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ObjectiveTo identify joint structural risk factors, measured using quantitative compositional and semiquantitative magnetic resonance imaging (MRI) scoring, associated with the development of accelerated knee osteoarthritis (AKOA) compared with a more normal rate of knee osteoarthritis (OA) development.DesignFrom the Osteoarthritis Initiative we selected knees with no radiographic OA (Kellgren-Lawrence grade [KL] 0/1) that developed advanced-stage OA (KL 3/4; AKOA) within a 4-year timeframe and a comparison group with a more normal rate of OA development (KL 0/1 to KL 2 in 4 years). MRIs at the beginning of the 4-year timeframe were assessed for cartilage T2 values and structural abnormalities using a modified Whole-Organ Magnetic Resonance Imaging Score (WORMS). Associations of MRI findings with AKOA versus normal OA were assessed using multivariable logistic regression models.ResultsA total of 106 AKOA and 168 subjects with normal OA development were included. Mean cartilage T2 values were not significantly associated with AKOA (odds ratio [OR] 1.06; 95% confidence interval [CI] 0.82-1.36). Risk factors for AKOA development included higher meniscus maximum scores (OR 1.37; 95% CI 1.11-1.68), presence of meniscal extrusion (OR 6.30; 95% CI 2.57-15.49), presence of root tears (OR 4.64; 95% CI 1.61-13.34), and higher medial tibia cartilage lesion scores (OR 1.96; 95% CI 1.19-3.24).ConclusionsWe identified meniscal damage, especially meniscal extrusion and meniscal root tears as risk factors for AKOA development. These findings contribute to identifying subjects at risk of AKOA at an early stage when preventative measures targeting modifiable risk factors such as meniscal repair surgery could still be effective.

ObjectiveMeniscal degeneration is strongly associated with osteoarthritis (OA). We aimed to evaluate a 3D ultrashort-echo-time Cones magnetization transfer (UTE-Cones-MT) sequence for quantification of macromolecular fraction (MMF) and MT ratio (MTR) in menisci of healthy volunteers and patients with different degrees of OA.MethodsPatients with mild OA (n = 19; 37-86 years; 10 males) or advanced OA (n = 12; 52-88 years; 4 males) and healthy volunteers (n = 17; 20-49 years; 7 males) were scanned with T2-FSE and UTE-Cones-MT sequences at 3T. Morphological assessment was performed using meniscal whole-organ magnetic resonance imaging score (WORMS). MMF and MTR were calculated for menisci, and correlated with age and meniscal WORMS scores. The diagnostic efficiency was performed by using receiver operating characteristic (ROC) curve and the area under the curve (AUC) analyses.ResultsDecreased MMF and MTR were observed in menisci of patients with mild or advanced OA compared with healthy subjects, and in menisci with tears (Grade 2-4) compared with normal menisci (Grade 0). Significant negative correlations were observed between MMF (r = -0.769, P

ObjectiveTo evaluate the association of fatty infiltration of the quadriceps and vastus medialis (VM) with an increase in knee cartilage, meniscus, or bone marrow lesions, using magnetic resonance imaging (MRI) in knee osteoarthritis (OA) over 3 years.MethodsParticipants (n = 69) with and without radiographic knee OA underwent MRI at baseline and 3 years later. Chemical shift-based water/fat MRI was used to quantify the intramuscular fat fraction and the lean anatomical cross-sectional area (ACSA) for the VM and entire quadriceps muscles. MRI images of the knee were analyzed using the semiquantitative modified whole-organ MRI score (mWORMS) grading to assess change in lesions in the articular cartilage, meniscus, and bone marrow. Logistic regression was used to assess whether baseline quadriceps and VM fat fraction and lean ACSA were associated with an increase in mWORMS scores. Odds ratios (ORs) were adjusted for age, sex, and body mass index.ResultsOverall, of the 69 subjects, 43 (62%) had an increase in cartilage lesions (26 of 43), meniscus lesions (19 of 43), or bone marrow lesions (22 of 43) scores. The quadriceps (OR 2.13 [95% confidence interval (95% CI) 1.09-4.15]) and VM (OR 2.05 [95% CI 1.25-3.36]) fat fraction were both associated with an increase in cartilage, meniscus, or bone marrow lesion scores over 3 years. The association of quadriceps or VM lean ACSA with the outcomes was not significant.ConclusionThese longitudinal findings using quantitative MRI methods for assessment of muscle adiposity highlight the role of quadriceps adiposity, specifically in the VM, in knee OA progression. However, studies in larger cohorts are needed to confirm these findings.

BACKGROUND. The extent of medial meniscal extrusion (MME) that is associated with structural and symptomatic progression of knee osteoarthritis has not been defined yet. OBJECTIVE. The purpose of our study was to investigate MRI-based thresholds of MME that are associated with structural progression of knee degenerative disease and symptoms over a period of 4 years. METHODS. We studied 328 knees of 235 participants that were randomly selected from the Osteoarthritis Initiative cohort. MME was quantified on coronal sections of intermediate-weighted MRI sequences obtained at 3 T. Knee pain and cartilage abnormalities were measured using the Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC) pain scale and the cartilage whole-organ MRI score (WORMS). General estimating equations with logistic regression models were used to correlate baseline MME and changes in pain (WOMAC) and cartilage damage (WORMS). ROC analyses were performed to determine the area under the ROC curve (AUROC). Individual thresholds were determined by maximizing the product of sensitivity and specificity. RESULTS. The AUROC for predicting progression of knee pain, medial compartment cartilage damage, and medial tibial cartilage damage were 0.71, 0.70, and 0.72, respectively, and the individual thresholds for MME were 2.5, 2.7, and 2.8 mm. A single threshold of 2.5 mm was determined by maximizing the mean of the product of sensitivity and specificity of the three outcome variables (knee pain progression, medial compartmental cartilage damage progression, and medial tibial cartilage damage progression). CONCLUSION. MME was associated with knee pain and cartilage damage progression over 4 years. A single threshold of 2.5 mm was found to be the most useful threshold for predicting knee pain, medial compartment cartilage damage progression, and tibial cartilage damage progression over 4 years. CLINICAL IMPACT. This threshold could be used to standardize the diagnostic criterion of extrusion and to better characterize the risk for subsequent structural and symptomatic progression of knee osteoarthritis.

ObjectiveTransforming growth factor β (TGFβ) signaling plays a complex tissue-specific and nonlinear role in osteoarthritis (OA). This study was conducted to determine the osteocytic contributions of TGFβ signaling to OA.MethodsTo identify the role of osteocytic TGFβ signaling in joint homeostasis, we used 16-week-old male mice (n = 9-11 per group) and female mice (n = 7-11 per group) with an osteocyte-intrinsic ablation of TGFβ receptor type II (TβRIIocy-/- mice) and assessed defects in cartilage degeneration, subchondral bone plate (SBP) thickness, and SBP sclerostin expression. To further investigate these mechanisms in 16-week-old male mice, we perturbed joint homeostasis by subjecting 8-week-old mice to medial meniscal/ligamentous injury (MLI), which preferentially disrupts the mechanical environment of the medial joint to induce OA.ResultsIn all contexts, independent of sex, genotype, or medial or lateral joint compartment, increased SBP thickness and SBP sclerostin expression were spatially associated with cartilage degeneration. Male TβRIIocy-/- mice, but not female TβRIIocy-/- mice, had increased cartilage degeneration, increased SBP thickness, and higher levels of SBP sclerostin compared with control mice (all P < 0.05), demonstrating that the role of osteocytic TGFβ signaling on joint homeostasis is sexually dimorphic. With changes in joint mechanics following injury, control mice had increased SBP thickness, subchondral bone volume, and SBP sclerostin expression (all P < 0.05). TβRIIocy-/- mice, however, were insensitive to subchondral bone changes with injury, suggesting that mechanosensation at the SBP requires osteocytic TGFβ signaling.ConclusionOur results provide new evidence that osteocytic TGFβ signaling is required for a mechanosensitive response to injury, and that osteocytes control SBP homeostasis to maintain cartilage health, identifying osteocytic TGFβ signaling as a novel therapeutic target for OA.

PurposeTo develop a deep learning-based method for knee menisci segmentation in 3D ultrashort echo time (UTE) cones MR imaging, and to automatically determine MR relaxation times, namely the T1, T1ρ , and T2∗ parameters, which can be used to assess knee osteoarthritis (OA).MethodsWhole knee joint imaging was performed using 3D UTE cones sequences to collect data from 61 human subjects. Regions of interest (ROIs) were outlined by 2 experienced radiologists based on subtracted T1ρ -weighted MR images. Transfer learning was applied to develop 2D attention U-Net convolutional neural networks for the menisci segmentation based on each radiologist's ROIs separately. Dice scores were calculated to assess segmentation performance. Next, the T1, T1ρ , T2∗ relaxations, and ROI areas were determined for the manual and automatic segmentations, then compared.ResultsThe models developed using ROIs provided by 2 radiologists achieved high Dice scores of 0.860 and 0.833, while the radiologists' manual segmentations achieved a Dice score of 0.820. Linear correlation coefficients for the T1, T1ρ , and T2∗ relaxations calculated using the automatic and manual segmentations ranged between 0.90 and 0.97, and there were no associated differences between the estimated average meniscal relaxation parameters. The deep learning models achieved segmentation performance equivalent to the inter-observer variability of 2 radiologists.ConclusionThe proposed deep learning-based approach can be used to efficiently generate automatic segmentations and determine meniscal relaxations times. The method has the potential to help radiologists with the assessment of meniscal diseases, such as OA.

