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Osteoporosis is the most common disease affecting bones worldwide. Dual x-ray absorptiometry (DXA) is the current reference standard for assessing bone health and, combined with other clinical parameters, provides a good estimation of fracture risk. DXA-based Trabecular Bone Score (TBS) can provide complementary indirect information about bone microarchitecture, which also deteriorates osteoporosis. QCT can provide a 3-D volumetric assessment of bone mineral density (BMD), and FEA of computed tomography (CT) images of bone can provide estimates of bone strength, which have the potential to add value, beyond BMD, for fracture risk assessment. Magnetic resonance imaging (MRI) of bone microarchitecture is an additional promising alternative to the assessment of BMD, and there is evidence that microarchitectural parameters could 1 day have benefits for diagnosing osteoporosis beyond BMD and/or FRAX. Assessment of bone via MRI also provides insight into other bone tissue properties (cortical porosity, marrow fat) that are altered in osteoporosis and that DXA cannot assess. Overall, bone health cannot be characterized solely by one parameter. Current imaging techniques/modalities in combination with advanced image processing hold the potential to provide a comprehensive understanding of the pathologic changes that occur in bone tissue in the setting of osteoporosis and pave the way for new imaging methods to diagnose, monitor, and predict osteoporosis.

Systemic lupus erythematosus (SLE) is a chronic, inflammatory disease with common musculoskeletal manifestations, notably reductions in bone quality. Bone marrow adipose tissue composition and quantity has been previously linked to bone quality and may play a role in SLE pathophysiology but has not been thoroughly studied.To use magnetic resonance spectroscopy (MRS) to investigate bone marrow adipose tissue quantity and composition in proximal femur subregions of untreated SLE patients compared to controls and treated patients.Prospective.A total of 64 female subjects: 28 SLE, 15 glucocorticoid (GC)-treated SLE and 21 matched controls.Stimulated echo acquisition mode (STEAM) sequence at 3 T.MRS was performed at multiple echo times in the femoral neck and trochanter regions and fatty acids (FA) composition was computed.Intergroup comparisons were carried out using ANOVA. A P value 0.05 was considered statistically significant.SLE patients had significantly higher saturated FA compared to controls in both the femoral neck (+0.12) and trochanter (+0.11), significantly lower monounsaturated FA in the trochanter compared to controls (-0.05), and significantly lower polyunsaturated FA in the femoral neck compared to both controls (-0.07) and SLE patients on GC therapy (-0.05).SLE patients have altered proximal femur marrow fat metabolism, which may reflect a manifestation of, or play a role in, the altered inflammatory response of these patients.2 TECHNICAL EFFICACY: Stage 2.

Quantitative MRI can detect early biochemical changes in cartilage; however, the conventional techniques only measure one parameter (e.g., Tsub1/sub, Tsub2/sub, and Tsub1ρ/sub) at a time while also being comparatively slow. We implemented a 3D magnetic resonance fingerprinting (3D-MRF) technique for simultaneous, volumetric mapping of Tsub1/sub, Tsub2/sub, and Tsub1ρ/subin knee articular cartilage in under 9 min. It is evaluated on 11 healthy volunteers (mean age: 53 ± 9 years), five mild knee osteoarthritis (OA) patients (Kellgren-Lawrence (KL) score: 2, mean age: 60 ± 4 years), and the National Institute of Standards and Technology (NIST)/International Society for Magnetic Resonance in Medicine (ISMRM) system phantom. Proton density image, and Tsub1/sub, Tsub2,/subTsub1ρ/subrelaxation times, and Bsub1/subsup+/supwere estimated in the NIST/ISMRM system phantom as well as in the human knee medial and lateral femur, medial and lateral tibia, and patellar cartilage. The repeatability and reproducibility of the proposed technique were assessed in the phantom using analysis of the Bland-Altman plots. The intrasubject repeatability was assessed with the coefficient of variation (CV) and root mean square CV (rmsCV). The Mann-Whitney U test was used to assess the difference between healthy subjects and mild knee OA patients. The Bland-Altman plots in the NIST/ISMRM phantom demonstrated an average difference of 0.001% ± 015%, 1.2% ± 7.1%, and 0.47% ± 3% between two scans from the same 3-T scanner (repeatability), and 0.002% ± 015%, 0.62% ± 10.5%, and 0.97% ± 14% between the scans acquired on two different 3-T scanners (reproducibility) for Tsub1/sub, Tsub2/sub, and Tsub1ρ/sub, respectively. The in vivo knee study showed excellent repeatability with rmsCV less than 1%, 2%, and 1% for Tsub1/sub, Tsub2/sub, and Tsub1ρ/sub, respectively. Tsub1ρ/subrelaxation time in the mild knee OA patients was significantly higher (p lt; 0.05) than in healthy subjects. The proposed 3D-MRF sequence is fast, reproducible, robust to Bsub1/subsup+/supinhomogeneity, and can simultaneously measure the Tsub1/sub, Tsub2/sub, Tsub1ρ/sub, and Bsub1/subsup+/supvolumetric maps of the knee joint in a single scan within a clinically feasible scan time.

