Supplemental educational program to heighten the impact of research - an opportunity for OA imaging.

Objective: To develop and evaluate a supplementary educational program ("IMPACT") centered on enabling participants to consider specifically and articulate explicitly the best path for and potential impact of their research. Design: Participants (trainees) and faculty mentors were from all areas of biomedical research. The group worked longitudinally in small, rotating groups, through a process of developing a written statement ("Impact Statement"), an overview ("Impact Storyline") and an oral presentation ("Impact Case") of their work. Results: One hundred and eighty-seven Fellows enrolled in the program. Of the 179 (96%) Fellows who completed the program, 159 (89%) responded to a post-program survey; 94% indicated that IMPACT was a significant learning experience, 89% indicated that they were more able to identify the long-term potential of their research, 95% felt more able to talk about their work to diverse audiences. Conclusion: This voluntary educational program was appreciated by the participants and led to increased confidence in their ability to drive their science towards a clear impact and communicating that potential to others. This type of program may aid in redirecting some of the efforts and resources of imaging in OA from the large focus on technical developments to more direct biological and clinical questions which might be resolved with current technology.

Unexplained Acute Distal Pancreatitis: Association With Subsequent Diagnosis of Pancreatic Cancer.

BACKGROUND. Distal pancreatitis is an atypical imaging subtype of acute pancreatitis involving only the pancreatic body and tail, the head being spared. If no cause is identified, suspicion of a small imaging-occult cancer may be warranted. OBJECTIVE. The purpose of this study was to determine the frequency of subsequently diagnosed pancreatic cancer in patients with unexplained acute distal pancreatitis and to compare this frequency to that found in patients with unexplained nondistal pancreatitis. METHODS. This retrospective study included patients who underwent contrast-enhanced CT between January 1, 2019, and December 31, 2020, that showed acute pancreatitis without identifiable explanation. Studies were classified as showing distal or nondistal acute pancreatitis on the basis of consensus. The Fisher exact test was used to compare the frequency of subsequent histologic diagnosis of pancreatic cancer between groups. Negative classification required 6 or more months of imaging follow-up and/or 12 or more months of clinical follow-up. Interreader agreement among seven readers of varying experience was assessed by Fleiss kappa. RESULTS. Among 215 patients with acute pancreatitis, 116 (54%) had no identifiable explanation and formed the study sample. A total of 100 of 116 (86%) patients (59 men, 41 women; mean age, 57 ± 18 [SD] years) had nondistal acute pancreatitis; 16 of 116 (14%) patients (10 men, six women; mean age, 66 ± 14 years) had distal acute pancreatitis. Among patients with nondistal pancreatitis, none were subsequently diagnosed with pancreatic cancer; 62 had sufficient follow-up (median, 2.5 years) to be classified as having negative follow-up for pancreatic cancer. Among patients with distal pancreatitis, nine were subsequently diagnosed with pancreatic cancer (median interval to suspected cancer on subsequent CT, 174 days); five had sufficient follow-up (median, 3.1 years) to be classified as having negative follow-up for pancreatic cancer. The frequency of pancreatic cancer was higher (p < .001) in patients with distal pancreatitis (9/14 [64%; 95% CI, 35-87%]) than in with those with nondistal pancreatitis (0/62 [0%; 95% CI, 0-6%]). Interreader agreement on classification of distal versus nondistal pancreatitis was almost perfect (κ = 0.81). CONCLUSION. Distal pancreatitis without identifiable cause on CT is an uncommon but unique imaging subtype of acute pancreatitis that is associated with a high frequency of pancreatic cancer. CLINICAL IMPACT. In patients with acute distal pancreatitis without identifiable cause, endoscopic ultrasound-guided biopsy should be considered to evaluate for an underlying small cancer.

Evidence for Left Atrial Volume Being an Indicator of Adverse Events in Patients With Acute Pulmonary Embolism: Retrospective Case-control Pilot Study.