ObjectiveTo compare the extent of cartilage deterioration in knees with prior meniscal resection related to trauma versus knees with resection related to degenerative disease, and to compare cartilage deterioration in knees with meniscal surgery to knees without meniscal surgery, controlling for prior knee trauma.Materials and methodsIn this cross-sectional study, we assessed cartilage deterioration in right knees of Osteoarthritis Initiative participants: (i) with meniscal surgery due to injury (n = 79); (ii) matched control knees with a prior injury but without meniscal surgery (n = 79); (iii) with meniscal surgery but without preceding injury (n = 36); and (iv) matched control knees without meniscal surgery or prior knee injury (n = 36). Cartilage composition was measured using T2 measurements derived using semi-automatic cartilage segmentation of the right. Linear regression analysis was used to compare compartmental values of T2 between groups.ResultsComparing the mean T2 values in surgical cases with and without injury our results did not show significant differences (group i vs. iii, p > 0.05). However, knees with previous meniscal surgery showed significantly (p

ObjectiveTo determine if presence of calcium-containing crystals (CaC) is associated with increased knee joint degeneration over 4 years and assess if total number of CaCs deposited is a useful measure of disease burden.DesignSeventy subjects with CaCs in right knees at baseline were selected from the Osteoarthritis Initiative and matched to 70 subjects without evidence of CaCs. T1-weighted gradient-echo sequences were used to confirm presence of CaCs and count the numbers of distinct circumscribed CaCs. Morphological abnormalities were assessed at baseline and 4-year follow-up using the modified semi-quantitative Whole-Organ Magnetic Resonance Imaging Score (WORMS). Linear regression models were used to analyze the associations between presence of CaCs at baseline and changes in WORMS and to analyze the associations between numbers of circumscribed CaCs at baseline and changes in WORMS.ResultsPresence of CaCs was associated with increased cartilage degeneration in the patella (coefficient: 0.33; 95% confidence interval (CI): 0.04-0.63), the medial femur (coefficient: 0.51; 95% CI: 0.18-0.83), the lateral tibia (coefficient: 0.36; 95% CI: 0.01-0.71) as well as the medial and lateral meniscus (coefficient: 0.38; 95% CI: 0.00-0.75 and coefficient: 0.72; 95% CI: 0.12-1.32). Knees with higher numbers of CaCs had increased cartilage degeneration in the patella and medial femur (coefficient: 0.09; 95% CI: 0.05-0.14; P

ObjectiveTo determine if radiographic medial tibiofemoral offset (MTFO) is associated with: (1) magnetic resonance imaging (MRI) pathology of cartilage, meniscus, and ligament; and (2) a distinct pattern of lateral cartilage degeneration on MRI.Materials and methodsThree hundred consecutive adult knee MRIs with anteroposterior (AP) radiographs were retrospectively reviewed, and 145 studies were included. MTFO was defined as a medial extension of the medial femoral condyle beyond the articular surface of the medial tibial plateau on weight-bearing AP radiographs. The patients were then divided into the MTFO (n = 61) or no-offset (n = 84) groups. On MRI data obtained on a 1.5-Tesla system, articular cartilage of the femoral condyle and tibial plateau were graded using a modified Outerbridge classification (36 sub-regions similar to whole-organ MRI Score (WORMS) system). In addition, MR pathology of the ACL, MCL, LCL, medial and lateral menisci, were determined.ResultsSignificantly increased (ANOVA p

ObjectivesTo develop an MR-based semi-quantitative meniscus scoring technique for postoperative assessment of the degree of meniscal resection, to test its reproducibility, and to study the relationship between the amount of resection and degenerative disease burden.MethodsWe studied the right knee of 135 participants from the Osteoarthritis Initiative that underwent meniscal surgery an average of 14 years previously. The amount of meniscal resection was assessed on baseline 3.0-T MRIs and calculated as meniscus resection score (MenRS) with a range of 0 to 18. Knee abnormalities at baseline and 48 months were graded using a modified Whole-Organ Magnetic Resonance Imaging Score (WORMS). Subjects were also stratified according to meniscal resection performed after injury versus without preceding injury. Statistical analysis included intra-class correlation coefficient (ICC) to determine reproducibility as well as regression models and partial correlations to correlate MenRS with WORMS outcomes.ResultsICC values for intra- and inter-observer reproducibility of MenRS were 0.980 and 0.977, respectively. Overall, the amount of meniscal resection showed a significant correlation with baseline WORMS grades: higher MenRS was associated with higher total WORMS grades (p = 0.004) and cartilage (p = 0.004) and ligament (p

OBJECTIVE:To determine the relationship of meniscal damage to magnetic resonance imaging (MRI) features of compartment-specific patellofemoral joint (PFJ) osteoarthritis (OA) at baseline and 2 years later. METHOD:Individuals from a prospective cohort of individuals aged 50-79 with or at risk of knee OA were included. At the 60-month and 84-month study visit, Whole-Organ MRI Score (WORMS) was used to assess meniscal tears and extrusions as well as cartilage damage and bone marrow lesions (BMLs) in the medial and lateral patella and trochlea. Worsening of structural features was defined as any increase in WORMS score from 60 to 84 months. Logistic regression was used to determine the cross-sectional and longitudinal relation of meniscus damage to features of compartment-specific PFJ OA. RESULTS:Relative to knees without lateral meniscal pathology at baseline, those with grades 3-4 lateral meniscal tear and extrusion had greater risk of worsening of cartilage damage in the lateral PFJ 2 years later (Risk ratio: 1.7 [95% CI: 1.1-2.7) and (1.7 [1.2-2.5]), respectively. Relative to those without medial meniscal pathology at baseline, those with grades 1-2 (0.6 [0.4-0.9]) and 3-4 (0.7 [0.5-1.0]) medial meniscal tears had lower risk of worsening of BMLs in the medial PFJ 2 years later. CONCLUSION:Meniscal tear and extrusion are associated with increased risk of medial and lateral PFJ OA and more severe meniscal pathology is associated with worsening of PFJ OA 2 years later. Lateral meniscal pathology appears to be more detrimental to the lateral PFJ.

ObjectiveTo evaluate the longitudinal changes in meniscal T1ρ/T2 signal post-reconstruction in patients with acute anterior cruciate ligament (ACL) injury and to investigate the association with T1ρ/T2 signal in articular knee cartilage.MethodIn this prospective study, knees of 37 patients with ACL-injury and reconstruction in addition to 13 healthy controls were scanned using magnetic resonance imaging (MRI) T1ρ/T2 mapping. Quantitative analysis of the meniscus was performed in the anterior/posterior horns of lateral/medial meniscus fourteen sub-compartments of cartilage spanning the medial/lateral area of the tibia and femoral condyles. Meniscus T1ρ/T2 signals were compared between injured, contralateral and control knees at baseline, 6-months, 1-year and 2-years using t-tests for cross-sectional comparisons and a mixed model for longitudinal comparisons. Pearson-partial correlations between meniscal and cartilage T1ρ/T2 were evaluated.ResultsThere was a significant decrease of T1ρ/T2 signal in the posterior horn of lateral meniscus (PHLAT) of injured knees during a 2-year period. In the posterior horn of medial meniscus (PHMED), T1ρ/T2 signal of injured knees was significantly elevated at all time points post-reconstruction compared to contralateral and control knees. Within injured knees, PHMED T1ρ/T2 signal showed significant positive correlations with medial tibia (MT) cartilage T1ρ/T2 signal at all time points.ConclusionA significant decrease in PHLAT T1ρ/T2 signal by 2-years suggests potential tissue recovery after ACL-injury. Elevated T1ρ/T2 signal in the PHMED of injured knees at 2-years correlating with knee cartilage T1ρ/T2 signal elevations suggests involvement of the PHMED in subacute cartilage degeneration after ACL-injury and reconstruction.

BackgroundArticular cartilage health is an important issue following anterior cruciate ligament (ACL) injury and primary ACL reconstruction. Factors present at the time of primary ACL reconstruction may influence the subsequent progression of articular cartilage damage.HypothesisLarger meniscus resection at primary ACL reconstruction, increased patient age, and increased body mass index (BMI) are associated with increased odds of worsened articular cartilage damage at the time of revision ACL reconstruction.Study designCase-control study; Level of evidence, 3.MethodsSubjects who had primary and revision data in the databases of the Multicenter Orthopaedics Outcomes Network (MOON) and Multicenter ACL Revision Study (MARS) were included. Reviewed data included chondral surface status at the time of primary and revision surgery, meniscus status at the time of primary reconstruction, primary reconstruction graft type, time from primary to revision ACL surgery, as well as demographics and Marx activity score at the time of revision. Significant progression of articular cartilage damage was defined in each compartment according to progression on the modified Outerbridge scale (increase ≥1 grade) or >25% enlargement in any area of damage. Logistic regression identified predictors of significant chondral surface change in each compartment from primary to revision surgery.ResultsA total of 134 patients were included, with a median age of 19.5 years at revision surgery. Progression of articular cartilage damage was noted in 34 patients (25.4%) in the lateral compartment, 32 (23.9%) in the medial compartment, and 31 (23.1%) in the patellofemoral compartment. For the lateral compartment, patients who had >33% of the lateral meniscus excised at primary reconstruction had 16.9-times greater odds of progression of articular cartilage injury than those with an intact lateral meniscus ( P < .001). For the medial compartment, patients who had

