supine position under spinal locoregional anaesthesia. All patients undergo knee osteotomy to obtain a correct lower limb realignment and an arthroscopic procedure to assess cartilage and meniscus status, with minor procedures performed for debris removal, when needed. Synovial tissue biopsies and synovial fluid sampling are also performed. After intraoperative confirmation of the inclusion criteria (total or subtotal meniscus deficiency and absence of severe focal cartilage impairment), half of the patients are randomised to also undergo an arthroscopic MAT to address the meniscal deficiency. A fresh-frozen non-irradiated and non-antigen-matched allograft is used, as previously described.25 Briefly, the MAT procedure is performed arthroscopically using a transtibial tunnel technique, with soft tissue fixation and without bone plugs. The graft fixation to the capsule is performed with all-inside sutures at the graft body level, with trans-osseous sutures to the posterior horn, and, if necessary, to the anterior horn (figure 1).
Meniscal allograft transplantation after fixation.
After the arthroscopy procedure, knee osteotomy is performed with different techniques based on the affected knee compartment26 27 (figure 2). In case of medial compartment involvement, both opening and closing-wedge tibial osteotomies can be used to address malalignment: a medial opening-wedge high tibial osteotomy (HTO) is usually performed in severe varus deformities and proximal tibial malrotation using a bone grafting. On the other hand, a lateral closing-wedge HTO can be performed for OA patients with light or moderate deformity and no morphotype alterations.28 Both techniques require fixation with plate and screws.29 In case of lateral compartment involvement, a distal femoral osteotomy (DFO) is performed to restore knee alignment. A medial closing-wedge or a lateral opening-wedge DFO is performed with a medial incision along the medial aspect of the distal femur up to the medial epicondyle or with a lateral incision along the lateral aspect of the distal femur up to the lateral epicondyle, respectively. Similarly to HTO, both techniques require fixation with specific plates and screws.30
Types of knee osteotomy: (A) medial opening-wedge HTO; (B) lateral opening-wedge DFO; (C) lateral closing-wedge HTO (highlighted area is removed); (D) medial closing-wedge DFO (highlighted area is removed). All pictures show the joint starting position. DFO, distal femoral osteotomy; HTO, high tibial osteotomy.
Postoperatively, all patients follow the same venous thromboembolism prophylaxis and functional rehabilitation protocol, wearing a leg brace locked in full extension for 30 days, which can be removed three times a day to perform passive exercises (continuous passive motion) to gradually restore range of motion up to a maximum of 90° of flexion within the first month. Afterwards, active complete range of motion is gradually recovered. Weight-bearing is not allowed on the operated leg for 30 days, followed by progression to full weight-bearing as tolerated. Muscular reinforcement with isometric exercises is started from the first week.
Outcomes
Clinical evaluation is performed by medical staff not involved in the treatment and is conducted through validated questionnaires and objective measurements before surgery and at 1, 3, 6 and 12 months of follow-up. In particular, the primary outcome is the International Knee Documentation Committee (IKDC) subjective score at the 12-month follow-up. The secondary outcomes include the IKDC subjective score at other follow-ups and the Western Ontario and McMaster Universities Osteoarthritis Index score, the Knee Injury and Osteoarthritis Outcome Score, the VAS for pain, the EuroQol Visual Analogue Scale, the Tegner activity level and objective parameters (transpatellar circumference, suprapatellar circumference and range of motion) at baseline and at 1, 3, 6 and 12 months of follow-up. Moreover, patient expectation on treatment efficacy is recorded at baseline using the following question: ‘What benefits do you expect to obtain after the treatment?’—full recovery, ‘definitely better’, ‘much better’, ‘slightly better’ and ‘about the same’. Finally, patient judgement is recorded at 6 and 12 months of follow-up using the following question: ‘Compared with the baseline status, how would you rate the treated knee now?’ The responses are recorded using a 5-point scale: ‘much better’, ‘slightly better’, ‘about the same’, ‘slightly worse’ and ‘much worse’.
Imaging analysis is performed evaluating treated knees with radiographs (knee anteroposterior and lateral views and full-length lower limb anteroposterior view) at baseline, 1-, 6- and 12-month follow-ups). OA severity is assessed by evaluating radiographs according to the Kellgren-Lawrence classification. Patients also undergo high-resolution 3 Tesla magnetic resonance (MR) imaging at baseline and at 12 months of follow-up and the Whole-Organ MRI Score is used to evaluate knee characteristics including articular cartilage morphology and signal, bone marrow oedema, subchondral cysts, articular profile, marginal osteophytes, ligaments and meniscal integrity and synovitis. During MR assessment, a set of reflective markers is applied around the joint line to be used for subsequent biomechanical evaluations.
