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.

Using deep learning for dermatologist-level detection of suspicious pigmented skin lesions from wide-field images.

A reported 96,480 people were diagnosed with melanoma in the United States in 2019, leading to 7230 reported deaths. Early-stage identification of suspicious pigmented lesions (SPLs) in primary care settings can lead to improved melanoma prognosis and a possible 20-fold reduction in treatment cost. Despite this clinical and economic value, efficient tools for SPL detection are mostly absent. To bridge this gap, we developed an SPL analysis system for wide-field images using deep convolutional neural networks (DCNNs) and applied it to a 38,283 dermatological dataset collected from 133 patients and publicly available images. These images were obtained from a variety of consumer-grade cameras (15,244 nondermoscopy) and classified by three board-certified dermatologists. Our system achieved more than 90.3% sensitivity (95% confidence interval, 90 to 90.6) and 89.9% specificity (89.6 to 90.2%) in distinguishing SPLs from nonsuspicious lesions, skin, and complex backgrounds, avoiding the need for cumbersome individual lesion imaging. We also present a new method to extract intrapatient lesion saliency (ugly duckling criteria) on the basis of DCNN features from detected lesions. This saliency ranking was validated against three board-certified dermatologists using a set of 135 individual wide-field images from 68 dermatological patients not included in the DCNN training set, exhibiting 82.96% (67.88 to 88.26%) agreement with at least one of the top three lesions in the dermatological consensus ranking. This method could allow for rapid and accurate assessments of pigmented lesion suspiciousness within a primary care visit and could enable improved patient triaging, utilization of resources, and earlier treatment of melanoma.

Non-invasive detection of severe neutropenia in chemotherapy patients by optical imaging of nailfold microcirculation.

White-blood-cell (WBC) assessment is employed for innumerable clinical procedures as one indicator of immune status. Currently, WBC determinations are obtained by clinical laboratory analysis of whole blood samples. Both the extraction of blood and its analysis limit the accessibility and frequency of the measurement. In this study, we demonstrate the feasibility of a non-invasive device to perform point-of-care WBC analysis without the need for blood draws, focusing on a chemotherapy setting where patients' neutrophils-the most common type of WBC-become very low. In particular, we built a portable optical prototype, and used it to collect 22 microcirculatory-video datasets from 11 chemotherapy patients. Based on these videos, we identified moving optical absorption gaps in the flow of red cells, using them as proxies to WBC movement through nailfold capillaries. We then showed that counting these gaps allows discriminating cases of severe neutropenia (<500 neutrophils per µL), associated with increased risks of life-threatening infections, from non-neutropenic cases (>1,500 neutrophils per µL). This result suggests that the integration of optical imaging, consumer electronics, and data analysis can make non-invasive screening for severe neutropenia accessible to patients. More generally, this work provides a first step towards a long-term objective of non-invasive WBC counting.

Detecting Motor Impairment in Early Parkinson's Disease via Natural Typing Interaction With Keyboards: Validation of the neuroQWERTY Approach in an Uncontrolled At-Home Setting.

