Has the reporting quality of published randomised controlled trial protocols improved since the SPIRIT statement? A methodological study.

OBJECTIVES: To determine the reporting quality of published randomised controlled trial (RCT) protocols before and after the Standard Protocol Items: Recommendations for Interventional Trials (SPIRIT) statement (2013), and any association with author, trial or journal factors. DESIGN: Methodological study. DATA SOURCES: MEDLINE, Embase and CENTRAL were electronically searched using optimised search strategies. ELIGIBILITY CRITERIA: Protocols written for an RCT of living humans, published in full text in a peer-reviewed journal and published in the English language. MAIN OUTCOME: Primary outcome was the overall proportion of checklist items which were adequately reported in RCT protocols published before and after the SPIRIT statement. RESULTS: 300 RCT protocols were retrieved; 150 from the period immediately before the SPIRIT statement (9 July 2012 to 28 December 2012) and 150 from a recent period after the SPIRIT statement (25 January 2019 to 20 March 2019). 47.9% (95% CI, 46.5% to 49.3%) of checklist items were adequately reported in RCT protocols before the SPIRIT statement and 56.7% (95% CI, 54.9% to 58.5%) after the SPIRIT statement. This represents an 8.8% (95% CI, 6.6% to 11.1%; p<0.0001) mean improvement in the overall proportion of checklist items adequately reported since the SPIRIT statement. While 40% of individual checklist items had a significant improvement in adequate reporting after the SPIRIT statement, 11.3% had a significant deterioration and there were no RCT protocols in which all individual checklist items were complete. The factors associated with higher reporting quality of RCT protocols in multiple regression analysis were author expertise or experience in epidemiology or statistics, multicentre trials, longer protocol word length and publicly reported journal policy of compliance with the SPIRIT statement. CONCLUSION: The overall reporting quality of RCT protocols has significantly improved since the SPIRIT statement, although a substantial proportion of individual checklist items remain poorly reported. Continued and concerted efforts are required by journals, editors, reviewers and investigators to improve the completeness and transparency of RCT protocols.

Quantitative subchondral bone perfusion imaging in knee osteoarthritis using dynamic contrast enhanced MRI.

OBJECTIVE: Subchondral bone changes, characterized by increased bone turnover and vascularity, are believed to stimulate progression and pain in knee osteoarthritis (OA). The objective of this study was to evaluate the bone perfusion in knee OA using quantitative dynamic contrast enhanced MRI (DCE-MRI). DESIGN: Unicompartmental knee OA patients were included and underwent 3 Tesla DCE-MRI and T2-weighted MRI. Quantitative DCE-MRI analysis of Ktrans and Kep, representing perfusion parameters, was performed to evaluate differences between the most and least affected knee compartment. First, DCE-MRI parameter differences between epimetaphyseal and subchondral bone in both femur and tibia were assessed. Second, DCE-MRI parameters in subchondral bone marrow lesions (BMLs) were compared to surrounding subchondral bone without BMLs. RESULTS: Twenty-three patients were analyzed. Median Ktrans and Kep in epimetaphyseal bone were significantly higher (p < 0.05) in the most affected (Ktrans: 0.014; Kep: 0.054 min-1) compared to least affected (Ktrans: 0.010; Kep: 0.016 min-1) compartment. For subchondral bone, DCE-MRI parameters were significantly higher (p < 0.05) in the most affected (Ktrans: 0.019; Kep: 0.091 min-1) compared to least affected (Ktrans: 0.014; Kep: 0.058 min-1) compartment as well. Subchondral BMLs detected on fat-saturated T2-weighted images were present in all patients. Median Ktrans (0.091 vs 0.000 min-1) and Kep (0.258 vs 0.000 min-1) were significantly higher within subchondral BMLs compared to surrounding subchondral bone without BMLs (p < 0.001). CONCLUSIONS: Increased perfusion parameters in epimetaphyseal bone, subchondral bone and BMLs are observed in unicompartmental knee OA. BMLs likely account for most of the effect of the higher bone perfusion in knee OA.

T2 mapping of the meniscus is a biomarker for early osteoarthritis.