Spondyloarthritis (SpA) is a group of chronic, immune-mediated, inflammatory diseases affecting the bone, synovium, and enthesis. Microbiome, the community of microorganisms that has co-evolved with human hosts, plays a pivotal role in human health and disease. This invisible "essential organ" supplies the host with a myriad of chemicals and molecules. In turn, microbial metabolites can serve as messengers for microbes to communicate with each other and in the cross-talk with host cells. Gut dysbiosis in SpA is associated with altered microbial metabolites, and an accumulated body of research has contributed to the understanding that changes in intestinal microbiota can modulate disease pathogenesis. We review the novel findings from human and animal studies to provide an overview of the contribution of individual microbial metabolites and antigens to SpA.

Regulatory approval of ultrahigh field (UHF) MR imaging scanners for clinical use has opened new opportunities for musculoskeletal imaging applications. UHF MR imaging has unique advantages in terms of signal-to-noise ratio, contrast-to-noise ratio, spectral resolution, and multinuclear applications, thus providing unique information not available at lower field strengths. But UHF also comes with a set of technical challenges that are yet to be resolved and may not be suitable for all imaging applications. This review focuses on the latest research in musculoskeletal MR imaging applications at UHF including morphologic imaging, T2, T2∗, and T1ρ mapping, chemical exchange saturation transfer, sodium imaging, and phosphorus spectroscopy imaging applications.

Identification of chemicals that affect hormone-regulated systems will help to predict endocrine disruption. In our previous study, a 46 gene biomarker was found to be an accurate predictor of estrogen receptor (ER) α modulation in chemically treated MCF-7 cells. Here, potential ERα modulators were identified using the biomarker by screening a microarray compendium consisting of ∼1600 gene expression comparisons representing exposure to ∼1200 chemicals. A total of ∼170 chemicals were identified as potential ERα modulators. In the Connectivity Map 2.0 collection, 75 and 39 chemicals were predicted to activate or suppress ERα, and they included 12 and six known ERα agonists and antagonists/selective ERα modulators, respectively. Nineteen and eight of the total number were also identified as active in an ERα transactivation assay carried out in an MCF-7-derived cell line used to screen the Tox21 10K chemical library in agonist or antagonist modes, respectively. Chemicals predicted to modulate ERα in MCF-7 cells were examined further using global and targeted gene expression in wild-type and ERα-null cells, transactivation assays, and cell-free ERα coregulator interaction assays. Environmental chemicals classified as weak and very weak agonists were confirmed to activate ERα including apigenin, kaempferol, and oxybenzone. Novel activators included digoxin, nabumetone, ivermectin, and six progestins. Novel suppressors included emetine, mifepristone, niclosamide, and proscillaridin. Our strategy will be useful to identify environmentally relevant ERα modulators in future high-throughput transcriptomic screens.

Acquired resistance to aromatase inhibitors (AIs) is a significant clinical issue in endocrine therapy for estrogen receptor (ER) positive breast cancer which accounts for the majority of breast cancer. Despite estrogen production being suppressed, ERα signaling remains active and plays a key role in most AI-resistant breast tumors. Here, we found that amphiregulin (AREG), an ERα transcriptional target and epidermal growth factor receptor (EGFR) ligand, is crucial for maintaining ERα expression and signaling in acquired AI-resistant breast cancer cells. AREG was deregulated and critical for cell viability in ER+ AI-resistant breast cancer cells, and ectopic expression of AREG in hormone responsive breast cancer cells promoted endocrine resistance. RNA-sequencing and reverse phase protein array analyses revealed that AREG maintains ERα expression and signaling by activation of PI3K/Akt/mTOR signaling and upregulation of Forkhead Box M1 (FoxM1) and Serum- and glucocorticoid-inducible kinase 3 (SGK3) expression. Our study uncovers a previously unappreciated role of AREG in maintaining ERα expression and signaling, and establishes the AREG-ERα crosstalk as a driver of acquired AI resistance in breast cancer.