BACKGROUND: Parkinson's disease (PD) is the second most prevalent neurodegenerative disease and one of the most common forms of movement disorder. Although there is no known cure for PD, existing therapies can provide effective symptomatic relief. However, optimal titration is crucial to avoid adverse effects. Today, decision making for PD management is challenging because it relies on subjective clinical evaluations that require a visit to the clinic. This challenge has motivated recent research initiatives to develop tools that can be used by nonspecialists to assess psychomotor impairment. Among these emerging solutions, we recently reported the neuroQWERTY index, a new digital marker able to detect motor impairment in an early PD cohort through the analysis of the key press and release timing data collected during a controlled in-clinic typing task. OBJECTIVE: The aim of this study was to extend the in-clinic implementation to an at-home implementation by validating the applicability of the neuroQWERTY approach in an uncontrolled at-home setting, using the typing data from subjects' natural interaction with their laptop to enable remote and unobtrusive assessment of PD signs. METHODS: We implemented the data-collection platform and software to enable access and storage of the typing data generated by users while using their computer at home. We recruited a total of 60 participants; of these participants 52 (25 people with Parkinson's and 27 healthy controls) provided enough data to complete the analysis. Finally, to evaluate whether our in-clinic-built algorithm could be used in an uncontrolled at-home setting, we compared its performance on the data collected during the controlled typing task in the clinic and the results of our method using the data passively collected at home. RESULTS: Despite the randomness and sparsity introduced by the uncontrolled setting, our algorithm performed nearly as well in the at-home data (area under the receiver operating characteristic curve [AUC] of 0.76 and sensitivity/specificity of 0.73/0.69) as it did when used to evaluate the in-clinic data (AUC 0.83 and sensitivity/specificity of 0.77/0.72). Moreover, the keystroke metrics presented a strong correlation between the 2 typing settings, which suggests a minimal influence of the in-clinic typing task in users' normal typing. CONCLUSIONS: The finding that an algorithm trained on data from an in-clinic setting has comparable performance with that tested on data collected through naturalistic at-home computer use reinforces the hypothesis that subtle differences in motor function can be detected from typing behavior. This work represents another step toward an objective, user-convenient, and quasi-continuous monitoring tool for PD.

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.

Toward imaging biomarkers for glycosaminoglycans.

Advances in the diagnosis and treatment of cartilage degeneration will be accelerated with the availability of validated biomarkers that reveal the features relevant to the health of cartilage. Using the delayed gadolinium-enhanced magnetic resonance imaging of cartilage (dGEMRIC) technique for evaluating tissue glycosaminoglycan as a case study, I review the types of evidence needed to validate imaging (or other) biomarkers. In addition, I present discussions about face validity and technical validity and offer a review of emerging data that provide pathophysiologic validity. Examples of such data include evidence that glycosaminoglycan content is restored after an injury-induced loss and evidence suggesting that dGEMRIC can indicate when it is too late for protective (load-modifying) surgery. These and other data suggest that new imaging biomarkers may indeed be able to provide a state-of-cartilage proxy that can be of use in the diagnosis and staging of disease.

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.

2007 Elizabeth Winston Lanier Award Winner. Magnetic resonance imaging of cartilage glycosaminoglycan: basic principles, imaging technique, and clinical applications.

Many new therapeutic strategies have been and are being developed to prevent, correct, or slow the progression of osteoarthritis. Our ability to evaluate the efficacy of these techniques, or to determine the situations for which they might provide the most benefit, critically depends on diagnostic measures that can serve as proxies for the present or predicted state of the cartilage. We focus here on a body of work surrounding the development of magnetic resonance imaging (MRI) techniques to noninvasively image the glycosaminoglycan (GAG) concentration of articular cartilage. These techniques are based on the concept of fixed charge in cartilage resulting from the glycosaminoglycans. Starting with sodium MRI, and the subsequent development of delayed gadolinium-enhanced MRI of cartilage (dGEMRIC) based on proton MRI, these techniques permit "visualization" of the charged GAG distribution in cartilage in vitro or in vivo. The dGEMRIC technique has been used in preliminary clinical studies to understand treatment strategies and to monitor disease, and as such is allowing studies that a decade ago would have been impossible. This new technical capability offers the promises of speeding development of effective therapies and focusing their use in areas where they can be most successful.

Relationship between cartilage stiffness and dGEMRIC index: correlation and prediction.