PURPOSE: To evaluate in vivo T2 mapping as quantitative, imaging-based biomarker for meniscal degeneration in humans, by studying the correlation between T2 relaxation time and degree of histological degeneration as reference standard. METHODS: In this prospective validation study, 13 menisci from seven patients with radiographic knee osteoarthritis (median age 67 years, three males) were included. Menisci were obtained during total knee replacement surgery. All patients underwent pre-operative magnetic resonance imaging using a 3-T MR scanner which included a T2 mapping pulse sequence with multiple echoes. Histological analysis of the collected menisci was performed using the Pauli score, involving surface integrity, cellularity, matrix organization, and staining intensity. Mean T2 relaxation times were calculated in meniscal regions of interest corresponding with the areas scored histologically, using a multi-slice multi-echo postprocessing algorithm. Correlation between T2 mapping and histology was assessed using a generalized least squares model fit by maximum likelihood. RESULTS: The mean T2 relaxation time was 22.4 ± 2.7 ms (range 18.5-27). The median histological score was 10, IQR 7-11 (range 4-13). A strong correlation between T2 relaxation time and histological score was found (rs = 0.84, CI 95% 0.64-0.93). CONCLUSION: In vivo T2 mapping of the human meniscus correlates strongly with histological degeneration, suggesting that T2 mapping enables the detection and quantification of early compositional changes of the meniscus in knee OA. KEY POINTS: • Prospective histology-based study showed that in vivo T 2 mapping of the human meniscus correlates strongly with histological degeneration. • Meniscal T 2 mapping allows detection and quantifying of compositional changes, without need for contrast or special MRI hardware. • Meniscal T 2 mapping provides a biomarker for early OA, potentially allowing early treatment strategies and prevention of OA progression.

Multi-scale imaging techniques to investigate solute transport across articular cartilage.

As articular cartilage is an avascular tissue, the transport of nutrients and cytokines through the tissue is essential for the health of cells, i.e. chondrocytes. Transport of specific contrast agents through cartilage has been investigated to elucidate cartilage quality. In laboratory, pre-clinical and clinical studies, imaging techniques such as magnetic imaging resonance (MRI), computed tomography (CT) and fluorescent microscopy have been widely employed to visualize and quantify solute transport in cartilage. Many parameters related to the physico-chemical properties of the solute, such as molecular weight, net charge and chemical structure, have a profound effect on the transport characteristics. Information on the interplay of the solute parameters with the imaging-dependent parameters (e.g. resolution, scan and acquisition time) could assist in selecting the most optimal imaging systems and data analysis tools in a specific experimental set up. Here, we provide a comprehensive review of various imaging systems to investigate solute transport properties in articular cartilage, by discussing their potentials and limitations. The presented information can serve as a guideline for applications in cartilage imaging and therapeutics delivery and to improve understanding of the set-up of solute transport experiments in articular cartilage.

No Difference on Quantitative Magnetic Resonance Imaging in Patellofemoral Cartilage Composition Between Patients With Patellofemoral Pain and Healthy Controls.

BACKGROUND: Retropatellar cartilage damage has been suggested as an etiological factor for patellofemoral pain (PFP), a common knee condition among young and physically active individuals. To date, there is no conclusive evidence for an association between cartilage defects and PFP. Nowadays, advanced quantitative magnetic resonance imaging (MRI) techniques enable estimation of cartilage composition. PURPOSE: To investigate differences in patellofemoral cartilage composition between patients with PFP and healthy control subjects using quantitative MRI. STUDY DESIGN: Cross-sectional study; Level of evidence, 3. METHODS: Patients with PFP and healthy control subjects underwent 3.0-T MRI including delayed gadolinium-enhanced MRI of cartilage and T1ρ and T2 mapping. Differences in relaxation times of patellofemoral cartilage were compared between groups by linear regression analyses, adjusted for age, body mass index, sex, sports participation, and time of image acquisition. RESULTS: This case-control study included 64 patients and 70 controls. The mean (±SD) age was 23.2 ± 6.4 years and the mean body mass index was 22.9 ± 3.4 kg/m(2); 56.7% were female. For delayed gadolinium-enhanced MRI of cartilage, the mean T1GD relaxation times of patellar (657.8 vs 669.4 ms) and femoral cartilage (661.6 vs 659.8 ms) did not significantly differ between patients and controls. In addition, no significant difference was found in mean T1ρ relaxation times of patellar (46.9 vs 46.0 ms) and femoral cartilage (50.8 vs 50.2 ms) and mean T2 relaxation times of patellar (33.2 vs 32.9 ms) and femoral cartilage (36.7 vs 36.6 ms) between patients and controls. Analysis of prespecified medial and lateral subregions within the patellofemoral cartilage also revealed no significant differences. CONCLUSION: There was no difference in composition of the patellofemoral cartilage, estimated with multiple quantitative MRI techniques, between patients with PFP and healthy control subjects. However, clinically relevant differences could not be ruled out for T1ρ in the adolescent population. Retropatellar cartilage damage has long been hypothesized as an important factor in the pathogenesis of PFP, but study findings suggest that diminished patellofemoral cartilage composition is not associated with PFP.