PURPOSE OF REVIEW: Osteoarthritis is a major source of disability, pain and socioeconomic cost worldwide. The epidemiology of the disorder is multifactorial including genetic, biological and biomechanical components, some of them detectable by MRI. This review provides the most recent update on MRI biomarkers which can provide functional information of the joint structures for diagnosis, prognosis and treatment response monitoring in osteoarthritis trials. RECENT FINDINGS: Compositional or functional MRI can provide clinicians with valuable information on glycosaminoglycan content (chemical exchange saturation transfer, sodium MRI, T(1ρ)) and collagen organization (T(2), T(2)*, apparent diffusion coefficient, magnetization transfer) in joint structures. Other parameters may also provide useful information, such as volumetric measurements of joint structures or advanced image data postprocessing and analysis. Automated tools seem to have a great potential to be included in these efforts providing standardization and acceleration of the image data analysis process. SUMMARY: Functional or compositional MRI has great potential to provide noninvasive imaging biomarkers for osteoarthritis. Osteoarthritis as a whole joint condition needs to be diagnosed in early stages to facilitate selection of patients into clinical trials and/or to measure treatment effectiveness. Advanced evaluation including machine learning, neural networks and multidimensional data analysis allow for wall-to-wall understanding of parameter interactions and their role in clinical evaluation of osteoarthritis.

Quantitative MRI can detect early biochemical changes in cartilage, but its bilateral use in clinical routines is challenging. The aim of this prospective study was to demonstrate the feasibility of magnetic resonance fingerprinting for bilateral simultaneous T(1), T(2), and T(1ρ) mapping of the hip joint. The study population consisted of six healthy volunteers with no known trauma or pain in the hip. Monoexponential T(1), T(2), and T(1ρ) relaxation components were assessed in femoral lateral, superolateral, and superomedial, and inferior, as well as acetabular, superolateral, and superomedial subregions in left and right hip cartilage. Aligned ranked nonparametric factorial analysis was used to assess the side’s impact on the subregions. Kruskal–Wallis and Wilcoxon tests were used to compare subregions, and coefficient of variation to assess repeatability. Global averages of T(1) (676.0 ± 45.4 and 687.6 ± 44.5 ms), T(2) (22.5 ± 2.6 and 22.1 ± 2.5 ms), and T(1ρ) (38.2 ± 5.5 and 38.2 ± 5.5 ms) were measured in the left and right hip, and articular cartilage, respectively. The Kruskal–Wallis test showed a significant difference between different subregions’ relaxation times regardless of the hip side (p < 0.001 for T(1), p = 0.012 for T(2), and p < 0.001 for T(lρ)). The Wilcoxon test showed that T(1) of femoral layers was significantly (p < 0.003) higher than that for acetabular cartilage. The experiments showed excellent repeatability with CV(rms) of 1%, 2%, and 4% for T(1), T(2), and T(1ρ,) respectively. It was concluded that bilateral T(1), T(2), and T(1ρ) relaxation times, as well as B(1)(+) maps, can be acquired simultaneously from hip joints using the proposed MRF sequence.

Detecting mutations in the plasma of patients with solid tumors is becoming a valuable method of diagnosing and monitoring cancer. The TERT promoter is mutated at high frequencies in multiple cancer types, most commonly at positions -124 and -146 (designated C228T and C250T, respectively). Detection of these mutations has been challenging because of the high GC content of this region (approximately 80%). We describe development of novel probe-based droplet digital PCR assays that specifically detect and quantify these two mutations, along with the less common 242-243 CC>TT mutation, and demonstrate their application using human tumor and plasma samples from melanoma patients. Assay designs and running conditions were optimized using cancer cell line genomic DNAs with the C228T or C250T mutations. The limits of detection were 0.062% and 0.051% mutant allele fraction for the C228T and C250T assays, respectively. Concordance of 100% was observed between droplet digital PCR and sequencing-based orthogonal methods in the detection of TERT mutant DNA in 32 formalin-fixed, paraffin-embedded melanoma tumors. TERT(mutant) DNA was also identified in 21 of 27 plasma samples (78%) from patients with TERT(mutant) tumors, with plasma mutant allele fractions ranging from 0.06% to 15.3%. There were no false positives in plasma. These data demonstrate the potential of these assays to specifically detect and quantify TERT(mutant) DNA in tumors and plasma of cancer patients.