ObjectivesTo investigate the association of weight change over 48 months with progression of meniscal intrasubstance degeneration (MID).MethodsWe studied 487 subjects with MID at baseline and after 48 months using 3-T MRI with the same protocol (FSE sequences with and without fat suppression). These participants lost weight (≥3%, n = 141), had moderate weight gain (3-10%, n = 77), substantial weight gain (>10%, n = 15) or maintained stable weight (n = 254). Progression of MID to a meniscal tear was assessed using the WORMS grading system and compared among weight change groups using logistic regression. ANOVA and chi-square tests were used to study the differences in subjects' characteristics.ResultsProgression of MID increased from weight loss to substantial weight gain (p < 0.001) and was significantly more likely with both moderate weight gain (odds ratio [OR], 4.9; 95% confidence interval [CI] 2.4-8.9) and substantial weight gain (OR, 9.5; 95% CI 3.2-28.5) compared to stable weight. Results were similar in both menisci for moderate weight gain (medial: OR, 6.8; 95% CI 3.5-11.3; lateral: OR, 2.6; 95% CI 1.1-6.6) and substantial weight gain (medial: OR, 21.0; 95% CI 5.1-80.7; lateral: OR, 9.7; 95% CI 0.95-100.2).ConclusionWeight gain is associated with an increased likelihood that meniscal intrasubstance degeneration will progress with the risk increasing with greater weight gain.Key points• Subjects who gained weight were more likely to develop meniscal tears. • Greater amount of weight gain was associated with an increasing likelihood of progression. • Prevention of weight gain has health benefits for the meniscus.

BackgroundPrior studies describe histological and immunohistochemical differences in collagen and proteoglycan content in different meniscal zones. The aim of this study is to evaluate horizontal and vertical zonal differentiation of T1rho and T2 relaxation times of the entire meniscus from volunteers without symptom and imaging abnormality.MethodsTwenty volunteers age between 19 and 38 who have no knee-related clinical symptoms, and no history of prior knee surgeries were enrolled in this study. Two T1rho mapping (b-FFE T1rho and SPGR T1rho) and T2 mapping images were acquired with a 3.0-T MR scanner. Each meniscus was divided manually into superficial and deep zones for horizontal zonal analysis. The anterior and posterior horns of each meniscus were divided manually into white, red-white and red zones for vertical zonal analysis. Zonal differences of average relaxation times among each zone, and both inter- and intra-observer reproducibility were statistically analyzed.ResultsIn horizontal zonal analysis, T1rho relaxation times of the superficial zone tended to be higher than those of the deep zone, and this difference was statistically significant in the medial meniscal segments (84.3 ms vs 76.0 ms on b-FFE, p 0.74) or good (0.60-0.74) in all meniscal segments on both horizontal and vertical zonal analysis, except for inter-class correlation coefficients of the lateral meniscus on SPGR. Compared with SPGR T1rho images, b-FFE T1rho images demonstrated more significant zonal differentiation with higher inter- and intra-observer reproducibility.ConclusionsThere are zonal differences in T1rho and T2 relaxation times of the normal meniscus.

ObjectiveTo assess the ability of matriptase, a type II transmembrane serine proteinase, to promote aggrecan loss from the cartilage of patients with osteoarthritis (OA) and to determine whether its inhibition can prevent aggrecan loss and cartilage damage in experimental OA.MethodsAggrecan release from human OA cartilage explants and human stem cell-derived cartilage discs was evaluated, and cartilage-conditioned media were used for Western blotting. Gene expression was analyzed by real-time polymerase chain reaction. Murine OA was induced by surgical destabilization of the medial meniscus, and matriptase inhibitors were administered via osmotic minipump or intraarticular injection. Cartilage damage was scored histologically and aggrecan cleavage was visualized immunohistochemically using specific neoepitope antibodies.ResultsThe addition of soluble recombinant matriptase promoted a time-dependent release of aggrecan (and collagen) from OA cartilage, which was sensitive to metalloproteinase inhibition and protease-activated receptor 2 antagonism. Although engineered human (normal) cartilage discs failed to release aggrecan following matriptase addition, both matrix metalloproteinase- and aggrecanase-mediated cleavages of aggrecan were detected in human OA cartilage. Additionally, while matriptase did not directly degrade aggrecan, it promoted the accumulation of low-density lipoprotein receptor-related protein 1 (LRP-1) in conditioned media of the OA cartilage explants. Matriptase inhibition via neutralizing antibody or small molecule inhibitor significantly reduced cartilage damage scores in murine OA, which was associated with reduced generation of metalloproteinase-mediated aggrecan cleavage.ConclusionMatriptase potently induces the release of metalloproteinase-generated aggrecan fragments as well as soluble LRP-1 from OA cartilage. Therapeutic targeting of matriptase proteolytic activity reduces metalloproteinase activity, further suggesting that this serine proteinase may have potential as a disease-modifying therapy in OA.

ObjectiveThe aim of this study was to assess cross-sectional and longitudinal effects of meniscal lesions on adjacent cartilage T1ρ and T2 relaxation times, patient-reported outcomes and gait biomechanics.DesignThirty patients with no cartilage morphological defects reported by Whole Organ MRI Score (WORMS) magnetic resonance imaging (MRI) grading and no radiographic osteoarthritis (OA) (Kellgren--Lawrence (KL) ≤ 1) were selected, 15 with posterior meniscus horn lesions and 15 matched controls without meniscal lesions. All were imaged on a 3T MR scanner for three consecutive years, except those who dropped from the study. Sagittal and frontal plane kinematic gait data were acquired at baseline. The Knee Injury and Osteoarthritis Outcome Score (KOOS) survey was taken each time. All images were automatically segmented and registered to an atlas for voxel-by-voxel cross-sectional and longitudinal analyses.ResultsRelaxation time comparisons between groups showed elevated T1ρ of the lateral tibia (LP) and elevated T2 of the medial tibia (MT) and LT at 1 and 2 years in the lesion group. Longitudinal comparisons within each group revealed greater relaxation time elevations over one and 2 years in the group with lesions. KOOS Quality of Life (QOL) was significantly different between the groups at all time points (P

BackgroundTo describe the scoring methodology and MRI assessments used to evaluate the cross-sectional features observed in cases and controls, to define change over time for different MRI features, and to report the extent of changes over a 24-month period in the Foundation for National Institutes of Health Osteoarthritis Biomarkers Consortium study nested within the larger Osteoarthritis Initiative (OAI) Study.MethodsWe conducted a nested case-control study. Cases (n = 406) were knees having both radiographic and pain progression. Controls (n = 194) were knee osteoarthritis subjects who did not meet the case definition. Groups were matched for Kellgren-Lawrence grade and body mass index. MRIs were acquired using 3 T MRI systems and assessed using the semi-quantitative MOAKS system. MRIs were read at baseline and 24 months for cartilage damage, bone marrow lesions (BML), osteophytes, meniscal damage and extrusion, and Hoffa- and effusion-synovitis. We provide the definition and distribution of change in these biomarkers over time.ResultsSeventy-three percent of the cases had subregions with BML worsening (vs. 66 % in controls) (p = 0.102). Little change in osteophytes was seen over 24 months. Twenty-eight percent of cases and 10 % of controls had worsening in meniscal scores in at least one subregion (p

ObjectiveHigh knee extensor strength may be important to protect against the development of knee osteoarthritis (OA) in populations at elevated risk, such as individuals with meniscal pathology. We investigated the extent to which high knee extensor muscle strength was associated with a decreased risk of developing radiographic or symptomatic knee OA in individuals with medial meniscal pathology.MethodsWe studied knees that at the baseline visit of the Multicenter Osteoarthritis Study had medial meniscal pathology but did not have radiographic knee OA (373 knees in 373 participants) or symptomatic knee OA (combination of radiographic knee OA and frequent knee symptoms; 531 knees in 531 participants). Isokinetic knee extensor strength was measured at baseline, and participants were followed for development of incident radiographic knee OA or incident symptomatic knee OA at 84 months. Separate binomial regression analyses with robust SEs adjusted for age, history of knee surgery, physical activity level, and clinic site were conducted for men and women.ResultsHigh knee extensor strength (normalized by allometric scaling) was associated with a reduced risk of radiographic knee OA in women (relative risk [RR] 0.52, 95% confidence interval [95% CI] 0.29-0.94) but not in men (RR 0.56, 95% CI 0.27-1.16). High knee extensor strength did not protect against the development of symptomatic knee OA, either in women or men.ConclusionThe results only partly confirm the hypothesis that high knee extensor muscle strength protects against later development of knee OA in individuals with medial meniscal pathology.

ObjectiveTo determine the association between changes in semiquantitative magnetic resonance imaging (MRI) biomarkers over 24 months and radiographic and pain progression over 48 months in knees with mild-to-moderate osteoarthritis (OA).MethodsWe undertook a nested case-control study as part of the Foundation for the National Institutes of Health Biomarkers Consortium Project. We used multivariable logistic regression models to examine the association between change over 24 months in semiquantitative MRI markers and radiographic and pain progression in knee OA. MRIs were read according to the MRI OA Knee Score system. We focused on changes in cartilage, osteophytes, meniscus, bone marrow lesions, Hoffa-synovitis, and effusion-synovitis.ResultsThe most parsimonious model included changes in cartilage thickness and surface area, effusion-synovitis, Hoffa-synovitis, and meniscal morphology (C statistic 0.740). Compared with no worsening, worsening in cartilage thickness in ≥3 subregions was associated with 2.8-fold (95% confidence interval [95% CI] 1.3-5.9) greater odds of being a case, and worsening in cartilage surface area in ≥3 subregions was associated with 2.4-fold (95% CI 1.3-4.4) greater odds of being a case. Worsening of meniscal morphology in any region was associated with 2.2-fold (95% CI 1.3-3.8) greater odds of being a case. Worsening effusion-synovitis and Hoffa-synovitis were also associated with a greater odds of being a case (odds ratios 2.7 and 2.0, respectively).ConclusionTwenty-four-month changes in cartilage thickness, cartilage surface area, effusion-synovitis, Hoffa-synovitis, and meniscal morphology were independently associated with OA progression, suggesting that these factors may serve as efficacy biomarkers in clinical trials of disease-modifying interventions for knee OA.