We sought to determine if a generalized relationship between the dGEMRIC index (T1Gd relaxation time) and compressive stiffness of articular cartilage could be defined across multiple samples. Osteochondral blocks were cut from 12 human tibial plateaus, six from cadaveric sources and six from total knee replacement surgeries. Each block contained submeniscal ("covered") and extrameniscal ("uncovered") cartilage regions. At approximately 18 sites per block, a pulse indentation was applied and local dGEMRIC index was determined using dGEMRIC MRI. No correlation was found between stiffness and full cartilage depth dGEMRIC index. When averaged over the depth comparable to the indentation, good correlations were found between stiffness and the dGEMRIC index whether all data were combined, or whether each sample/region was considered independently. However, the standard error of the estimate for predicting stiffness from the local dGEMRIC index was improved when the uncovered and covered regions were considered separately. Further improvement in predictive capacity was obtained if, rather than predict absolute stiffness, differences in the dGEMRIC index across a region were used to predict difference in stiffness. The dGEMRIC index is highly correlated to mechanical stiffness. A generalized relationship was found to provide good correspondence across sources and regions. Use of the dGEMRIC index as a predictive measure of stiffness is possible, depending on the application's acceptable error.

Advanced tools for tissue engineering: scaffolds, bioreactors, and signaling.

This article contains the collective views expressed at the second session of the workshop "Tissue Engineering--The Next Generation,'' which was devoted to the tools of tissue engineering: scaffolds, bioreactors, and molecular and physical signaling. Lisa E. Freed and Farshid Guilak discussed the integrated use of scaffolds and bioreactors as tools to accelerate and control tissue regeneration, in the context of engineering mechanically functional cartilage and cardiac muscle. Edward Guo focused on the opportunities that tissue engineering generates for studies of mechanobiology and on the need for tissue engineers to learn about mechanical forces during tissue and organ genesis. Martha L. Gray focused on the potential of biomedical imaging for noninvasive monitoring of engineered tissues and on the opportunities biomedical imaging can generate for the development of new markers. Robert Tranquillo reviewed the approach to tissue engineering of a spectrum of avascular habitually loaded tissues- blood vessels, heart valves, ligaments, tendons, cartilage, and skin. Jeffrey W. Holmes offered the perspective of a "reverse paradigm''--the use of tissue constructs in quantitative studies of cell-matrix interactions, cell mechanics, matrix mechanics, and mechanobiology. Milica Radisic discussed biomimetic design of tissue-engineering systems, on the example of synchronously contractile cardiac muscle. Michael V. Sefton proposed a new, simple approach to the vascularization of engineered tissues. This session stressed the need for advanced scaffolds, bioreactors, and imaging technologies and offered many enlightening examples on how these advanced tools can be utilized for functional tissue engineering and basic research in medicine and biology.

Spatially-localized correlation of dGEMRIC-measured GAG distribution and mechanical stiffness in the human tibial plateau.

The concentration of glycosaminoglycan (GAG) in articular cartilage is known to be an important determinant of tissue mechanical properties based on numerous studies relating bulk GAG and mechanical properties. To date limited information exists regarding the relationship between GAG and mechanical properties on a spatially-localized basis in intact samples of native tissue. This relation can now be explored by using delayed gadolinium-enhanced MRI of cartilage (dGEMRIC--a recently available non-destructive magnetic resonance imaging method for measuring glycosaminoglycan concentration) combined with non-destructive mechanical indentation testing. In this study, three tibial plateaus from patients undergoing total knee arthroplasty were imaged by dGEMRIC. At 33-44 test locations for each tibial plateau, the load response to focal indentation was measured as an index of cartilage stiffness. Overall, a high correlation was found between the dGEMRIC index (T(1Gd)) and local stiffness (Pearson correlation coefficients r = 0.90, 0.64, 0.81; p < 0.0001) when the GAG at each test location was averaged over a depth of tissue comparable to that affected by the indentation. When GAG was averaged over larger depths, the correlations were generally lower. In addition, the correlations improved when the central and peripheral (submeniscal) areas of the tibial plateau were analyzed separately, suggesting that a factor other than GAG concentration is also contributing to indentation stiffness. The results demonstrate the importance of MRI in yielding spatial localization of GAG concentration in the evaluation of cartilage mechanical properties when heterogeneous samples are involved and suggest the possibility that the evaluation of mechanical properties may be improved further by adding other MRI parameters sensitive to the collagen component of cartilage.