Polybrominated diphenyl ethers (PBDEs) have been used as flame retardants in household materials. Their environmental persistence has led to continuous human exposure and significant tissue levels. Three PBDE congeners (BDE-47, BDE-100, and BDE-153) have been frequently detected in human serum. Although these compounds appear to possess endocrine disrupting activity, studies are largely missing to determine the biological mechanisms of PBDEs in breast cancer cells. Here, we assessed PBDE bioactivities with three complementary strategies: receptor binding/activity assays; nonbiased RNA-sequencing analysis using an estrogen-dependent breast cancer cell line MCF-7aroERE; and in vivo assessments using patient-derived xenograft (PDX) models of human breast cancer. According to the results from in vitro experiments, the PBDE congeners regulate distinct nuclear receptor signaling pathways. BDE-47 acts as a weak agonist of both estrogen receptor α (ERα) and estrogen-related receptor α (ERRα); it could stimulate proliferation of MCF-7aroERE and induced expression of ER-regulated genes (including cell cycle genes). BDE-153 was found to act as a weak antagonist of ERα. BDE-100 could act as (1) an agonist of aryl hydrocarbon receptor (AhR), inducing expression of CYP1A1 and CYP1B1 and (2) as a very weak agonist/antagonist of ERα. In vivo, a mixture of the three congeners with ratios detected in human serum was tested in an ER+ PDX model. The mixture exhibited estrogenic activity through apoptosis/cell cycle regulation and increased the expression of a proliferation marker, Ki-67. These results advance our understanding of the mechanisms of PBDE exposure in breast cancer cells.

To quantify and compare subregional proximal femur bone marrow fat composition in premenopausal and postmenopausal women using chemical shift-encoded-MRI (CSE-MRI).A multi gradient-echo sequence at 3 T was used to scan both hips of premenopausal (n = 9) and postmenopausal (n = 18) women. Subregional fat composition (saturation, poly-unsaturation, mono-unsaturation) was quantitatively assessed in the femoral head, femoral neck, Ward's triangle, greater trochanter, and proximal shaft in bone marrow adipose tissue and separately within red and yellow marrow adipose tissue.Significant differences in fat composition in postmenopausal compared to premenopausal women, which varied depending on the subregion analyzed, were found. Within both whole and yellow marrow adipose tissue, postmenopausal women demonstrated higher saturation (+14.7% to +43.3%), lower mono- (-11.4% to -33%) and polyunsaturation (-52 to -83%) (p 0.05). Within red marrow adipose tissue, postmenopausal women demonstrated lower fat quantity (-16% to -24%) and decreased polyunsaturation (-80 to -120%) in the femoral neck, greater trochanter, and Ward's triangle (p 0.05).CSE-MRI can be used to detect subregional differences in proximal femur marrow adipose tissue composition between pre- and post-menopausal women in clinically feasible scan times.

RATIONALE AND OBJECTIVES: To determine the impact of COVID-19 workflow changes on patient throughput at the outpatient imaging facilities of a large healthcare system in New York City. MATERIALS AND METHODS: COVID-19 workflow changes to permit social distancing and patient and staff safety included screening at the time of scheduling, encouraging patients to use our digital platform to complete registration/safety forms prior to appointments, stationing screeners at all entrances, limiting waiting room capacity, implementing a texting system to notify patients of delays, limiting dressing room use by encouraging patients to wear exam-appropriate clothing, and accelerating MRI protocols without reducing image quality. We assessed patients' pre-exam wait times, MR exam times, overall time spent on site, and registration for and use of the digital portal before (February 2020) and after (June 2020) implementation of these measures. RESULTS: Across 17 outpatient imaging centers, workflow changes resulted in a 23.1% reduction (-6.8 minutes) in all patients' pre-exam wait times (p

Objective Predictive biomarkers of progression in knee osteoarthritis are sought to enable clinical trials of structure-modifying drugs. A peripheral blood leukocyte (PBL) inflammatory gene signature, MRI-based bone marrow lesions (BML) and meniscus extrusion scores, meniscal lesions, and osteophytes on X-ray each have been shown separately to predict radiographic joint space narrowing (JSN) in subjects with symptomatic knee osteoarthritis (SKOA). In these studies, we determined whether the combination of the PBL inflammatory gene expression and these imaging findings at baseline enhanced the prognostic value of either alone. Methods PBL inflammatory gene expression (increased mRNA for IL-1β, TNFα, and COX-2), routine radiographs, and 3T knee MRI were assessed in two independent populations with SKOA: an NYU cohort and the Osteoarthritis Initiative (OAI). At baseline and 24 months, subjects underwent standardized fixed-flexion knee radiographs and knee MRI. Medial JSN (mJSN) was determined as the change in medial JSW. Progressors were defined by an mJSN cut-point (≥ 0.5 mm/24 months). Models were evaluated by odds ratios (OR) and area under the receiver operating characteristic curve (AUC). Results We validated our prior finding in these two independent (NYU and OAI) cohorts, individually and combined, that an inflammatory PBL inflammatory gene expression predicted radiographic progression of SKOA after adjustment for age, sex, and BMI. Similarly, the presence of baseline BML and meniscal lesions by MRI or semiquantitative osteophyte score on X-ray each predicted radiographic medial JSN at 24 months. The combination of the PBL inflammatory gene expression and medial BML increased the AUC from 0.66 (p = 0.004) to 0.75 (p p Conclusion The use of the PBL inflammatory gene expression together with imaging biomarkers as combinatorial predictive biomarkers, markedly enhances the identification of radiographic progressors. The identification of the SKOA population at risk for progression will help in the future design of disease-modifying OA drug trials and personalized medicine strategies.