Is T1ρ Mapping an Alternative to Delayed Gadolinium-enhanced MR Imaging of Cartilage in the Assessment of Sulphated Glycosaminoglycan Content in Human Osteoarthritic Knees? An in Vivo Validation Study.

PURPOSE: To determine if T1ρ mapping can be used as an alternative to delayed gadolinium-enhanced magnetic resonance imaging of cartilage (dGEMRIC) in the quantification of cartilage biochemical composition in vivo in human knees with osteoarthritis. MATERIALS AND METHODS: This study was approved by the institutional review board. Written informed consent was obtained from all participants. Twelve patients with knee osteoarthritis underwent dGEMRIC and T1ρ mapping at 3.0 T before undergoing total knee replacement. Outcomes of dGEMRIC and T1ρ mapping were calculated in six cartilage regions of interest. Femoral and tibial cartilages were harvested during total knee replacement. Cartilage sulphated glycosaminoglycan (sGAG) and collagen content were assessed with dimethylmethylene blue and hydroxyproline assays, respectively. A four-dimensional multivariate mixed-effects model was used to simultaneously assess the correlation between outcomes of dGEMRIC and T1ρ mapping and the sGAG and collagen content of the articular cartilage. RESULTS: T1 relaxation times at dGEMRIC showed strong correlation with cartilage sGAG content (r = 0.73; 95% credibility interval [CI] = 0.60, 0.83) and weak correlation with cartilage collagen content (r = 0.40; 95% CI: 0.18, 0.58). T1ρ relaxation times did not correlate with cartilage sGAG content (r = 0.04; 95% CI: -0.21, 0.28) or collagen content (r = -0.05; 95% CI = -0.31, 0.20). CONCLUSION: dGEMRIC can help accurately measure cartilage sGAG content in vivo in patients with knee osteoarthritis, whereas T1ρ mapping does not appear suitable for this purpose. Although the technique is not completely sGAG specific and requires a contrast agent, dGEMRIC is a validated and robust method for quantifying cartilage sGAG content in human osteoarthritis subjects in clinical research.

Delayed gadolinium-enhanced MRI of the meniscus (dGEMRIM) in patients with knee osteoarthritis: relation with meniscal degeneration on conventional MRI, reproducibility, and correlation with dGEMRIC.

OBJECTIVES: To assess (1) whether normal and degenerated menisci exhibit different T1GD on delayed gadolinium-enhanced MRI of the meniscus (dGEMRIM), (2) the reproducibility of dGEMRIM and (3) the correlation between meniscus and cartilage T1GD in knee osteoarthritis (OA) patients. METHODS: In 17 OA patients who underwent dGEMRIM twice within 7 days, meniscus and cartilage T1GD was calculated. Meniscus pathology was evaluated on conventional MRI. T1GD in normal and degenerated menisci were compared using a Student's t-test. Reproducibility was assessed using ICCs. Pearson's correlation was calculated between meniscus and cartilage T1GD. RESULTS: A trend towards lower T1GD in degenerated menisci (mean: 402 ms; 95% CI: 359-444 ms) compared to normal menisci (mean: 448 ms; 95% CI: 423-473 ms) was observed (p = 0.05). Meniscus T1GD ICCs were 0.85-0.90. The correlation between meniscus and cartilage T1GD was moderate in the lateral (r = 0.52-0.75) and strong in the medial compartment (r = 0.78-0.94). CONCLUSIONS: Our results show that degenerated menisci have a clear trend towards lower T1GD compared to normal menisci. Since these results are highly reproducible, meniscus degeneration may be assessed within one delayed gadolinium-enhanced MRI simultaneously with cartilage. The strong correlation between meniscus and cartilage T1GD suggests concomitant degeneration in both tissues in OA, but also suggests that dGEMRIC may not be regarded entirely as sulphated glycosaminoglycan specific. KEY POINTS: dGEMRIM T1 GD can possibly be used to assess meniscal degeneration; dGEMRIM yields highly reproducible meniscal T1 GD in early stage osteoarthritic patients; Concomitant degeneration of cartilage and meniscus tissue occurs in early stage osteoarthritis; dGEMRIC cannot be regarded as entirely sulphated glycosaminoglycan specific.