ObjectiveTo assess whether medial tibiofemoral joint space width (JSW) on 3-dimensional (3-D) standing computed tomography (SCT) correlates more closely with magnetic resonance imaging cartilage morphology (CM) and meniscal scores than does radiographic 2-D JSW.MethodsParticipants in the Multicenter Osteoarthritis Study, who had standing fixed-flexion posteroanterior knee radiographs, were recruited. Medial tibiofemoral 3-D JSW on SCT and 2-D JSW on fixed-flexion radiographs were compared with medial tibiofemoral cartilage and meniscal morphology using the Whole-Organ Magnetic Resonance Imaging Score (WORMS). Associations between the area of the articular surface with 3-D JSW

BackgroundWhether preradiographic lesions in knees at risk for osteoarthritis are incidental versus disease is unclear. We hypothesised, in persons without but at higher risk for knee osteoarthritis, that: 12-48 month MRI lesion status worsening is associated with 12-48 month incident radiographic osteoarthritis (objective component of clinical definition of knee osteoarthritis) and 48-84 month persistent symptoms.MethodsIn 849 Osteoarthritis Initiative participants Kellgren/Lawrence (KL) 0 in both knees, we assessed cartilage damage, bone marrow lesions (BMLs), and menisci on 12 month (baseline) and 48 month MRIs. Multivariable logistic regression was used to evaluate associations between 12-48 month worsening versus stable status and outcome (12-48 month incident KL ≥1 and KL ≥2, and 48-84 month persistent symptoms defined as frequent symptoms or medication use most days of ≥1 month in past 12 month, at consecutive visits 48-84 months), adjusting for age, gender, body mass index (BMI), injury and surgery.ResultsMean age was 59.6 (8.8), BMI 26.7 (4.2) and 55.9% were women. 12-48 month status worsening of cartilage damage, meniscal tear, meniscal extrusion, and BMLs was associated with 12-48 month incident radiographic outcomes, and worsening of cartilage damage and BMLs with 48-84 month persistent symptoms. There was a dose-response association for magnitude of worsening of cartilage damage, meniscal tear, meniscal extrusion, and BMLs and radiographic outcomes, and cartilage damage and BMLs and persistent symptoms.ConclusionsIn persons at higher risk, worsening MRI lesion status was associated with concurrent incident radiographic osteoarthritis and subsequent persistent symptoms. These findings suggest that such lesions represent early osteoarthritis, and add support for a paradigm shift towards investigation of intervention effectiveness at this stage.

BackgroundRevision anterior cruciate ligament (ACL) reconstruction has been documented to have worse outcomes compared with primary ACL reconstructions.Purpose/hypothesisThe purpose of this study was to determine if the prevalence, location, and/or degree of meniscal and chondral damage noted at the time of revision ACL reconstruction predicts activity level, sports function, and osteoarthritis symptoms at 2-year follow-up. The hypothesis was that meniscal loss and high-grade chondral damage noted at the time of revision ACL reconstruction will result in lower activity levels, decreased sports participation, more pain, more stiffness, and more functional limitation at 2 years after revision surgery.Study designCohort study; Level of evidence, 2.MethodsBetween 2006 and 2011, a total of 1205 patients who underwent revision ACL reconstruction by 83 surgeons at 52 hospitals were accumulated for study of the relationship of meniscal and articular cartilage damage to outcome. Baseline demographic and intraoperative data, including the International Knee Documentation Committee (IKDC) subjective knee evaluation, Knee injury and Osteoarthritis Outcome Score (KOOS), Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC), and Marx activity score, were collected initially and at 2-year follow-up to test the hypothesis. Regression analysis was used to control for age, sex, body mass index, smoking status, activity level, baseline outcome scores, revision number, time since last ACL reconstruction, incidence of having a previous ACL reconstruction on the contralateral knee, previous and current meniscal and articular cartilage injury, graft choice, and surgeon years of experience to assess the meniscal and articular cartilage risk factors for clinical outcomes 2 years after revision ACL reconstruction.ResultsAt 2-year follow-up, 82% (989/1205) of the patients returned their questionnaires. It was found that previous meniscal injury and current articular cartilage damage were associated with the poorest outcomes, with prior lateral meniscectomy and current grade 3 to 4 trochlear articular cartilage changes having the worst outcome scores. Activity levels at 2 years were not affected by meniscal or articular cartilage pathologic changes.ConclusionPrior lateral meniscectomy and current grade 3 to 4 changes of the trochlea were associated with worse outcomes in terms of decreased sports participation, more pain, more stiffness, and more functional limitation at 2 years after revision surgery, but they had no effect on activity levels.RegistrationNCT00625885.

PurposeTo develop and compare with the classical region of interest (ROI)-based approach a fully automatic, local, and unbiased way of studying the knee T1ρ relaxation time by creating an atlas and using voxel-based relaxometry (VBR) in osteoarthritis (OA) and anterior cruciate ligament (ACL) subjects.Materials and methodsIn this study 110 subjects from two cohorts: 1) Mild OA 40 patients with mild-OA Kellgren-Lawrence (KL) ≤ 2 and 15 controls KL ≤ 1; 2) ACL cohort (a model for early OA): 40 ACL-injured patients imaged prior to ACL reconstruction and 1-year postsurgery and 15 controls are analyzed. All the subjects were acquired at 3T with a protocol that includes: 3D-FSE (CUBE) and 3D-T1ρ . A nonrigid registration technique was applied to align all the images on a single template. This allows for performing VBR to assess local statistical differences of T1ρ values using z-score analysis. VBR results were compared with those obtained with classical ROI-based technique.ResultsROI-based results from atlas-based segmentation were consistent with classical ROI-based method (coefficient of variation [CV] = 3.83%). Voxel-based group analysis revealed local patterns that were overlooked by the ROI-based approach; eg, VBR showed posterior lateral femur and posterior lateral tibia significant T1ρ elevations in ACL-injured patients (sample mean z-score=9.7 and 10.3). Those elevations were overlooked by the classical ROI-based approach (sample mean z-score=1.87 and -1.73) CONCLUSION: VBR is a feasible and accurate tool for the local evaluation of the biochemical composition of knee articular cartilage. VBR is capable of detecting specific local patterns on T1ρ maps in OA and ACL subjects.

This study assessed the effects of static loading on MRI relaxation times of menisci in individuals with and without radiographic knee OA. High-resolution fast spin-echo (FSE) and T(1ρ)/T(2) relaxation time MR sequences were obtained with and without loading at 50% body weight in 124 subjects. T(1ρ)/T(2) relaxation times were calculated in menisci, and meniscus lesions were assessed through clinical grading. Student's t-test compared OA and control unloaded relaxation times as well as within-group changes with loading, Generalized Linear Models evaluated zonal variation, and ANCOVA compared loading response between groups. Unloaded T(1ρ) and T(2) in the middle and inner zones of the lateral anterior horn and outer zone of the medial posterior horn were significantly higher in OA and suggest that meniscal OA change occurs unevenly. Zonal T(1ρ) and T(2) showed differing patterns between anterior and posterior horns, suggesting differences in macromolecular organization. Significant increases with loading were seen largely in the T(2) of controls and less frequently in subjects with OA. In the medial posterior horn, T(1ρ) and T(2) decreased with loading in OA but changed negligibly in controls; these significantly different loading responses between groups may indicate load transmission failure in OA menisci.

BackgroundAnterior cruciate ligaments (ACL) injuries represent a major risk factor for early osteoarthritis (OA).PurposeTo evaluate the prevalence and 4-year progression of knee OA measured with 3T MR-imaging in individuals with ruptured, reconstructed or normal ACL and to assess the impact of thigh muscle characteristics.MethodsA total of 54 knees (23/54 male, 31/54 female) were recruited from the Osteoarthritis Initiative (OAI). At baseline, 15/54 subjects had prevalent ACL ruptures and 15/54 subjects had prevalent ACL reconstruction (24/54 normal ACL). Western Ontario and McMasters Universities Arthritis Index (WOMAC) scores, Physical Activity Scores of the Elderly (PASE) and thigh muscle characteristics including strength, fat infiltration (Goutallier score) and thigh muscle cross-sectional area (CSA) MR measurements were obtained at baseline. Whole-organ MR-imaging Scores (WORMS) were obtained at baseline and at a 4-year follow-up time-point. Multivariate regression models, adjusting for covariates (age, gender, body mass index), were used for statistical analysis.ResultsAt baseline, subjects with prevalent ACL ruptures had worse WORMS total scores (mean±SEM, 44.1±3.5) than subjects with ACL reconstruction (30.8±4.0; P = 0.015) and worse than subjects with normal ACL (21.3±3.0; P