To evaluate the effect of circular polarization (CP) and elliptical polarization (EP) of the BIn vitro Ti and CoCr total hip arthroplasty implants were evaluated using high transmit and receive bandwidth turbo spin echo (HBW-TSE) and slice encoding for metal artifact correction (SEMAC) metal artifact reduction techniques. Each technique was implemented at 1.5-T, which only allows for CP of BIn the acetabular cup and femoral neck, 1.5-T CP achieved smaller artifact sizes than 3.0-T CP (28-29% on HBW-TSE, p = 0.002-0.005; 17-34% on SEMAC, p = 0.019-0.102) and 3.0-T EP (25-28% on HBW-TSE, p = 0.010-0.011; 14-36% on SEMAC, p = 0.058-0.135) techniques. In the femoral stem region, 3.0-T EP achieved more efficient artifact suppression than 3.0-T CP (HBW-TSE 44-45%, p0.001-0.022; SEMAC 76-104%, p0.001-0.022) and 1.5-T CP (HBW-TSE 76-96%, p0.001-0.003; SEMAC 138-173%, p = 0.003-0.005) techniques.Despite slightly superior metal reduction ability of the 1.5-T in the region of the acetabular cup and prosthesis neck, 3.0-T MRI of hip arthroplasty implants using elliptically polarized RF pulses may overall be more effective in reducing metal artifacts than the current standard 1.5-T MRI techniques, which by default implements circularly polarized RF pulses.

BACKGROUND: The methods for assessing knee osteoarthritis (OA) do not provide enough comprehensive information to make robust and accurate outcome predictions. PURPOSE: To develop a deep learning (DL) prediction model for risk of OA progression by using knee radiographs in patients who underwent total knee replacement (TKR) and matched control patients who did not undergo TKR. MATERIALS AND METHODS: In this retrospective analysis that used data from the OA Initiative, a DL model on knee radiographs was developed to predict both the likelihood of a patient undergoing TKR within 9 years and Kellgren-Lawrence (KL) grade. Study participants included a case-control matched subcohort between 45 and 79 years. Patients were matched to control patients according to age, sex, ethnicity, and body mass index. The proposed model used a transfer learning approach based on the ResNet34 architecture with sevenfold nested cross-validation. Receiver operating characteristic curve analysis and conditional logistic regression assessed model performance for predicting probability and risk of TKR compared with clinical observations and two binary outcome prediction models on the basis of radiographic readings: KL grade and OA Research Society International (OARSI) grade. RESULTS: Evaluated were 728 participants including 324 patients (mean age, 64 years ± 8 [standard deviation]; 222 women) and 324 control patients (mean age, 64 years ± 8; 222 women). The prediction model based on DL achieved an area under the receiver operating characteristic curve (AUC) of 0.87 (95% confidence interval [CI]: 0.85, 0.90), outperforming a baseline prediction model by using KL grade with an AUC of 0.74 (95% CI: 0.71, 0.77; P < .001). The risk for TKR increased with probability that a person will undergo TKR from the DL model (odds ratio [OR], 7.7; 95% CI: 2.3, 25; P < .001), KL grade (OR, 1.92; 95% CI: 1.17, 3.13; P = .009), and OARSI grade (OR, 1.20; 95% CI: 0.41, 3.50; P = .73). CONCLUSION: The proposed deep learning model better predicted risk of total knee replacement in osteoarthritis than did binary outcome models by using standard grading systems.

The female mammary epithelium undergoes reorganization during development, pregnancy, and menopause, linking higher risk with breast cancer development. To characterize these periods of complex remodeling, here we report integrated 50 K mouse and 24 K human mammary epithelial cell atlases obtained by single-cell RNA sequencing, which covers most lifetime stages. Our results indicate a putative trajectory that originates from embryonic mammary stem cells which differentiates into three epithelial lineages (basal, luminal hormone-sensing, and luminal alveolar), presumably arising from unipotent progenitors in postnatal glands. The lineage-specific genes infer cells of origin of breast cancer using The Cancer Genome Atlas data and single-cell RNA sequencing of human breast cancer, as well as the association of gland reorganization to different breast cancer subtypes. This comprehensive mammary cell gene expression atlas (https://mouse-mammary-epithelium-integrated.cells.ucsc.edu) presents insights into the impact of the internal and external stimuli on the mammary epithelium at an advanced resolution., Kohei Saeki et al. present a mammary cell atlas derived from mouse and human single-cell RNA-sequence data. They characterize key life stages in which the mammary gland undergoes complex remodeling and, using breast cancer expression data, infer cells of origin for carcinogenesis of various breast cancer subtypes.