PURPOSE: To assess the association between computed tomography pulmonary angiography (CTPA) atrial measurements and both 30-day pulmonary embolism (PE)-related adverse events and mortality, and non-PE-related mortality, and to identify the best predictors of these outcomes by comparing atrial measurements and widely used clinical and imaging variables. PATIENTS AND METHODS: Retrospective single-center pilot study. Acute PE patients diagnosed on CTPA who also had a transthoracic echocardiogram, electrocardiogram, and troponin T were included. CTPA left atrial (LA) and right atrial (RA) volume and short-axis diameter were measured and compared between outcome groups, along with right ventricular/left ventricular diameter ratio, interventricular septal bowing, tricuspid annular plane systolic excursion, electrocardiogram, and troponin T. RESULTS: A total of 350 patients. LA volume and diameter were associated with PE-related adverse events (P≤0.01). LA volume was the only atrial measurement associated with PE-related mortality (P=0.03), with no atrial measurements associated with non-PE-related mortality. Troponin was most associated with PE-related adverse events and mortality (both area under the curve [AUC]=0.77). On multivariate analysis, combination models did not greatly improve PE-related adverse events prediction compared with troponin alone. For PE-related mortality, the best models were the combination of troponin, age, and either LA volume (AUC=0.86) or diameter (AUC=0.87). CONCLUSION: Among patients with acute PE, CTPA LA volume is the only imaging parameter associated with PE-related mortality and is the best imaging predictor of this outcome. Reduced CTPA LA volume and diameter, along with increased RA/LA volume and diameter ratios, are significantly associated with 30-day PE-related adverse events, but not with non-PE-related mortality.

A Tissue-Penetrating Double Network Restores the Mechanical Properties of Degenerated Articular Cartilage.

Incorporation of an interpenetrating polymer network into an existing single polymer network enables augmentation of the original substrate's mechanical properties, and translation of this concept from purely synthetic materials to natural-synthetic hybrid systems provides the opportunity to reinforce mechanical properties of bulk biological substrates. In many disease states, the mechanical properties of bodily tissues deteriorate rendering them prone to further material failure. Herein, a tissue-supplementing technique is described in which an interpenetrating biomimetic hydrogel is polymerized in situ throughout cartilage tissue. The treatment restores the inferior compressive properties of osteoarthritic cartilage to that of healthy cartilage, preferentially localizing to weaker regions of tissue. Furthermore, the treatment technique preserves cartilage under harsh articulation conditions, showing promise as a materials-based treatment for early-stage osteoarthritis.

MR diffusion is sensitive to mechanical loading in human intervertebral disks ex vivo.

PURPOSE: To use T2 and diffusion MR to determine the change in the mechanical function of human disks with increased degenerative state. MATERIALS AND METHODS: Spatial changes in T2 and diffusion were quantified in five cadaveric human lumbar disks under compressive loads. Regression models were used to investigate the relationship between the change in MR parameters and the disk's dynamic and viscoelastic properties. RESULTS: Compressive loading caused a significant reduction in the disk's mean diffusivity ([11.3 versus 9.7].10(-4) .mm(2) /s, P < 0.001) but little change in T2 (P < 0.05). Diffusivity and T2 were correlated with the disk's dynamic (P < 0.01 and P < 0.05) and long-term viscoelastic (P < 0.05 and P < 0.05) stiffness. Diffusivity but not T2, was correlated with its viscoelastic dampening (r(2) = 0.45, P < 0.01) and instantaneous stiffness (r(2) = 0.44, P < 0.05). Nucleus diffusivity was significantly higher than the annulus's (-21% to -4%, P < 0.01). MR-estimated hydration was correlated with the instantaneous viscoelastic stiffness of the nucleus (r(2) = 0.35, P < 0.05) and the dynamic (r(2) = 0.44, P < 0.05) and long-term viscoelastic (r(2) = 0.42, P < 0.05) stiffness in the annulus. T2 correlated with diffusivity at low load (r(2) = 0.66, P < 0.05), but not at high load. CONCLUSION: The strong correlations between diffusivity and the rheological assessments of disk mechanics suggest that MR might permit quantitative assessment of disk functional status and structural integrity.

Delayed gadolinium-enhanced magnetic resonance imaging of medial tibiofemoral cartilage and its relationship with meniscal pathology: a longitudinal study using 3.0T magnetic resonance imaging.