Biomechanical assessment is performed through gait analysis before surgery and at 12 months of follow-up. Motion data and biomechanical parameters (joint rotations and moments, spatiotemporal data, electromyography and dynamometric data) of the joints of the lower limbs and trunk are collected during motor task execution. To digitally reconstruct the lower limb bone segments during motion, a set of reflective markers is attached to the skin in defined anatomical landmarks. In detail, these are the left and right superior anterior–posterior iliac spines on the pelvis, the greater trochanter and medial and lateral epicondyles on the thigh; the head of the fibula, the tibial tuberosity, and the medial and lateral malleoli on the lower leg; the calcaneal insertion of the Achilles tendon and the head of the first, second and fifth metatarsal bones on the foot. An additional set of four markers is attached at the level of the Gerdy’s tubercle, at the level of the medial joint line, on the distal apex of the patella and at about 2 cm proximally to the lateral epicondyle. This additional set of markers is used to report the ground reaction force at the knee level of the patient-specific tibial plateau morphology, to characterise the overall alignment of the knee joint before and after surgery, in addition to kinematic and kinetic data reconstruction (ie, joint rotations and moments). Gait analysis is combined with electromyography using surface electrodes to assess the activation of a number of lower limb muscles. The used protocol is standardised and it consists of the execution of simple (ie, regular walking) and demanding motor tasks (ie, chair standing/sitting, stair climbing/descending and squatting).31 Kinematics and kinetics of the knee are assessed bilaterally and in association with the hip and ankle joints. Biomechanical data derived from a normal population evaluated in a previous gait analysis study is used as a reference for the normality.32
Biological analyses are performed to evaluate changes over time in biomarker values related to cartilage turnover and inflammation. In particular, serum/plasma and urine samples are collected at baseline and at 24 hours, 1, 3, 6 and 12 months after surgery. A wide number of biomarkers of collagen degradation/synthesis (ie, C-telopeptide fragment of Collagen Type II—CTX-II, procollagen II C-propeptide—CPII) and inflammation (ie, interleukin-6, CXCL8, CCL2) are assessed by enzyme-linked immunosorbent or multiplex immunoassay.33 34 Moreover, to evaluate the joint inflammation level at baseline, synovial tissue biopsies and synovial fluid samples collected during the surgical procedure are assessed by the Immunologic Synovitis Score and for soluble inflammatory factors, respectively.35
Participant timeline
The study has a total duration of 36 months. Patient enrolment started in July 2023. The first patient was treated on 30 August 2023. The study conclusion is foreseen before the end of 2026. After the screening visit, patients complete clinical questionnaires and undergo imaging analysis (knee radiographs and MR), biomechanical analysis, as well as blood and urine sampling. Follow-up assessments last 12 months: baseline (T0), 24 hours (T1), 1 month (T2), 3 months (T3), 6 months (T4) and 12 months (T5). Detailed participant timeline is outlined in table 1.
Study schedule
Recruitment
Patients undergo an outpatient visit conducted by the trained medical staff of IRCCS Istituto Ortopedico Rizzoli to assess patients’ eligibility and inform patients of the design and content of the study. They have access to this visit either by passing through an outpatient selection visit in a research outpatient setting, by referral from their GP or by spontaneously requesting an orthopaedic outpatient visit in the hospital.
Blinding
This is a double-blind RCT with both participants and investigators (physicians, radiologists, biomechanical engineers and biologists) evaluating patients and/or outcomes being blinded to the treatment allocation. Radiologists are blinded at baseline and at the 6-month follow-up, while it was not possible to perform MR analyses in blind. Moreover, the statistician involved in the study will be blinded to the treatment groups for data analysis. The treatment will be revealed to the patients and evaluators only after the final 12-month follow-up. The blindness of treated patients is further guaranteed by the same surgical approaches and incisions for both treatments. The medical report does not include whether the patients received the MAT or not as this states: ‘meniscal treatment as per study protocol’. Moreover, the rehabilitation protocol is the same for both groups, so that physical therapists and all healthcare providers in the ward are blinded to the treatment. Early unblinding may occur in case of withdrawal from the study.