Elucidating the mechanisms behind how exposure to environmental chemicals can lead to cancer is not easy due to the complex natures of these compounds and the challenges to establish biologically relevant experimental models to study them. Environmental chemicals often present selective mechanisms of action on different cell types and can be involved in the modulation of targeted cells and their microenvironment, including immune cells. Currently, the limitations of traditional epidemiologic correlation analyses, in vitro cell-based assays, and animal models are that they are unable to comprehensively examine cellular heterogeneity and the tissue-selective influences. To this end, we propose utilizing single-cell RNA-sequencing (scRNA-seq) to more effectively capture the subtle and complex effects of environmental chemicals and how their exposure could lead to cancer. scRNA-seq's capabilities for studying gene expression level data at a significantly higher resolution relative to bulk RNA-sequencing (RNA-seq) enable studies to evaluate how environmental chemicals regulate gene transcription on different cell types as well as how these compounds impact signaling pathways and interactions between cells in the tissue microenvironment. These studies will be valuable for evaluating environmental chemicals' carcinogenic properties at the individual cell level. See all articles in this CEBP Focus section, “Environmental Carcinogenesis: Pathways to Prevention.”

BACKGROUND A current challenge in osteoporosis is identifying patients at risk of bone fracture. PURPOSE To identify the machine learning classifiers that predict best osteoporotic bone fractures and, from the data, to highlight the imaging features and the anatomical regions that contribute most to prediction performance. STUDY TYPE Prospective (cross-sectional) case-control study. POPULATION Thirty-two women with prior fragility bone fractures, of mean age = 61.6 and body mass index (BMI) = 22.7 kg/m2 , and 60 women without fractures, of mean age = 62.3 and BMI = 21.4 kg/m2 . Field Strength/ Sequence: 3D FLASH at 3T. ASSESSMENT Quantitative MRI outcomes by software algorithms. Mechanical and topological microstructural parameters of the trabecular bone were calculated for five femoral regions, and added to the vector of features together with bone mineral density measurement, fracture risk assessment tool (FRAX) score, and personal characteristics such as age, weight, and height. We fitted 15 classifiers using 200 randomized cross-validation datasets. Statistical Tests: Data: Kolmogorov-Smirnov test for normality. Model Performance: sensitivity, specificity, precision, accuracy, F1-test, receiver operating characteristic curve (ROC). Two-sided t-test, with P < 0.05 for statistical significance. RESULTS The top three performing classifiers are RUS-boosted trees (in particular, performing best with head data, F1 = 0.64 ± 0.03), the logistic regression and the linear discriminant (both best with trochanteric datasets, F1 = 0.65 ± 0.03 and F1 = 0.67 ± 0.03, respectively). A permutation of these classifiers comprised the best three performers for four out of five anatomical datasets. After averaging across all the anatomical datasets, the score for the best performer, the boosted trees, was F1 = 0.63 ± 0.03 for All-features dataset, F1 = 0.52 ± 0.05 for the no-MRI dataset, and F1 = 0.48 ± 0.06 for the no-FRAX dataset. Data Conclusion: Of many classifiers, the RUS-boosted trees, the logistic regression, and the linear discriminant are best for predicting osteoporotic fracture. Both MRI and FRAX independently add value in identifying osteoporotic fractures. The femoral head, greater trochanter, and inter-trochanter anatomical regions within the proximal femur yielded better F1-scores for the best three classifiers. LEVEL OF EVIDENCE 2 Technical Efficacy: Stage 2 J. Magn. Reson. Imaging 2019;49:1029-1038.

PURPOSE: To implement a novel technique for simultaneous, quantitative multiparametric mapping of the knee articular cartilage. METHODS: A novel MR fingerprinting pulse sequence is proposed and implemented for simultaneous measurements of proton density, T(1), T(2,) and T (1) (ρ) relaxation times at 3T. The repeatability and reproducibility of the proposed technique were assessed in model phantoms. Institutional review board‐approved MR fingerprinting imaging sequence was performed on healthy volunteers and patients with mild knee osteoarthritis. The Wilcoxon test was used to compare healthy controls and patients. The intra‐ and intersubject repeatability were assessed with coefficient of variation and the RMS coefficient of variation, respectively RESULTS: The Bland‐Altman plots demonstrated an average difference of 4.67 ms, −0.09 ms, and 0.05 ms between 2 scans in the same scanner; and 9.68 ms, 0.29 ms, and −0.72 ms between the scans acquired on 2 different scanners for T(1), T(2), and T (1) (ρ), respectively. The in vivo knee study showed excellent repeatability with RMS coefficient of variation less than 3%, 6%, and 5% for T(1), T(2), and T (1) (ρ), respectively. The Wilcoxon test showed a significant difference between control and mild osteoarthritis patients for T(1) (P = .04), T(2) (P = .01), and T (1) (ρ) (P = .02) relaxation time in medial tibial cartilage, as well as for T(2) relaxation time (P = .02) in medial femoral cartilage. CONCLUSION: The proposed MRF sequence is fast and can simultaneously measure the T(1), T(2), T (1) (ρ), and [Formula: see text] maps in a single scan. It is able to discriminate between mild osteoarthritis patients and healthy volunteers.