OBJECTIVE: To evaluate the relationship between medial meniscal pathology and cartilage matrix status using delayed gadolinium-enhanced magnetic resonance imaging of cartilage (dGEMRIC) in medial tibiofemoral cartilage in a sample of middle-aged women. METHODS: A total of 148 women ages ≥40 years were included, and 3.0T MRI of the knee was performed at baseline and at 1 year. T2-weighted, fat-suppressed and 3-dimensional inversion recovery-prepared spoiled gradient-recalled echo sequences were acquired 90 minutes after gadolinium injection. Baseline medial meniscal pathology was scored on a scale of 0-3, where 0 = normal, 1 = intrasubstance meniscal signal change, 2 = single tears, and 3 = complex tears/maceration. The central medial femur, the medial tibial plateau, and the posterior medial femur were subjected to dGEMRIC at baseline and at 1 year. Analysis of covariance was used to examine whether baseline and 1-year dGEMRIC indices in the same regions were related to the severity of meniscal damage at baseline, using normal medial menisci (grade 0) as the reference. RESULTS: Medial compartments with grade 3 lesions showed significantly lower dGEMRIC indices (less proteoglycan content) at the central medial femur region compared with compartments with normal menisci. Mean ± SEM differences in dGEMRIC indices between grade 3 and grade 0 menisci at the central medial femur were -119.1 ± 34.2 msec at baseline (P = 0.03) and -120.3 ± 35.2 msec at followup (P = 0.04). CONCLUSION: High-grade damage of the medial meniscus showed significant associations with lower dGEMRIC indices. The dGEMRIC technique may be a useful tool in detecting early degenerative changes of cartilage when meniscal function is lost.

Association of changes in delayed gadolinium-enhanced MRI of cartilage (dGEMRIC) with changes in cartilage thickness in the medial tibiofemoral compartment of the knee: a 2†year follow-up study using 3.0†T MRI.

OBJECTIVE: To determine the association between changes in the delayed gadolinium-enhanced MRI of cartilage (dGEMRIC) index over 2 years as a measure of cartilage proteoglycan concentration, with changes in cartilage thickness in the medial tibiofemoral compartment of knees in middle-aged women. METHODS: One hundred and forty-eight women (one knee for each subject) aged ≥40 years were included. 3.0 T MR images of the knee were acquired at baseline, 1 year and 2 years. Three-dimensional (3D) spoiled gradient recalled echo (SPGR) sequences (for cartilage thickness) and 3D inversion recovery-prepared SPGR sequences after dGEMRIC were acquired. Segmentation was performed in the medial central (weight-bearing) femur and tibia to determine cartilage proteoglycan concentration and thickness. The association of change in the dGEMRIC indices between baseline and 1-year follow-up with (a) concomitant changes in cartilage thickness and (b) change in cartilage thickness between 1 and 2 years was assessed using linear regression. RESULTS: In the whole-sample model, a decrease in dGEMRIC indices over time at the central medial femur significantly predicted an increase in cartilage thickness at both the central medial femur (p=0.008) and the medial tibia (p=0.04). CONCLUSIONS: A decrease in dGEMRIC indices was associated with an increase in cartilage thickness in the medial compartment. Our results suggest that an increase in cartilage thickness may also be related to a decrease in proteoglycan concentration, which may represent swelling of cartilage in early stages of degeneration.

Why radiography should no longer be considered a surrogate outcome measure for longitudinal assessment of cartilage in knee osteoarthritis.

Imaging of cartilage has traditionally been achieved indirectly with conventional radiography. Loss of joint space width, or 'joint space narrowing', is considered a surrogate marker for cartilage thinning. However, radiography is severely limited by its inability to visualize cartilage, the difficulty of ascertaining the optimum and reproducible positioning of the joint in serial assessments, and the difficulty of grading joint space narrowing visually. With the availability of advanced magnetic resonance imaging (MRI) scanners, new pulse sequences, and imaging techniques, direct visualization of cartilage has become possible. MRI enables visualization not only of cartilage but also of other important features of osteoarthritis simultaneously. 'Pre-radiographic' cartilage changes depicted by MRI can be measured reliably by a semiquantitative or quantitative approach. MRI enables accurate measurement of longitudinal changes in quantitative cartilage morphology in knee osteoarthritis. Moreover, compositional MRI allows imaging of 'pre-morphologic' changes (that is, visualization of subtle intrasubstance matrix changes before any obvious morphologic alterations occur). Detection of joint space narrowing on radiography seems outdated now that it is possible to directly visualize morphologic and pre-morphologic changes of cartilage by using conventional as well as complex MRI techniques.