Delayed gadolinium-enhanced MRI of cartilage (dGEMRIC) shows no change in cartilage structural composition after viscosupplementation in patients with early-stage knee osteoarthritis.

INTRODUCTION: Viscosupplementation with hyaluronic acid (HA) of osteoarthritic (OA) knee joints has a well-established positive effect on clinical symptoms. This effect, however, is only temporary and the working mechanism of HA injections is not clear. It was suggested that HA might have disease modifying properties because of its beneficial effect on cartilage sulphated glycosaminoglycan (sGAG) content. Delayed gadolinium-enhanced MRI of cartilage (dGEMRIC) is a highly reproducible, non-invasive surrogate measure for sGAG content and hence composition of cartilage. The aim of this study was to assess whether improvement in cartilage structural composition is detected using dGEMRIC 14 weeks after 3 weekly injections with HA in patients with early-stage knee OA. METHODS: In 20 early-stage knee OA patients (KLG I-II), 3D dGEMRIC at 3T was acquired before and 14 weeks after 3 weekly injections with HA. To evaluate patient symptoms, the knee injury and osteoarthritis outcome score (KOOS) and a numeric rating scale (NRS) for pain were recorded. To evaluate cartilage composition, six cartilage regions in the knee were analyzed on dGEMRIC. Outcomes of dGEMRIC, KOOS and NRS before and after HA were compared using paired t-testing. Since we performed multiple t-tests, we applied a Bonferroni-Holm correction to determine statistical significance for these analyses. RESULTS: All KOOS subscales ('pain', 'symptoms', 'daily activities', 'sports' and 'quality of life') and the NRS pain improved significantly 14 weeks after Viscosupplementation with HA. Outcomes of dGEMRIC did not change significantly after HA compared to baseline in any of the cartilage regions analyzed in the knee. CONCLUSIONS: Our results confirm previous findings reported in the literature, showing persisting improvement in symptomatic outcome measures in early-stage knee OA patients 14 weeks after Viscosupplementation. Outcomes of dGEMRIC, however, did not change after Viscosupplementation, indicating no change in cartilage structural composition as an explanation for the improvement of clinical symptoms.

[Quantitative measurement of articular cartilage quality using MRI]. / Meting van kraakbeenkwaliteit met behulp van MRI.

'Delayed gadolinium-enhanced MRI of cartilage' (dGEMRIC) and 'T2 mapping' are novel MRI techniques to quantitatively measure the quality of articular cartilage. The advantage of these novel techniques is that they are able to detect the loss of important composites of cartilage before damage to and deformities of the cartilage become visible on radiographs or on conventional MRI. These novel MRI techniques can be used to investigate the effectiveness of potentially preventative or disease-modifying therapy at an early stage of cartilage disease, e.g. in osteoarthritis. It is possible that in the future dGEMRIC and T2 mapping will be used in routine clinical practice to diagnose osteoarthritis at an earlier stage and to predict disease progression. However, much more research is still needed. At the Erasmus Medical Center in Rotterdam, the Netherlands, work is being carried out on the validation, implementation and translation into clinical practice of these and other novel techniques of quantitative measurement of cartilage quality.

Quantitative MRI techniques of cartilage composition.