Purpose To compare patellar instability with magnetic resonance imaging analysis using continuous real-time radial gradient-echo (GRE) imaging in the assessment of symptomatic patients and asymptomatic subjects. Methods Symptomatic patients with suspected patellofemoral maltracking and asymptomatic volunteers were scanned in real time by a radial 2-dimensional GRE sequence at 3 T in axial orientation at the patella level through a range of flexion-extension. The degree of lateral maltracking, as well as the associated tibial tubercle–trochlear groove distance and trochlea depth, was measured. Patellar lateralization was categorized as normal (≤2 mm), mild (>2 to ≤5 mm), moderate (>5 to ≤10 mm), or severe (>10 mm). The patellofemoral cartilage was also assessed according to the modified Outerbridge grading system. Results The study included 20 symptomatic patients (13 women and 7 men; mean age, 36 ± 12.8 years) and 10 asymptomatic subjects (3 women and 7 men; mean age, 33.1 years). The mean time to perform the dynamic component ranged from 3 to 7 minutes. Lateralization in the symptomatic group was normal in 10 patients, mild in 1, moderate in 8, and severe in 1. There was no lateral tracking greater than 3 mm in the volunteer group. Lateral maltracking was significantly higher in symptomatic patients than in asymptomatic subjects (4.4 ± 3.7 mm vs 1.5 ± 0.71 mm, P = .007). Lateral tracking significantly correlated with tibial tubercle–trochlear groove distance ( r = 0.48, P = .006). There was excellent agreement on lateral tracking between the 2 reviewers (intraclass correlation coefficient, 0.979; 95% confidence interval, 0.956-0.990). Conclusions The inclusion of a dynamic radial 2-dimensional GRE sequence is a rapid and easily performed addition to the standard magnetic resonance imaging protocol and allows dynamic quantitative assessment of patellar instability and lateral maltracking in symptomatic patients. With a paucity of reported data using this technique confirming that these results reach clinical significance, future work is required to determine how much lateral tracking is clinically significant. Level of Evidence Level III, case control.

Purpose To describe a nonlinear finite element analysis method by using magnetic resonance (MR) images for the assessment of the mechanical competence of the hip and to demonstrate the reproducibility of the tool. Materials and Methods This prospective study received institutional review board approval and fully complied with HIPAA regulations for patient data. Written informed consent was obtained from all subjects. A nonlinear finite element analysis method was developed to estimate mechanical parameters that relate to hip fracture resistance by using MR images. Twenty-three women (mean age ± standard deviation, 61.7 years ± 13.8) were recruited from a single osteoporosis center. To thoroughly assess the reproducibility of the finite element method, three separate analyses were performed: a test-retest reproducibility analysis, where each of the first 13 subjects underwent MR imaging on three separate occasions to determine longitudinal variability, and an intra- and interoperator reproducibility analysis, where a single examination was performed in each of the next 10 subjects and four operators independently performed the analysis two times in each of the subjects. Reproducibility of parameters that reflect fracture resistance was assessed by using the intraclass correlation coefficient and the coefficient of variation. Results For test-retest reproducibility analysis and inter- and intraoperator analyses for proximal femur stiffness, yield strain, yield load, ultimate strain, ultimate load, resilience, and toughness in both stance and sideways-fall loading configurations each had an individual median coefficient of variation of less than 10%. Additionally, all measures had an intraclass correlation coefficient higher than 0.99. Conclusion This experiment demonstrates that the finite element analysis model can consistently and reliably provide fracture risk information on correctly segmented bone images.