ObjectivesTo provide a comprehensive simultaneous relation of various semiquantitative knee OA MRI features as well as the presence of baseline radiographic osteoarthritis (OA) to quantitative longitudinal cartilage loss.MethodsWe studied Multicenter OA Study (MOST) participants from a longitudinal observational study that included quantitative MRI measurement of cartilage thickness. These subjects also had Whole Organ MRI Score (WORMS) scoring of cartilage damage, bone marrow lesions (BMLs), meniscal pathology, and synovitis, as well as baseline radiographic evaluation for Kellgren and Lawrence (KL) grading. Knee compartments were classified as progressors when exceeding thresholds of measurement variability in normal knees. All potential risk factors of cartilage loss were dichotomized into "present" (score ≥2 for cartilage, ≥1 for others) or "absent". Differences in baseline scores of ipsi-compartmental risk factors were compared between progressor and non-progressor knees by multivariable logistic regression, adjusting for age, sex, body mass index, alignment axis (degrees) and baseline KL grade. Odds ratios (OR) and 95% CIs were calculated for medial femorotibial compartment (MFTC) and lateral femorotibial compartment (LFTC) cartilage loss. Cartilage loss across both compartments was studied using Generalized Estimating Equations.Results196 knees of 196 participants were included (age 59.8 ± 6.3 years [mean ± SD], BMI 29.5 ± 4.6, 62% women). For combined analyses of MFTC and LFTC, baseline factors related to cartilage loss were radiographic OA (KL grade ≥2: aOR 4.8 [2.4-9.5], cartilage damage (aOR 2.3 [1.2-4.4])), meniscal damage (aOR 3.9 [2.1-7.4]) and extrusion (aOR 2.9 [1.6-5.3]), all in the ipsilateral compartment, but not BMLs or synovitis.ConclusionBaseline radiographic OA and semiquantitatively (SQ) assessed MRI-detected cartilage damage, meniscal damage and extrusion, but not BMLs or synovitis is related to quantitatively measured ipsi-compartmental cartilage thinning over 30 months.

ObjectiveTo identify patterns of coexisting lesions seen on magnetic resonance imaging (MRI) in knees that are free of radiographic osteoarthritis (OA) and to examine the relationship of these MRI-detected lesions to incident OA.MethodsStudy subjects were individuals enrolled in the Multicenter Osteoarthritis Study, a prospective cohort study. In each subject, 1 knee in which radiographic OA was absent in both the tibiofemoral and patellofemoral joints at baseline was selected for study, with followup for 84 months. We used a novel approach, latent class analysis, to group the constellation of MRI lesions in each joint, i.e., cartilage damage, bone marrow lesion, meniscal tear, meniscal extrusion, synovitis, and effusion, into a manageable number of subgroups. The association of these subgroups with incident radiographic OA in the same joint was assessed using logistic regression.ResultsAmong 885 eligible knees (203 with incident disease in the tibiofemoral joint, 64 with incident disease in the patellofemoral joint), 4 latent subgroups in the tibiofemoral joint were identified (described briefly as minimal lesions, mild lesions, moderate lesions [but limited meniscal lesions], and severe lesions). The odds ratios of incident tibiofemoral joint OA in the latter 3 subgroups (compared to the knees with minimal lesions as the referent) were 5.6, 1.8, and 5.0, respectively. A similar set of 4 subgroups in the patellofemoral joint was identified, except that the fourth subgroup had limited meniscal lesions. The odds ratios of incident disease in the patellofemoral joint were 3.8, 5.1, and 13.7 in the subgroups with mild lesions, moderate lesions, and severe lesions, respectively.ConclusionDifferent patterns of coexisting MRI lesions, which have different implications with regard to risk of knee OA, were identified. Meniscal damage seemed to play a different role in the development of incident disease in tibiofemoral versus patellofemoral joints.

ObjectiveThe aim of the study was to determine whether quantitative ultrashort echo time (UTE) -T1ρ magnetic resonance (MR) measurements are sensitive to proteoglycan degradation in human menisci by trypsin digestion.MethodsConventional and quantitative UTE-T1ρ MR sequences were performed on 4 meniscal samples using a 3T scanner. Magnetic resonance imaging was performed before and after 4, 8, and 12 hours of trypsin solution immersion, inducing proteoglycan loss. One sample was used as a control. Digest solutions were analyzed for glycosaminoglycan (GAG) content. The UTE-T1ρ studies were analyzed for quantitative changes.ResultsImages showed progressive tissue swelling, fiber disorganization, and increase in signal intensity after GAG depletion. The UTE-T1ρ values tended to increase with time after trypsin treatment (P = 0.06). Cumulative GAG loss into the bath showed a trend of increased values for trypsin-treated samples (P = 0.1).ConclusionsUltrashort echo time T1ρ measurements can noninvasively detect and quantify severity of meniscal degeneration, which has been correlated with progression of osteoarthritis.

BackgroundKnees undergoing revision anterior cruciate ligament reconstruction (rACLR) have a high prevalence of articular cartilage lesions.HypothesisThe prevalence of chondrosis at the time of rACLR is associated with meniscal status and lower extremity alignment.Study designCross-sectional study; Level of evidence, 3.MethodsData from the prospective Multicenter ACL Revision Study (MARS) cohort were reviewed to identify patients with preoperative lower extremity alignment films. Lower extremity alignment was defined by the weightbearing line (WBL) as a percentage of the tibial plateau width, while the chondral and meniscal status of each weightbearing compartment was recorded at the time of surgery. Multivariable proportional odds models were constructed and adjusted for relevant factors to examine which risk factors were independently associated with the degree of medial and lateral compartment chondrosis.ResultsThe cohort included 246 patients with lower extremity alignment films at the time of rACLR. Mean (±SD) patient age was 26.9 ± 9.5 years and body mass index (BMI) was 26.4 ± 4.6. The medial compartment had more chondrosis (grade 2/3, 42%; grade 4, 6.5%) than did the lateral compartment (grade 2/3, 26%; grade 4, 6.5%). Disruption of the meniscus was noted in 35% of patients on the medial side and 16% in the lateral side. The mean WBL was 0.43 ± 0.13. Medial compartment chondrosis was associated with BMI (P = .025), alignment (P = .002), and medial meniscal status (P = .001). None of the knees with the WBL lateral to 0.625 had grade 4 chondrosis in the medial compartment. Lateral compartment chondrosis was significantly associated with age (P = .013) and lateral meniscal status (P < .001). Subjects with "intact" menisci were found to decrease their odds of having chondrosis by 64% to 84%.ConclusionThe status of articular cartilage in the tibiofemoral compartments at the time of rACLR is related to meniscal status. Lower extremity alignment and BMI are associated with medial compartment chondrosis.

BackgroundVitamin K-dependent (VKD) proteins, including the mineralization inhibitor matrix-gla protein (MGP), are found in joint tissues including cartilage and bone. Previous studies suggest low vitamin K status is associated with higher osteoarthritis (OA) prevalence and incidence.ObjectiveTo clarify what joint tissues vitamin K is relevant to in OA, we investigated the cross-sectional and longitudinal association between vitamin K status and knee OA structural features measured using magnetic resonance imaging (MRI).MethodsPlasma phylloquinone (PK, vitamin K1) and dephosphorylated-uncarboxylated MGP ((dp)ucMGP) were measured in 791 older community-dwelling adults who had bilateral knee MRIs (mean ± SD age = 74 ± 3 y; 67% female). The adjusted odds ratios (and 95% confidence intervals) [OR (95%CI)] for presence and progression of knee OA features according to vitamin K status were calculated using marginal models with generalized estimating equations (GEEs), adjusted for age, sex, body mass index (BMI), triglycerides and other pertinent confounders.ResultsLongitudinally, participants with very low plasma PK (

ObjectiveTo establish a novel method of quantifying meniscal deformation using loaded MRI. More specifically, the goals were to evaluate the (1) accuracy, (2) inter-rater reliability, (3) intra-rater reliability, and (4) scan-rescan reliability. The secondary purpose of this experiment was to evaluate group differences in meniscal deformation in participants with and without radiographic knee OA.Materials and methodsWeight-bearing 3-T MRIs of the knee in full extension and 30° of flexion were processed to create 3D models of meniscal deformation. Accuracy was assessed using a custom-designed phantom. Twenty-one participants either with or without signs of OA were evaluated, and another six participants (14 knees, one subject was scanned twice) underwent repeated imaging to assess scan-rescan reproducibility. Intraclass correlation coefficient (ICC), root-mean squared error (RMSE), and root-mean-square percent coefficient-of-variation (RMS%CV) analyses were performed. Exploratory comparisons were made between those with and without OA to evaluate potential group differences.ResultsAll variables were found to be accurate with RMSE ranging from 0.08 to 0.35 mm and 5.99 to 14.63 mm(2). Reproducibility of peak anterior-posterior meniscal deformation was excellent (ICC > 0.821; p

PurposeTo determine the association of MRI-assessed worsening of tibiofemoral cartilage damage, meniscal damage, meniscal extrusion, separately and together, with progression of radiographic joint space narrowing (JSN).Method and materialsThe Multicenter Osteoarthitis Study (MOST) Study is a cohort study of subjects with or at risk for knee osteoarthritis (OA). Knees with radiographic OA Kellgren-Lawrence grade 2 at baseline and with baseline and 30-month 1.0 T MRIs were selected for reading using the WORMS system for cartilage damage, meniscal damage, and meniscal extrusion. The association of worsening of cartilage damage, meniscal damage, and/or meniscal extrusion with increases in the JSN was performed using logistic regression.ResultsA total of 276 knees (one per subject) were included (women 68.5%, mean age 62.9 ± 7.8, mean body mass index (BMI) 30.2 ± 5.0). Worsening of each MRI feature was associated with any increase in JSN (P < 0.01). Worsening of cartilage damage was more frequently observed than worsening of meniscal damage and extrusion, and was significantly associated with both slow and fast progression of JSN. An increasing risk of JSN worsening was associated with increasing number of worsening MRI features (P for trend < 0.0001).ConclusionWorsening of tibiofemoral cartilage damage, meniscal damage, and meniscal extrusion are independent predictors of JSN progression in the same compartment. Worsening of cartilage damage is more frequently observed in JSN when compared to meniscal worsening. A strong cumulative effect on JSN progression is observed for worsening of more than one MRI feature.