Toward imaging biomarkers for osteoarthritis.

Many new therapeutic strategies have been and are being developed to correct, prevent, or slow the progression of osteoarthritis. Our ability to evaluate the efficacy of these techniques, or to determine the situations for which they might provide the most benefit, critically depends on diagnostic measures that can serve as proxies for the present or predicted state of the cartilage. Many of the magnetic resonance imaging techniques that have been emerging over the past decades appear promising in that they have shown technical validity in measuring the morphologic and molecular state of cartilage. With continued development and added insight from pilot clinical studies, these or related methods may soon be in customary use. These techniques are part of a paradigm shift where therapeutic strategies are developed hand-in-hand with diagnostic approaches-a shift that offers the promise of speeding development of effective therapies, and focusing their use in areas where they can be most successful.

T2 and T1rho MRI in articular cartilage systems.

T2 and T1rho have potential to nondestructively detect cartilage degeneration. However, reports in the literature regarding their diagnostic interpretation are conflicting. In this study, T2 and T1rho were measured at 8.5 T in several systems: 1) Molecular suspensions of collagen and GAG (pure concentration effects): T2 and T1rho demonstrated an exponential decrease with increasing [collagen] and [GAG], with [collagen] dominating. T2 varied from 90 to 35 ms and T1rho from 125 to 55 ms in the range of 15-20% [collagen], indicating that hydration may be a more important contributor to these parameters than previously appreciated. 2) Macromolecules in an unoriented matrix (young bovine cartilage): In collagen matrices (trypsinized cartilage) T2 and T1rho values were consistent with the expected [collagen], suggesting that the matrix per se does not dominate relaxation effects. Collagen/GAG matrices (native cartilage) had 13% lower T2 and 17% lower T1rho than collagen matrices, consistent with their higher macromolecular concentration. Complex matrix degradation (interleukin-1 treatment) showed lower T2 and unchanged T1rho relative to native tissue, consistent with competing effects of concentration and molecular-level changes. In addition, the heterogeneous GAG profile in these samples was not reflected in T2 or T1rho. 3) Macromolecules in an oriented matrix (mature human tissue): An oriented collagen matrix (GAG-depleted human cartilage) showed T2 and T(1rho) variation with depth consistent with 16-21% [collagen] and/or fibril orientation (magic angle effects) seen on polarized light microscopy, suggesting that both hydration and structure comprise important factors. In other human cartilage regions, T2 and T1rho abnormalities were observed unrelated to GAG or collagen orientation differences, demonstrating that hydration and/or molecular-level changes are important. Overall, these studies illustrate that T2 and T1rho are sensitive to biologically meaningful changes in cartilage. However, contrary to some previous reports, they are not specific to any one inherent tissue parameter.

Assessment of early osteoarthritis in hip dysplasia with delayed gadolinium-enhanced magnetic resonance imaging of cartilage.