PGC-1α promotes recovery after acute kidney injury during systemic inflammation in mice.

Sepsis-associated acute kidney injury (AKI) is a common and morbid condition that is distinguishable from typical ischemic renal injury by its paucity of tubular cell death. The mechanisms underlying renal dysfunction in individuals with sepsis-associated AKI are therefore less clear. Here we have shown that endotoxemia reduces oxygen delivery to the kidney, without changing tissue oxygen levels, suggesting reduced oxygen consumption by the kidney cells. Tubular mitochondria were swollen, and their function was impaired. Expression profiling showed that oxidative phosphorylation genes were selectively suppressed during sepsis-associated AKI and reactivated when global function was normalized. PPARγ coactivator-1α (PGC-1α), a major regulator of mitochondrial biogenesis and metabolism, not only followed this pattern but was proportionally suppressed with the degree of renal impairment. Furthermore, tubular cells had reduced PGC-1α expression and oxygen consumption in response to TNF-α; however, excess PGC-1α reversed the latter effect. Both global and tubule-specific PGC-1α-knockout mice had normal basal renal function but suffered persistent injury following endotoxemia. Our results demonstrate what we believe to be a novel mechanism for sepsis-associated AKI and suggest that PGC-1α induction may be necessary for recovery from this disorder, identifying a potential new target for future therapeutic studies.

A randomized, double-blind study of AMG 108 (a fully human monoclonal antibody to IL-1R1) in patients with osteoarthritis of the knee.

INTRODUCTION: AMG 108 is a fully human, immunoglobulin subclass G2 (IgG2) monoclonal antibody that binds the human interleukin-1 (IL-1) receptor type 1, inhibiting the activity of IL-1a and IL-1b. In preclinical studies, IL-1 inhibition was shown to be beneficial in models of osteoarthritis (OA). The purpose of this two-part study was to evaluate the safety and pharmacokinetics (PK; Part A) and clinical effect (Part B) of AMG 108 in a double-blind, placebo-controlled, multiple-dose study in patients with OA of the knee. METHODS: In Part A, patients received placebo or AMG 108 subcutaneously (SC; 75 mg or 300 mg) or intravenously (IV; 100 mg or 300 mg) once every 4 weeks for 12 weeks; in Part B, patients received placebo or 300 mg AMG 108 SC, once every 4 weeks for 12 weeks. The clinical effect of AMG 108 was measured in Part B by using the Western Ontario and McMaster Universities (WOMAC) osteoarthritis index pain score. RESULTS: In Part A, 68 patients were randomized, and 64 received investigational product. In Part B, 160 patients were randomized, and 159 received investigational product. AMG 108 was well tolerated. Most adverse events (AEs), infectious AEs, serious AEs and infections, as well as withdrawals from the study due to AEs occurred at similar rates in both active and placebo groups. One death was reported in an 80-year-old patient (Part A, 300 mg IV AMG 108; due to complications of lobar pneumonia). AMG 108 serum concentration-time profiles exhibited nonlinear PK. The AMG 108 group in Part B had statistically insignificant but numerically greater improvement in pain compared with the placebo group, as shown by the WOMAC pain scores (median change, -63.0 versus -37.0, respectively). CONCLUSIONS: The safety profile of AMG 108 SC and IV was comparable with placebo in patients with OA of the knee. Patients who received AMG 108 showed statistically insignificant but numerically greater improvements in pain; however, minimal, if any, clinical benefit was observed. TRIAL REGISTRATION: This study is registered with ClinicalTrials.gov with the identifier NCT00110942.

Articular cartilage in the knee: current MR imaging techniques and applications in clinical practice and research.

Magnetic resonance (MR) imaging is the most important imaging modality for the evaluation of traumatic or degenerative cartilaginous lesions in the knee. It is a powerful noninvasive tool for detecting such lesions and monitoring the effects of pharmacologic and surgical therapy. The specific MR imaging techniques used for these purposes can be divided into two broad categories according to their usefulness for morphologic or compositional evaluation. To assess the structure of knee cartilage, standard spin-echo (SE) and gradient-recalled echo (GRE) sequences, fast SE sequences, and three-dimensional SE and GRE sequences are available. These techniques allow the detection of morphologic defects in the articular cartilage of the knee and are commonly used in research for semiquantitative and quantitative assessments of cartilage. To evaluate the collagen network and proteoglycan content in the knee cartilage matrix, compositional assessment techniques such as T2 mapping, delayed gadolinium-enhanced MR imaging of cartilage (or dGEMRIC), T1ρ imaging, sodium imaging, and diffusion-weighted imaging are available. These techniques may be used in various combinations and at various magnetic field strengths in clinical and research settings to improve the characterization of changes in cartilage.