ObjectiveLittle is known about early knee osteoarthritis (OA). The significance of lesions on magnetic resonance imaging (MRI) in older persons without radiographic OA is unclear. Our objectives were to determine the extent of tissue pathology by MRI and evaluate its significance by testing the following hypotheses: cartilage damage, bone marrow lesions, and meniscal damage are associated with prevalent frequent knee symptoms and incident persistent symptoms; bone marrow lesions and meniscal damage are associated with incident tibiofemoral (TF) cartilage damage; and bone marrow lesions are associated with incident patellofemoral (PF) cartilage damage.MethodsIn a cohort study of 849 Osteoarthritis Initiative (OAI) participants who had a bilateral Kellgren/Lawrence (K/L) score of 0, we assessed cartilage damage, bone marrow lesions, and meniscal damage using the MRI OA Knee Score, as well as prevalent frequent knee symptoms, incident persistent symptoms, and incident cartilage damage. Multiple logistic regression (one knee per person) was used to evaluate associations between MRI lesions and each of these outcomes.ResultsOf the participants evaluated, 76% had cartilage damage, 61% had bone marrow lesions, 21% had meniscal tears, and 14% had meniscal extrusion. Cartilage damage (any; TF and PF), bone marrow lesions (any; TF and PF), meniscal extrusion, and body mass index (BMI) were associated with prevalent frequent symptoms. Cartilage damage (isolated PF; TF and PF), bone marrow lesions (any; isolated PF; TF and PF), meniscal tears, and BMI were associated with incident persistent symptoms. Hand OA, but no individual lesion type, was associated with incident TF cartilage damage, and bone marrow lesions (any; any PF) with incident PF damage. Having more lesion types was associated with a greater risk of outcomes.ConclusionMRI-detected lesions are not incidental and may represent early disease in persons at increased risk of knee OA.

PurposeTo assess the association of meniscal root tear with the development or worsening of tibiofemoral cartilage damage.Materials and methodsInstitutional review board approval and written informed consent from all subjects were obtained. A total of 596 knees with radiographically depicted osteoarthritis were randomly selected from the Multicenter Osteoarthritis study cohort. Cartilage damage was semiquantitatively assessed by using the Whole-Organ Magnetic Resonance Imaging Score (WORMS) system (grades 0-6). Subjects were separated into three groups: root tear only, meniscal tear without root tear, and neither meniscal nor root tear. A log-binomial regression model was used to calculate the relative risks for knees to develop incident or progressing cartilage damage in the root tear group and the meniscal tear group, with the no tear group serving as a reference.ResultsIn the medial tibiofemoral joint, there were 37 knees with isolated medial posterior root tear, 294 with meniscal tear without root tear, and 264 without meniscal or root tear. There were only two lateral posterior root tears, and no anterior root tears were found. Thus, the focus was on the medial posterior root tear. The frequency of severe cartilage damage (WORMS ≥ 5) was higher in the group with root tear than in the group without root or meniscal tear (76.7% vs 19.7%, P < .0001) but not in the group with meniscal but no root tear (76.7% vs 65.2%, P = .055). Longitudinal analyses included 33 knees with isolated medial posterior root tear, 270 with meniscal tear, and 245 with no tear. Adjusted relative risk of cartilage loss was 2.03 (95% confidence interval [CI]: 1.18, 3.48) for the root tear group and 1.84 (95% CI: 1.32, 2.58) for the meniscal tear group.ConclusionIsolated medial posterior meniscal root tear is associated with incident and progressive medial tibiofemoral cartilage loss.

ObjectiveTo describe cartilage matrix and morphology changes, assessed using quantitative magnetic resonance imaging (MRI), after acute anterior cruciate ligament (ACL) injury relative to controls and longitudinally during 2 years following reconstruction.MethodFifteen patients with acute ACL injuries and 16 healthy volunteers with a similar demographic profile but no history of osteoarthritis or knee injury were studied. The injured knee of each participant was imaged with a 3.0 T MR scanner at baseline (prior to ACL reconstruction); patients' knees were re-imaged 1 and 2 years after ACL reconstruction. Cartilage T1ρ and T2 values in full thickness, superficial layers, and deep layers, and cartilage thickness of the full layer were quantified within subcompartments of the knee joint.ResultsIn the posterolateral tibial cartilage, T1ρ values were significantly higher in ACL-injured knees than control knees at baseline and were not fully recovered 2 after ACL reconstruction. T1ρ values of medial tibiofemoral cartilage in ACL-injured knees increased over the 2-year study and were significantly elevated compared to that of the control knees. T2 values in cartilage of the central aspect of the medial femoral condyle at the 2-year follow-up were significantly elevated compared with control knees. Cartilage in the posterior regions of the lateral tibia was significantly thinner, while cartilage in the central aspect of the medial femur was significantly thicker than that of controls. Patients with lesions in the posterior horn of the medial meniscus exhibited significantly higher T1ρ values in weight-bearing regions of the tibiofemoral cartilage than that of control subjects over the 2-year period, whereas patients without medial meniscal tears did not.ConclusionQuantitative MRI provides powerful in vivo tools to quantitatively evaluate early changes of cartilage matrix and morphology after acute ACL injury and reconstruction, which may possibly relate to the development of post-traumatic osteoarthritis in such joints.

ObjectiveSynovitis is thought to be a secondary phenomenon in the osteoarthritis (OA) process and the menisci might be triggers of localized synovitis. The aim was to assess the cross-sectional associations of posterior horn meniscal damage with perimeniscal synovitis, and with synovitis posterior to the posterior cruciate ligament (PCL) using contrast enhanced (CE) MRI.DesignThe Multicenter Osteoarthritis (MOST) Study is a longitudinal observational study of subjects with or at risk for knee OA. Subjects are a subset of MOST who were examined with 1.5T CE MRI and had semiquantitative synovitis (scored from 0 to 2 at 11 locations) and meniscal readings (scored with WORMS from 0 to 4) available. Logistic regression was used to assess the association of posterior meniscal damage and perimeniscal synovitis in the same compartment, and between posterior meniscal damage and synovitis posterior to the PCL.ResultsThree hundred and seventy seven knees were included (mean age 61.1 years±6.9, mean BMI 29.6±4.9, 44.3% women). The odds for ipsi-compartmental perimeniscal synovitis were increased for knees with medial posterior horn meniscal damage (adjusted odds ratio [aOR] 2.5, 95% confidence intervals [95% CI] 1.3,4.8), but not for lateral damage (aOR 1.7, 95% CI 0.4,6.6). No positive associations were found for meniscal damage and presence of synovitis posterior to the PCL (aOR 0.9, 95% CI 0.6,1.5).ConclusionsMeniscal damage of the posterior horns is associated with ipsi-compartmental perimensical synovitis. No associations were found for posterior horn meniscal damage with synovitis posterior to the PCL, which suggests that synovitis posterior to the PCL is likely to be triggered by different pathomechanisms.

PurposeTo assess risk of cartilage loss in the tibiofemoral joint in relation to baseline damage severity, and to analyse the association of nearby pathologic findings on the risk of subsequent cartilage loss.MethodsThe Multicenter Osteoarthritis Study is a longitudinal study of individuals with or at high risk for knee osteoarthritis. MRI examinations were assessed according to the Whole Organ MRI Score. Included were all knees with available baseline and 30 months MRIs. Ordinal logistic regression was used to estimate risk of cartilage loss in each subregion in relation to the number of associated articular features including bone marrow lesions, meniscal damage and extrusion and also in regard to baseline damage severity, respectively.Results13 524 subregions of 1365 knees were included. 3777 (27.9%) subregions exhibited prevalent cartilage damage at baseline and 1119 (8.3%) subregions showed cartilage loss at 30-month follow-up. Risk of cartilage loss was increased for subregions with associated features (OR 2.53, 95% CI 2.03 to 3.15 for one, 4.32 95% CI 3.42 to 5.47 for two and 5.30 95% CI 3.95 to 7.12 for three associated features; p for trend

PurposeTo prospectively evaluate changes in T1ρ and T2 relaxation times in the meniscal body with acute loading using MRI in osteoarthritic knees and to compare these findings with those of age-matched healthy controls.Materials and methodsFemale subjects above 40 years of age with (N1  = 20) and without osteoarthritis (OA) (N2  = 10) were imaged on a 3 Tesla MR scanner using a custom made loading device. MR images were acquired, with the knee flexed at 20°, with and without a compressive load of 50% of the subject's bodyweight. The subjects were categorized based on the radiographic evidence of OA. Three different zones (outer, middle, and inner) of meniscus body were defined (each occupying 1/3rd the width). After adjusting for age and body mass index in the general linear regression model, repeated measures analysis of variance was used to detect significant differences in T1ρ and T2 with and without loading.ResultsIn the unloaded condition, the average T1ρ and T2 times were elevated in the outer and middle zones of the medial meniscus in OA subjects compared with the controls. In the loaded condition, T1ρ and T2 times of the outer zone of the medial meniscus was significantly elevated in OA subjects compared with controls. Finally the change (from unloaded to loaded) was significantly higher in controls than OA subjects (15.1% versus 8.3%; P = 0.039 for ΔT1ρ , and 11.5% versus 6.9%, P = 0.049 for ΔT2 ).ConclusionThese findings suggest that while the OA process appears to affect the relaxation times of all regions within the meniscus, it may affect some regions sooner or to a greater degree. Furthermore, the differences in the change in relaxation times between unloaded and loaded conditions may reveal evidence about load transmission failure of the outer zone of the medial meniscus in subjects with knee OA. It is possible that these metrics (ΔT1ρ and ΔT2 ) may be valuable as an early biomechanical biomarker, which could be used to predict load transmission to the underlying articular cartilage.