Due to aging populations and increasing rates of obesity in the developed world, the prevalence of osteoarthritis (OA) is continually increasing. Decreasing the societal and patient burden of this disease motivates research in prevention, early detection of OA, and novel treatment strategies against OA. One key facet of this effort is the need to track the degradation of tissues within joints, especially cartilage. Currently, conventional imaging techniques provide accurate means to detect morphological deterioration of cartilage in the later stages of OA, but these methods are not sensitive to the subtle biochemical changes during early disease stages. Novel quantitative techniques with magnetic resonance imaging (MRI) provide direct and indirect assessments of cartilage composition, and thus allow for earlier detection and tracking of OA. This review describes the most prominent quantitative MRI techniques to date-dGEMRIC, T2 mapping, T1rho mapping, and sodium imaging. Other, less-validated methods for quantifying cartilage composition are also described-Ultrashort echo time (UTE), gagCEST, and diffusion-weighted imaging (DWI). For each technique, this article discusses the proposed biochemical correlates, as well its advantages and limitations for clinical and research use. The article concludes with a detailed discussion of how the field of quantitative MRI has progressed to provide information regarding two specific patient populations through clinical research-patients with anterior cruciate ligament rupture and patients with impingement in the hip. While quantitative imaging techniques continue to rapidly evolve, specific challenges for each technique as well as challenges to clinical applications remain.

No effect of hole geometry in microfracture for talar osteochondral defects.

BACKGROUND: Débridement and bone marrow stimulation is an effective treatment option for patients with talar osteochondral defects. However, whether surgical factors affect the success of microfracture treatment of talar osteochondral defects is not well characterized. QUESTIONS/PURPOSES: We hypothesized (1) holes that reach deeper into the bone marrow-filled trabecular bone allow for more hyaline-like repair; and (2) a larger number of holes with a smaller diameter result in more solid integration of the repair tissue, less need for new bone formation, and higher fill of the defect. METHODS: Talar osteochondral defects that were 6 mm in diameter were drilled bilaterally in 16 goats (32 samples). In eight goats, one defect was treated by drilling six 0.45-mm diameter holes in the defect 2 mm deep; in the remaining eight goats, six 0.45-mm diameter holes were punctured to a depth of 4 mm. All contralateral defects were treated with three 1.1-mm diameter holes 3 mm deep, mimicking the clinical situation, as internal controls. After 24 weeks, histologic analyses were performed using Masson-Goldner/Safranin-O sections scored using a modified O'Driscoll histologic score (scale, 0-22) and analyzed for osteoid deposition. Before histology, repair tissue quality and defect fill were assessed by calculating the mean attenuation repair/healthy cartilage ratio on Equilibrium Partitioning of an Ionic Contrast agent (EPIC) micro-CT (µCT) scans. Differences were analyzed by paired comparison and Mann-Whitney U tests. RESULTS: Significant differences were not present between the 2-mm and 4-mm deep hole groups for the median O'Driscoll score (p = 0.31) and the median of the µCT attenuation repair/healthy cartilage ratios (p = 0.61), nor between the 0.45-mm diameter and the 1.1-mm diameter holes in defect fill (p = 0.33), osteoid (p = 0.89), or structural integrity (p = 0.80). CONCLUSIONS: The results indicate that the geometry of microfracture holes does not influence cartilage healing in the caprine talus. CLINICAL RELEVANCE: Bone marrow stimulation technique does not appear to be improved by changing the depth or diameter of the holes.

Image registration improves human knee cartilage T1 mapping with delayed gadolinium-enhanced MRI of cartilage (dGEMRIC).

OBJECTIVES: To evaluate the effect of automated registration in delayed gadolinium-enhanced MRI of cartilage (dGEMRIC) of the knee on the occurrence of movement artefacts on the T1 map and the reproducibility of region-of-interest (ROI)-based measurements. METHODS: Eleven patients with early-stage knee osteoarthritis and ten healthy controls underwent dGEMRIC twice at 3 T. Controls underwent unenhanced imaging. ROIs were manually drawn on the femoral and tibial cartilage. T1 calculation was performed with and without registration of the T1-weighted images. Automated three-dimensional rigid registration was performed on the femur and tibia cartilage separately. Registration quality was evaluated using the square root Cramér-Rao lower bound (CRLB(σ)). Additionally, the reproducibility of dGEMRIC was assessed by comparing automated registration with manual slice-matching. RESULTS: Automated registration of the T1-weighted images improved the T1 maps as the 90% percentile of the CRLB(σ) was significantly (P < 0.05) reduced with a median reduction of 55.8 ms (patients) and 112.9 ms (controls). Manual matching and automated registration of the re-imaged T1 map gave comparable intraclass correlation coefficients of respectively 0.89/0.90 (patients) and 0.85/0.85 (controls). CONCLUSIONS: Registration in dGEMRIC reduces movement artefacts on T1 maps and provides a good alternative to manual slice-matching in longitudinal studies.