BACKGROUND: The efficacy of surgical and medical treatment of osteoarthritis is difficult to assess because of the lack of a noninvasive, sensitive measure of cartilage integrity. Delayed gadolinium-enhanced magnetic resonance imaging of cartilage (dGEMRIC) was designed to specifically examine glycosaminoglycan changes in articular cartilage that occur during the development of osteoarthritis. Our primary goal was to compare this technique with measurement of the joint space width on conventional radiographs in patients with hip dysplasia. We performed this comparison by assessing the correlation between the findings of each technique and clinically important factors such as pain, severity of dysplasia, and age. METHODS: Sixty-eight hips in forty-three patients were included in the study. Clinical symptoms were assessed with use of the Western Ontario and McMaster Universities Osteoarthritis (WOMAC) questionnaire. The width of the joint space as well as the lateral center-edge angle of Wiberg (as a measure of the severity of the dysplasia) was measured on standard standing radiographs. Magnetic resonance imaging maps of glycosaminoglycan distribution were made with T1-calculated images after administration of gadopentetate (2-) (Gd-DTPA (2-) ). The dGEMRIC index was calculated as the average of the T1 values for the acetabular and femoral head cartilages. RESULTS: The dGEMRIC index correlated with both pain (rs = -0.50, p < 0.0001) and the lateral center-edge angle (rs = 0.52, p < 0.0001), whereas the joint space width did not correlate with either, with the numbers available. There was a correlation between the dGEMRIC index and pain whether or not a labral tear was present. The dGEMRIC index was significantly different (p < 0.0001) among three groups of hips classified according to whether they had mild, moderate, or severe dysplasia, whereas the joint space width did not differ significantly among these three groups. There was no significant correlation between age and any of the other parameters. CONCLUSIONS: We demonstrated that, in patients with hip dysplasia, the dGEMRIC index-a measure of the biochemical integrity of cartilage-correlates with pain and the severity of the dysplasia and is significantly different among groups of hips with mild, moderate, and severe dysplasia, suggesting that it may be a sensitive measure of early osteoarthritis. Additional studies are needed to determine whether dGEMRIC can be used to predict disease progression in different situations and/or demonstrate responses to therapeutic interventions.

What's new in cartilage?

Magnetic resonance (MR) imaging of articular cartilage is important in evaluation of new surgical and pharmacologic treatments for cartilage damage. Many techniques exist for MR imaging of articular cartilage. Standard techniques for morphologic imaging of cartilage include fast spin-echo and spoiled gradient-echo imaging. These methods provide high-resolution morphologic images of cartilage but are time-consuming in the clinical setting. New methods for faster or higher-resolution morphologic imaging include techniques based on steady-state free precession imaging. These fast techniques will allow detailed evaluation of cartilage in the routine clinical setting. There are also several MR imaging methods that may provide information about the structure and physiology of cartilage. Physiologic imaging may allow detailed evaluation of the glycosaminoglycan matrix or collagen network of articular cartilage and may be the most sensitive method for detection of early changes. With the development of new therapies for osteoarthritis and cartilage injury, MR imaging of articular cartilage is of increasing clinical importance. MR imaging will play an important role in evaluation of the effectiveness of these therapies.

Differential recovery of glycosaminoglycan after IL-1-induced degradation of bovine articular cartilage depends on degree of degradation.

In the present study we examined cartilage matrix repair following IL-1-induced matrix depletion. Previous data indicated that, in some cases, chondrocytes can synthesize macromolecules to establish a functional extracellular matrix in response to a matrix-damaging insult or when placed in a three-dimensional environment with inadequate matrix. However, the conditions under which such 'repair' can occur are not entirely clear. Prior studies have shown that chondrocytes in trypsin-depleted young bovine articular cartilage can replenish tissue glycosaminoglycan (GAG) and that the rate of replenishment is relatively uniform throughout the tissue, suggesting that all chondrocytes have similar capacity for repair. In the present study we used the characteristic heterogeneous distribution of matrix depletion in response to IL-1 exposure in order to investigate whether the severity of depletion influenced the rate of GAG replenishment. We used the delayed Gadolinium-Enhanced Magnetic Resonance Imaging of Cartilage (dGEMRIC) method to monitor the spatial and temporal evolution of tissue GAG concentration ([GAG]). For both mild (n=4) and moderate (n=10) IL-1-induced GAG depletion, we observed partial recovery of GAG (80% and 50% of baseline values, respectively) over a 3-week recovery period. During the first 2 weeks of recovery, [GAG] increased homogeneously at 10-15 mg/ml per week. However, during the third week the regions most severely depleted following IL-1 exposure showed negligible [GAG] accumulation, whereas those regions affected the least by IL-1 demonstrated the greatest accumulation. This finding could suggest that the most severely degraded regions do not recover fully, possibly because of more severe collagen damage; this possibility requires further examination.