BackgroundThe purpose of this investigation is to evaluate the T(1ρ) relaxation times of articular cartilage surrounding focal defects in the tibiofemoral joint.MethodsQuantitative cartilage assessment was performed using 3T MRI with T(1ρ) mapping in 19 healthy individuals and 44 OA patients. Sagittal T2-weighted fast spin echo (FSE) images were acquired for lesion assessment. Differences were determined using analysis of variance (ANOVA).ResultsCartilage lesions were found in 37% of controls, and 93% of OA patients. Meniscal tears were found in 16% of controls and 57% of OA patients. We observed no difference in T(1ρ) relaxation times when comparing cartilage immediately surrounding a focal defect, and the remaining cartilage within that compartment. The medial femoral condyle (MFC) had the highest incidence of cartilage defects. MFC and medial meniscus posterior horn T(1ρ) were higher in subjects having multiple focal lesions (p = 0.048, pb 0.001 respectively) and extensive full thickness lesions (p = 0.009, pb 0.001 respectively) compared to subjects with no MFC defects. Significant elevations in T(1ρ) of the adjacent compartment (medial tibia) and medial meniscus were observed in subjects with MFC lesions.ConclusionIncreased relaxation times in the involved compartment as well as the adjacent compartment and associated meniscus underscore the interdependence of these structures at bearing load. However, no differences in cartilage composition immediately surrounding a defect were noted. Finally, an association was observed between cartilage defects and meniscal damage in advanced disease.Clinical relevanceCartilage defects were not associated with degeneration in the immediately adjacent cartilage.

ObjectiveTo evaluate whether T(2) and T(1ρ) relaxation times of knee cartilage determined with 3T magnetic resonance imaging (MRI) at baseline predict longitudinal progression of cartilage degenerative changes.MethodsQuantitative analysis of cartilage was performed using 3T MRI with both T(2) and T(1ρ) mapping techniques in 55 subjects without evidence of severe osteoarthritis (OA) [Kellgren-Lawrence (KL) score of 0-3] at baseline. Morphological abnormalities of cartilage, menisci, ligaments and bone marrow were analyzed on sagittal fat-saturated intermediate-weighted fast spin echo (FSE) sequences. Progression of degenerative changes was analyzed over a period of 2 years. Progression was detected in 27 subjects while in 28 subjects no changes were found. Differences between T(2) and T(1ρ) relaxation times in these two cohorts were compared using one-way analysis of variance (ANOVA) and t tests.ResultsBaseline T(2) and T(1ρ) values were significantly higher in the progression cohort in all compartments (P < 0.05) except the lateral tibia (LT) for T(2) and the medial tibia (MT) for T(1ρ). Progression of cartilage degenerative disease was most pronounced at the medial femoral condyles and at the femoro-patellar joint; differences between the two cohorts for T(2) and T(1ρ) were also most significant in these compartments.ConclusionsT(2) and T(1ρ) measurements were significantly higher at baseline in individuals that showed progression of cartilage abnormalities over a period of 2 years and may therefore serve as potential predictors for progression of degenerative cartilage abnormalities in knee OA.

ObjectiveTo analyze knee trabecular bone structure and spatial cartilage T(1ρ) and T(2) relaxation times using 3-T magnetic resonance imaging (MRI) in subjects with and without tears of posterior horn of the medial meniscus (PHMM).Design3-T MRI from 59 subjects (>18 years), were used to evaluate PHMM tears based on modified Whole-Organ Magnetic Resonance Imaging Score (WORMS) scoring; and to calculate apparent trabecular bone-volume over total bone volume fraction (app. BV/TV), apparent trabecular number (app. Tb.N), apparent trabecular separation (app. Tb.Sp) and apparent trabecular thickness (app. Tb.Th) for overall femur/tibia and medial/lateral femur/tibia; and relaxation times for deep and superficial layers of articular cartilage. A repeated measures analysis using Generalized Estimating Equation (GEE) was performed to compare trabecular bone and cartilage relaxation time parameters between people with (n = 35) and without (n = 24) PHMM tears, while adjusting for age and knee OA presence.ResultsSubjects with PHMM tears had lower app. BV/TV and app. Tb.N, and greater app. Tb.Th, and app. Tb.Sp. They also had higher T(1ρ) times in the deep cartilage layer for lateral tibia and medial femur and higher T(2) relaxation times for the deep cartilage layer across all compartments.ConclusionsPHMM tears are associated with differences in underlying trabecular bone and deep layer of cartilage. Over-load of subchondral bone can lead to its sclerosis and stress shielding of trabecular bone leading to the resorptive changes observed in this study. The results underline the importance of interactions of trabecular bone and cartilage in the pathogenesis of knee OA in people with PHMM tears.

BackgroundCartilage repair (CR) procedures are widely accepted for treatment of isolated cartilage defects in the knee joint. However, it is not well known whether these procedures prevent degenerative joint disease.HypothesisCartilage repair procedures prevent accelerated qualitative and quantitative progression of meniscus degeneration in individuals with focal cartilage defects.Study designCohort study; Level of evidence, 2.MethodsNinety-four subjects were studied. Cartilage repair procedures were performed on 34 patients (osteochondral transplantation, n = 16; microfracture, n = 18); 34 controls were matched. An additional 13 patients received CR and anterior cruciate ligament (ACL) reconstruction (CR&ACL), and 13 patients received only ACL reconstruction. Magnetic resonance imaging at 3.0-tesla with T(1ρ) mapping and sagittal fat-saturated intermediate-weighted fast spin echo (FSE) sequences was performed to quantitatively and qualitatively analyze menisci (Whole-Organ Magnetic Resonance Imaging Score [WORMS] assessment). Patients in the CR and CR&ACL groups were examined 4 months (n = 34; n = 13), 1 year (n = 21; n = 8), and 2 years (n = 9; n = 5) after CR. Control subjects were scanned at baseline and after 1 and 2 years, ACL patients after 1 and 2 years.ResultsAt baseline, global meniscus T(1ρ) values (mean ± SEM) were higher in individuals with CR (14.2 ± 0.5 ms; P = .004) and in individuals with CR&ACL (17.1 ± 0.9 ms; P < .001) when compared with controls (12.8 ± 0.6 ms). After 2 years, there was a statistical difference between T(1ρ) at the overlying meniscus above cartilage defects (16.4 ± 1.0 ms) and T(1ρ) of the subgroup of control knees without cartilage defects (12.1 ± 0.8 ms; P < .001) and a statistical trend to the CR group (13.3 ± 1.0 ms; P = .09). At baseline, 35% of subjects with CR showed morphological meniscus tears at the overlying meniscus; 10% of CR subjects showed an increase in the WORMS meniscus score within the first year, and none progressed in the second year. Control subjects with (without) cartilage defects showed meniscus tears in 30% (5%) at baseline; 38% (19%) increased within the first year, and 15% (10%) within the second year.ConclusionThis study demonstrated more severe meniscus degeneration after CR surgery compared with controls. However, progression of T(1ρ) values was not observed from 1 to 2 years after surgery. These results suggest that CR may prevent degenerative meniscus changes.

ObjectiveTo examine the relationship of knee malalignment with occurrence of incident and enlarging bone marrow lesions (BMLs) and regression of BMLs.MethodsSubjects from the Multicenter Osteoarthritis Study aged 50-79 years with or at high risk of knee osteoarthritis were studied. Full-limb radiographs were taken at baseline and hip-knee-ankle mechanical axis was measured. Baseline and 30-month magnetic resonance imaging (MRI) of knees (n = 1782) were semiquantitatively assessed for BMLs. Outcome was defined as a change in BML score in femoral/tibial condyle in medial/lateral compartments. Medial compartment in varus alignment and lateral compartment in valgus alignment were combined to form 'more loaded' compartment, while lateral compartment in valgus and medial compartment in varus were combined to form 'less loaded' compartment. Relative risk (RR) of BML score increase or decrease in relation to malalignment was estimated using a log linear regression model with the Poisson assumption, adjusting for age, gender, body mass index, physical activity scale for the elderly, race and clinic site. Further, results were stratified by ipsilateral meniscal and cartilage status at baseline.ResultsBaseline varus alignment was associated with higher risk of BML score increase from baseline to follow-up in the medial compartment [adjusted RRs (95%CI): 1.5 (1.2-1.9)] and valgus alignment in the lateral compartment [1.4 (1.0-2.1)]. Increase in BML score was more likely in the more loaded compartments [1.7 (1.4-2.0)] in malaligned knees. Regardless of ipsilateral cartilage or meniscus status, adjusted RR for BML score increase was higher in the more loaded compartments of malaligned knees than those with neutral alignment. Decrease in BML score was less likely in the more loaded compartments in malaligned knees [0.8 (0.7-1.0)].ConclusionKnee malalignment is associated with increased risk of incident and enlarging BMLs in the more loaded compartments of the tibiofemoral joint.