Allocation
A total of 52 eligible patients is randomly allocated to receive either a combination of knee osteotomy and MAT or knee osteotomy alone, in a 1:1 ratio (26 patients for each group of treatment). The list for treatment allocation is provided by an independent professional statistician (blinded to the treatments) using a computer-generated random number and then kept in a dedicated data manager office. The allocation is managed by research staff members dedicated to study organisation and monitoring with no direct involvement in the clinical procedures. The allocation is communicated to the surgeon via phone by the research staff after intraoperative confirmation of the patient’s eligibility. The randomisation list is password-protected and accessible only by staff members with no direct involvement in the treatment and evaluation.
Adverse events assessment process
All complications and adverse events are assessed and recorded. Patients are requested to report any adverse events to the research staff and can inform physicians of potential adverse events at all follow-ups (medical examinations) or through patient–physician communication between follow-ups via phone calls or emails. Adverse events are monitored throughout the study, intraoperatively and at all clinical follow-up evaluations. Every adverse event is recorded in the patient case report form (CRF). The CRF also includes the use of pain medications (brand drug name or generic substitute, frequency and duration) and is recorded at all medical examinations. Serious adverse events are considered those resulting in death or being life-threatening, requiring hospitalisation or intervention to prevent permanent impairment or damage. Serious adverse events will be communicated to the Ethics Committee. An insurance has been arranged for this study in case of severe adverse events.
To ensure high-quality execution of the trial in accordance with the protocol, all trial staff is trained by the chief investigators and provided with a standard protocol which contains details of standard operating procedures, trial contacts and guidelines.
Data collection and management
Data are collected on a paper-based CRF, with the help of research-trained orthopaedic surgery residents blinded to treatment allocation. Subsequently, trained data analysts process all data for statistical analysis. Radiographs and MR scans are stored on IRCCS Istituto Ortopedico Rizzoli’s Picture Archiving and Communication System. Surgical data are collected electronically by orthopaedic surgeons shortly after surgery. Biomechanical data are collected using purpose-designed software for multisegmental body model reconstruction and joint kinematic and kinetic reconstruction and then stored in a proprietary laboratory repository. All data are stored in a password-protected spreadsheet on a server hosted at IRCCS Istituto Ortopedico Rizzoli. Data transfer is encrypted with all data deidentified. Only trained research personnel specifically dedicated to data handling can access the database.
Statistical methods
Sample size calculation was performed by an independent statistician. Power analysis (G*Power V.3.1.9.2) was conducted on the primary endpoint (IKDC subjective score variation from baseline to the follow-up of 12 months). From previous studies, the IKDC subjective score’s SD was 9.836 and its minimal clinically important difference was 9.9.37 Using assumptions of 90% power and 5% probability of type 1 error (alpha=0.05), the minimum sample size is 22 patients for each group. With an enrolment of 44 patients and assuming a 15% drop-out rate, 52 patients are required (26 for each group). The primary analysis on the primary outcome is performed with a per-protocol approach, plus a further intention-to-treat analysis, in which imputation methods assume that the data observed (on baseline characteristics, treatment and outcomes, for instance) can be used to predict the missing data.38 39 To this purpose, all patients who have started the treatment are considered part of the research, regardless of whether they will complete it. Missing data will be analysed using the multiple imputation analysis, performed by filling the missing data with random values from the distribution of the variable.40 Per-protocol analyses will be performed for the secondary outcomes: all secondary outcomes are considered supportive, explanatory or hypothesis-generating rather than confirmatory.
Continuous variables are expressed as means and SD if normally distributed; if not they are expressed as medians and range. Categorical variables are expressed as frequencies and percentage. Normality of the distribution is assessed using the Shapiro-Wilk test. The Levene test is used to assess the homoscedasticity of the data. The repeated measures Analysis of Variance (ANOVA), followed by the posthoc Sidak pairwise test is performed to compare scores at different follow-ups. The OneWay ANOVA test is performed to assess the difference between groups in continuous and normally distributed and homoscedastic data; the Mann-Whitney test is used otherwise. The general linear repeated model (no missing follow-up and normally distributed and homoscedastic data) or the generalised linear mixed model (all the other cases) is used to assess the influences of the groups on the repeated measures of the outcomes. The group is the fixed effect, and the potential correction for confounding factors is considered as random effect. The Pearson χ2 exact test is performed to investigate the relationships between grouping variables. The Spearman’s rank correlation is used to assess correlations between the numerical scores and continuous data. For all tests, p<0.05 is considered statistically significant.