Delayed contrast-enhanced MRI of cartilage: comparison of nonionic and ionic contrast agents.

The objective of this study was to evaluate if cartilage fixed charge density is the only factor determining the distribution of the measured delayed gadolinium-enhanced magnetic resonance imaging of cartilage index, T(1) (Gd-DTPA(2-) ), across cartilage in the clinical delayed gadolinium-enhanced magnetic resonance imaging of cartilage protocol. Nineteen subjects with osteoarthritis and 14 controls were included. Cartilage T(1) (Gd) was measured following administration of 0.2 mmol kg(-1) of nonionic (Gd-DTPA-BMA) and, at a different date, anionic (Gd-DTPA(2-). T(1) (Gd-DTPA-BMA) was plotted against T(1) (Gd-DTPA(2-); a slope of 0 would indicate domination by charge effects; a nonzero slope would suggest that other factors influence T(1) (Gd-DTPA-BMA), and hence potentially T(1) (Gd-DTPA(2-). The low slope of the curve found in osteoarthritis subjects (0.31) indicates that Gd-DTPA-BMA penetrated most osteoarthritis cartilage to the same extent, and T(1) (Gd-DTPA-BMA) did not differentiate cartilages, which were differentiated by T(1) (Gd-DTPA(2-). The higher slopes in control subjects (0.88) are possibly due to inhibited transport of contrast agent into healthier cartilage, potentially exaggerated by the fast body clearance of the nonionic contrast agent. Overall, the use of anionic Gd-DTPA(2-) for delayed gadolinium-enhanced magnetic resonance imaging of cartilage is indicated for better discrimination of the health status of cartilage. Future studies could be designed to use contrast-enhanced dynamics to understand the transport properties of tissues in the joint and to evaluate the concentration of tissue constituents.

Measures of molecular composition and structure in osteoarthritis.

Osteoarthritis involves ongoing degradative and healing processes that occur at the molecular level in multiple tissues in the joint in response to a number of biochemical and mechanical factors. Understanding these dynamic processes before they affect the structural aspects of the joint motivates the need for metrics to better visualize the compositional and structural molecular aspects of the tissues in vivo. As reviewed here, most of the work to date in this regard has been focused on magnetic resonance imaging approaches for interrogating molecular features of cartilage, including T2 mapping, T1rho mapping, delayed gadolinium-enhanced magnetic resonance imaging of cartilage (dGEMRIC), and sodium imaging. Specific examples illustrate new opportunities and insights emerging from these methods.

Radiographic and patient factors associated with pre-radiographic osteoarthritis in hip dysplasia.

BACKGROUND: Hip dysplasia leads to abnormal loading of articular cartilage, which results in osteoarthritis. The purpose of this study was to investigate the anatomic and demographic factors associated with the early onset of osteoarthritis in dysplastic hips by utilizing the delayed gadolinium-enhanced magnetic resonance imaging of cartilage (dGEMRIC) index as a marker of the disease. METHODS: Ninety-six symptomatic dysplastic hips in seventy-four patients were assessed with standard radiographs and a dGEMRIC scan. The lateral center-edge angle of Wiberg, the acetabular index of Tönnis, and the break in the Shenton line were measured on a standing anteroposterior radiograph. Anterior undercoverage was assessed by measuring the anterior center-edge angle on a Lequesne false-profile view. A labral tear was considered to be present when contrast agent was seen through the entire thickness of the labrum on magnetic resonance arthrography. Osteoarthritis was defined as a dGEMRIC value of <390 msec (two standard deviations below the dGEMRIC index in normal hips). RESULTS: The mean dGEMRIC index (and standard deviation) for this cohort (473 +/- 104 msec) was significantly lower than that of a morphologically normal hip (570 +/- 90 msec). The anterior center-edge angle, the joint space width, and the presence of a labral tear were all found to be associated with osteoarthritis in the univariate analysis. Multivariate analysis identified age, the anterior center-edge angle, and the presence of a labral tear as independent factors associated with osteoarthritis. A second model was fitted with omission of the anterior center-edge angle because the lateral and anterior center-edge angles were highly correlated and the lateral center-edge angle is a more common clinical measure. This model identified age, the lateral center-edge angle, and the presence of a labral tear as significant independent factors associated with osteoarthritis. CONCLUSIONS: As has been demonstrated in previous studies of the hip, this investigation showed osteoarthritis to be associated with increasing age and the severity of dysplasia, as demonstrated both by the Wiberg lateral center-edge angle and the Lequesne anterior center-edge angle. Additionally, we identified a labral tear as being a risk factor for osteoarthritis.