ObjectiveIn order to increase sensitivity to detect longitudinal change, recording of within-grade changes was introduced for cartilage morphology and bone marrow lesion (BML) assessment in semiquantitative magnetic resonance imaging (MRI) scoring of knee osteoarthritis (OA). The aim of this study was to examine the validity provided by within-grade scoring.DesignThe Multicenter Osteoarthritis (MOST) study is a longitudinal study of subjects with or at risk of knee OA. Baseline and 30 months MRIs were read according to the modified Whole-Organ Magnetic Resonance Imaging Score (WORMS) system including within-grade changes for cartilage and BMLs. We tested the validity of within-grade changes by whether the 30-month changes in cartilage and BML assessment were predicted by baseline ipsi-compartmental meniscal damage and malalignment, factors known to affect cartilage loss and BMLs, using ordinal logistic regression.Results1867 Knees (from 1411 participants) were included. Severe medial meniscal damage predicted partial grade (adjusted odds ratio (aOR) 4.4, 95% confidence interval (95% CI) 2.2, 8.7) but not ≥full grade (aOR 1.3, 95% CI 0.8, 2.2) worsening of cartilage loss and predicted both, partial grade (aOR 9.6, 95% CI 3.6, 25.1) and ≥full grade (aOR 5.1, 95% CI 3.2, 8.2) worsening of BMLs. Severe, but not moderate, malalignment predicted ipsi-compartmental within-grade (medial cartilage damage: aOR 5.5, 95% CI 2.6, 11.6; medial worsening of BMLs: aOR 4.9, 95% CI 2.0, 12.3) but not full grade worsening of BMLs and cartilage damage.ConclusionsWithin-grade changes in semiquantitative MRI assessment of cartilage and BMLs are valid and their use may increase the sensitivity of semiquantitative readings in detecting longitudinal changes in these structures.

BackgroundUnderstanding the acute response of healthy knee cartilage to running may provide valuable insight into functional properties. In recent years, quantitative magnetic resonance (MR) imaging techniques (T1(ρ) and T2 relaxation measurement) have shown tremendous potential and unique ability to noninvasively and quantitatively determine cartilage response to physiologic levels of loading occurring with physiologic levels of exercise.PurposeTo measure the short-term changes in MR T1(ρ) and T2 relaxation times of knee articular cartilage and meniscus in healthy individuals immediately after 30 minutes of running.Study designDescriptive laboratory study.MethodsTwenty young healthy volunteers, aged 22 to 35 years, underwent 3T MR imaging of the knee before and immediately after 30 minutes of running. Quantitative assessment of the cartilage and menisci was performed using MR images with a T1(ρ) and T2 mapping technique. After adjusting for age, sex, and body mass index, repeated-measures analysis of variance was used to determine the effects of running on MR relaxation times.ResultsThe post-run T1(ρ) and T2 measurement showed significant reduction in all regions of cartilage except the lateral tibia when compared with the pre-run condition. The medial tibiofemoral (T1(ρ): 9.4%, P < .0001; T2: 5.4%, P = .0049) and patellofemoral (T1(ρ): 12.5%, P < .0001; T2: 5.7%, P = .0007) compartments experienced the greatest reduction after running. The superficial layer of the articular cartilage showed significantly higher change in relaxation times than the deep layer (T1(ρ): 9.6% vs 8.2%, P = .050; T2: 6.0% vs 3.5%, P = .069). The anterior and posterior horns of the medial meniscus (9.7%, P = .016 and 11.4%, P = .001) were the only meniscal subregions with significant changes in T1(ρ) after running.ConclusionShorter T1(ρ) and T2 values after running suggest alteration in the water content and collagen fiber orientation of the articular cartilage. Greater changes in relaxation times of the medial compartment and patellofemoral joint cartilage indicate greater load sharing by these areas during running.

PurposeTo assess the associations of meniscal tears, knee mal-alignment, cartilage damage, knee effusion, and body mass index with meniscal extrusion.Materials and methodsThe Multicenter Osteoarthritis study is an observational study of individuals who have or are at risk for knee osteoarthritis (OA). The HIPAA-compliant protocol was approved by the institutional review boards of all participating centers, and written informed consent was obtained from all patients. All subjects with available baseline knee radiographs and magnetic resonance (MR) images were included. MR imaging assessment of meniscal morphologic characteristics, meniscal position, and cartilage morphologic characteristics with use of the Whole-Organ Magnetic Resonance Imaging Score system was performed by two musculoskeletal radiologists. Cross-sectional associations of severity of meniscal tears, knee malalignment, tibiofemoral cartilage damage, knee effusion, and body mass index with meniscal extrusion were assessed by using logistic regression, with multiadjustments when testing each predictor.ResultsA total of 1527 subjects (2131 knees; 2116 medial and 2106 lateral menisci) were included. Medially, meniscal tears, varus malalignment, and cartilage damage were associated with meniscal extrusion, with odds ratios (ORs) of 6.3 (95% confidence interval [CI]: 5.0, 8.0), 1.3 (95% CI: 1.1, 1.7), and 1.8 (95% CI: 1.4, 2.2), respectively. Laterally, meniscal tears, valgus malalignment, and cartilage damage were associated with meniscal extrusion, with ORs of 10.3 (95% CI: 7.1, 14.9), 2.2 (95% CI: 1.5, 3.2), and 2.0 (95% CI: 1.3, 2.9), respectively.ConclusionMeniscal tears are not the only factors associated with meniscal extrusion; other factors include knee malalignment and cartilage damage. Meniscal extrusion is probably an effect of the complex interactions among joint tissues and mechanical stresses involved in the OA process.

PurposeStandard knee MRI is performed under unloading (ULC) conditions and not much is known about changes of the meniscus, ligaments or cartilage under loading conditions (LC). The aim is to study the influence of loading of different knee structures at 3Tesla (T) in subjects with osteoarthritis (OA) and normal controls.Materials and methods30 subjects, 10 healthy and 20 with radiographic evidence of OA (10 mild and 10 moderate) underwent 3T MRI under ULC and LC at 50% body weight. All images were analyzed by two musculoskeletal radiologists identifying and grading cartilage, meniscal, ligamentous abnormalities. The changes between ULC and LC were assessed. For meniscus, cartilage and ligaments the changes of lesions, signal and shape were evaluated. In addition, for the meniscus changes in extrusion were examined. A multivariate regression model was used for correlations to correct the data for the impact of age, gender, BMI. A paired T-Test was performed to calculate the differences in meniscus extrusion.ResultsSubjects with degenerative knee abnormalities demonstrated significantly increased meniscus extrusion under LC when compared to normal subjects (p=0.0008-0.0027). Subjects with knee abnormalities and higher KL scores showed significantly more changes in lesion, signal and shape of the meniscus (80% (16/20) vs. 20% (2/10); p=0.0025), ligaments and cartilage during LC.ConclusionThe study demonstrates that axial loading has an effect on articular cartilage, ligament, and meniscus morphology, which is more significant in subjects with degenerative disease and may serve as an additional diagnostic tool for disease diagnosis and assessing progression in subjects with knee OA.

PurposeTo prospectively evaluate changes in T1rho and T2 relaxation time in the meniscus using 3.0 T MRI in asymptomatic knees of marathon runners and to compare these findings with those of age-matched healthy subjects.Material and methodsThirteen marathon runners underwent 3.0 T MRI including T1rho and T2 mapping sequences before, 48-72 h after, and 3 months after competition. Ten controls were examined at baseline and after 3 months. All images were analyzed by two musculoskeletal radiologists identifying and grading cartilage, meniscal, ligamentous. and other knee abnormalities with WORMS scores. Meniscal segmentation was performed to generate T1rho and T2 maps in six compartments.ResultsNo differences in morphological knee abnormalities were found before and after the marathon. However, all marathon runners showed a significant increase in T1rho and T2 values after competition in all meniscus compartments (p

BackgroundHistorically, magnetic resonance imaging (MRI) has been very useful in diagnosing meniscal tears but not as valuable in predicting whether a meniscal tear is reparable. Given that several recent studies suggested that MRI can be used to predict tear reparability, the topic has resurfaced as a controversy in the orthopaedic and radiology literatures.HypothesisExperienced musculoskeletal radiologists can use MRI to predict the reparability of meniscal tears with good to excellent accuracy using the same arthroscopic criteria used by surgeons intraoperatively.Study designCohort study (diagnosis); Level of evidence, 3.MethodsFifty-eight patients with meniscal tears treated with repair were matched by age and sex with 61 patients with tears treated with meniscectomy. Two senior musculoskeletal radiologists independently and blindly reviewed preoperative MRI of these 119 meniscal tears. Using established arthroscopic criteria, the radiologists were asked to grade each tear 0 to 4, with 1 point for each of the following: a tear larger than 10 mm, within 3 mm of the meniscosynovial junction, greater than 50% thickness, and with an intact inner meniscal fragment. Only a tear with a score of 4 would be predicted to be reparable.ResultsThe 2 radiologists' ability to correctly estimate reparability was poor, with 58.0% and 62.7% correct predictions (κ = 0.155 and 0.250, respectively). Interrater reliability assessment showed that the raters agreed on a score of 4 (reparable) versus