Data monitoring
A central project data manager is tasked to perform data quality control on all collected data. An interim report and a final report are submitted to the Italian Ministry of Health which funded the project (RF-2021–12374767). The monitoring personnel belongs to the Applied and Translational Research centre, which is a research division of the Scientific Direction of IRCCS Istituto Ortopedico Rizzoli and it is independent of the medical personnel performing the study procedures. A further project auditing is performed by the Clinical Trial Centre, which is another independent entity of the Institute. The final study report is also sent to the Ethics Committee.
Ethics and dissemination
Research ethics approval and consent
Ethical approval was obtained on 15 March 2023, from the Emilia Romagna Ethics Committee (CE-AVEC), Bologna, Italy (protocol number: 153/2023/Sper/IOR). All participants will give informed written consent during the baseline outpatient medical examination with the trained medical staff and prior to enrolment. Participants may withdraw from the trial at any time.
Protocol amendments
Minor protocol amendments, for example, database changes to facilitate monitoring processes or to improve outcome assessment by questionnaire, will be fully documented. Major amendments (eg, changes to the patient information sheet and consent form, change of a local project leader or the inclusion of a new project site) will be submitted to the Ethics Committee for approval.
Confidentiality and access to data
Data are recorded using CRFs and processed centrally at the IRCCS Istituto Ortopedico Rizzoli, Bologna, Italy. CRF hard copies are stored in a locked area with restricted and secured access. Electronic data are stored on password-protected servers with restricted access. All collected data are kept strictly confidential. Backups of all electronic data occur daily to minimise risks of data loss. After study completion, data paper-based copies will be archived in a secure storage. Identifiers will be kept separately and will be accessible only to restricted study personnel in case follow-up of study patients will be necessary. Electronic data will continue to be kept in a secure electronic database for 25 years in accordance with local regulations, which will remain password protected with access given only to the study investigators unless otherwise authorised by the study team. Only members of the research team who need to contact study patients, enter data, or perform data quality controls have access to the study patient information.
Dissemination policy
This trial is produced according to the SPIRIT international standards. Results will be disseminated through peer-reviewed publications and will be submitted for presentation at national and international conferences. As raw data sharing may jeopardise patients’ privacy, data will only be accessible for internal control and data auditing to the designed people and to the Ethics Committee. The authorship is based on the International Committee of Medical Journal Editors 2018 Recommendations.
Scientific relevance and broader impact
This double-blind RCT will provide for the first time high-level evidence to investigate the possible synergistic effect of the combined approach with MAT and knee osteotomy for the treatment of patients with unicompartmental knee OA associated with knee malalignment and meniscus deficiency. This will be investigated through an innovative combination of subjective and objective outcomes with functional knee biomechanical assessment via gait analysis, as well as with biological analyses performed on specific biomarkers both at local and systemic levels. These results will aim at providing definitive evidence on the combined approach with knee osteotomy and MAT through an interdisciplinary team to investigate the benefits in terms of clinical outcome, but also of restoration of a healthier joint environment and a more physiological function of the treated knee. This will have a significant clinical relevance, offering clear indications on the most effective solution to treat the challenging patients affected by unicompartmental OA in malaligned knees with meniscus deficiency, aiming at retaining an active lifestyle and otherwise destined to more sacrificing procedures.
Ethics statements
Patient consent for publication
Acknowledgments
Thanks to Silvia Bassini for the contribution to the graphical representation technique and to Elettra Pignotti for her help with the statistical analysis.
References
Footnotes
Contributors ADM is the principal investigator of this study and acted as guarantor. LZ and AB wrote the manuscript; LZ, AB, LDM, SZ and ADM will conduct the trial. MM is responsible for imaging evaluation. GL is responsible for biological analyses. CB is responsible for biomechanical analyses. ADM, SZ and GF applied for funding and supervise the trial. All authors read and approved the final protocol.
Funding This study is funded by the Italian Ministry of Health in the Project ‘Ricerca Finalizzata’ (RF-2021-12374767) ‘BIOlogical and BIOmechanical changes after Meniscus Allograft Transplantation in osteoarthritic patients treated with knee osteotomy – BIOMAT’.
Competing interests SZ has received institutional support from FidiaFarmaceutici S.p.A., Cartiheal, IGEA Clinical Biophysics, BIOMET and Kensey Nash; grant support from I+ SRL; and royalties from Springer outside the submitted work. The principal investigator and the other authors declare no financial or competing interest.
Patient and public involvement Patients and/or the public were not involved in the design, conduct, reporting or dissemination plans of this research.
Provenance and peer review Not commissioned; externally peer reviewed.