Tracking longitudinal changes in knee degeneration and repair.

The ability to track longitudinal changes in knee degeneration and repair is critical to understanding the natural history of joint disease as well as the impact of therapeutics and lifestyle interventions. Traditionally, longitudinal changes in the knee have been monitored with radiography, which focuses on relatively late disease progression. The ability of magnetic resonance imaging to monitor tissue composition may enable monitoring of early degeneration as well as repair. Most studies thus far have focused on cartilage, although there is increasing recognition of the need for molecular imaging of bone, ligament, and meniscus. The three magnetic resonance imaging parameters that have been utilized up to this point in studies of cartilage in the knee are T2-weighted, T1rho-weighted, and delayed gadolinium-enhanced magnetic resonance imaging of cartilage (dGEMRIC). Perhaps the main impact of these newer methods lies in their ability to demonstrate, in vivo, that native cartilage can repair or reverse apparent degenerative changes. This ability should alter the mind-set of clinical investigators and encourage them to shift the focus of their studies to early detection of degeneration and to interventions that reverse the damage before long-term effects become apparent. In fact, a number of clinical studies have demonstrated an improvement in the biochemical status of cartilage over time, including an increase in the dGEMRIC index with exercise intervention, after traumatic injury, and after surgical interventions. The ability of magnetic resonance imaging to visualize osteoarthritis as a regional and responsive (reversible) disease may lead to new paradigms for developing and applying lifestyle, medical, and surgical therapeutic interventions.

The effect of paraformaldehyde fixation on the delayed gadolinium-enhanced MRI of cartilage (dGEMRIC) measurement.

The delayed Gadolinium-Enhanced Magnetic Resonance Imaging of Cartilage (dGEMRIC) method allows for both qualitative and quantitative measurement of the spatial distribution of glycosaminoglycan [GAG] in excised cartilage. The objective of this study was to determine the effect of paraformaldehyde fixation on dGEMRIC measurements. Five bovine and seven human cartilage pieces were punched into 5-mm plugs, fixed for 18 h in 4% paraformaldehyde solution, and washed. The magnetic resonance imaging (MRI) parameter T1 was measured prior and post fixation in cartilage without (T1(0)) and with (T1(Gd)), the ionically charged MRI contrast agent Gd(DTPA)(2-). Images of tissue before and after fixation were qualitatively very similar. The ratios of T1(0), T1(Gd), and calculated [GAG] after fixation, relative to before fixation, were near or slightly higher than 1 for both bovine cartilage (1.01 +/- 0.01, 1.04 +/- 0.02, 1.05 +/- 0.03, respectively) and for human cartilage (0.96 +/- 0.11, 1.03 +/- 0.05, 1.09 +/- 0.13). Thus, these data suggest that dGEMRIC can be used on previously fixed samples to assess the three dimensional spatial distribution of GAG.

Osteoarthritis: current role of imaging.

Osteoarthritis (OA) is the most prevalent joint disease; it is increasingly common in the aging population of Western society and has a major health economic impact. Despite surgery and symptom-oriented approaches there is no efficient treatment. Conventional radiography has played a role in the past in confirming diagnosis and demonstrating late bony changes and joint space narrowing. MRI has become the method of choice in large research endeavors and may become important for individualized treatment planning. This article focuses on radiography and MRI, with insight into other modalities, such as ultrasound, scintigraphy, and CT. Their role in OA diagnosis, follow-up, and research is discussed.