Rationale and Objectives Severe progressive multifocal heterotopic ossification (HO) is a rare occurrence seen predominantly in patients who have fibrodysplasia ossificans progressiva (FOP) and is difficult to quantitate owing to patient-, disease-, logistical-, and radiation-related issues. The purpose of this study was to develop and validate a scoring system based on plain radiographs for quantitative assessment of HO lesions in patients with FOP. Materials and Methods Institutional review board approval was obtained from the University of Pennsylvania, and all data comply with Health Insurance Portability and Accountability Act regulations. The University of Pennsylvania Institutional Animal Care and Use Committee approved the use of mice in this study. First, we used a mouse model of FOP-like HO to validate a semiquantitative analog scale for estimating relative heterotopic bone volume. Second, we used this validated scale to estimate the relative amount of HO from a retrospective analysis of plain radiographs from 63 patients with classic FOP. Finally, the scale was applied to a retrospective analysis of computed tomographic images from three patients with FOP. Results In the FOP-mouse model, the observed rating on the analog scale is highly correlated to heterotopic bone volumes measured by microcomputed tomography ( R 2 = 0.89). The scoring system that was applied to radiographs of patients with FOP captured the clinical range of HO typically present at all axial and appendicular sites. Analysis of computed tomographic scans of patients with FOP found that observed radiograph ratings were highly correlated with HO volume ( R 2 = 0.80). Conclusions The scoring system described here could enable practical, quantitative assessment of HO in clinical trials to evaluate new treatment modalities, especially for FOP. The development of the six-point analog scale described here provides and validates a much-needed, reproducible, and quantifiable method for describing and assessing HO in patients with FOP. This scale has the potential to be a key descriptor that can inform patients with FOP and clinicians about disease progression and response of HO lesions to interventions and treatments.

The aromatase inhibitors (AIs), letrozole (Femar®/Femara®) and exemestane (Aromasin®), are widely used to treat estrogen receptor (ER) positive breast cancer in postmenopausal patients. In the setting of metastatic breast cancer, these drugs may be used after another causing new responses in selected patients after progressing on the first choice. The precise explanation for this “lack of cross resistance” is still missing. NEOLETEXE is a neoadjuvant, randomized, open-label, cross-over trial. Postmenopausal patients with ER-positive, HER-2 negative, locally advanced breast cancer were enrolled. All patients were randomized to treatment starting with either letrozole or exemestane for at least 2 months followed by another 2 months on the alternative AI. The total estrogenic activities in blood samples were determined using the AroER tri-screen assay developed in the Chen laboratory. Using this highly sensitive assay, estrogenic activity was detected at three time points for all patients. Importantly, a significantly higher total estrogenic activity was found during therapy with exemestane compared to letrozole in 21 out of 26 patients. When letrozole was included in the AroER tri-screen assay, the estrogenic activities in most samples collected during exemestane treatment were further reduced, suggesting that low levels of androgens remained in specimens obtained after exemestane treatment. Our results suggest the AroER tri-screen to be a very sensitive method to estimate the overall estrogen-mediated activity in human samples even during therapy with highly potent aromatase inhibitors. In the present study, serum estrogen activity was significantly higher during exemestane therapy when compared to letrozole therapy.

Mutational heterogeneity can contribute to therapeutic resistance in solid cancers. In melanoma, the frequencies of intertumoral and intratumoral heterogeneity are controversial. We examined mutational heterogeneity within individual patients with melanoma using multiplatform analysis of commonly mutated driver and nonpassenger genes. We analyzed paired primary and metastatic tumors from 60 patients and multiple metastatic tumors from 39 patients whose primary tumors were unavailable (n = 271 tumors). We used a combination of multiplex SNaPshot assays, Sanger sequencing, mutation-specific PCR, or droplet digital PCR to determine the presence of BRAFV600, NRASQ61, TERT–124C>T, and TERT–146C>T mutations. Mutations were detected in BRAF (39%), NRAS (21%), and/or TERT (78%). Thirteen patients had TERTmutant discordant tumors; seven of these had a single tumor with both TERT–124C>T and TERT–146C>T mutations present at different allele frequencies. Two patients had both BRAF and NRAS mutations; one had different tumors and the other had a single tumor with both mutations. One patient with a BRAFmutant primary lacked mutant BRAF in at least one of their metastases. Overall, we identified mutational heterogeneity in 18 of 99 patients (18%). These results suggest that some primary melanomas may be composed of subclones with differing mutational profiles. Such heterogeneity may be relevant to treatment responses and survival outcomes.

Mass cytometers are time-of-flight (TOF) mass spectrometer-coupled flow cytometers (known as CyTOFs) that quantify the abundance of metal-tagged antibodies (Abs) or other cellular probes within single cell suspensions or laser-ablated tissue sections. While many strategies exist for covalently crosslinking to proteins, the Fluidigm MaxPar

PURPOSE: The application of Artificial Intelligence tools has found new recent applications in medical applications. These tools have the potential to capture underlying trends and patterns, otherwise impossible with previous modeling capabilities. Both Machine Learning and Deep Learning models have found applications in osteoporosis, both to model the risk of fragility fracture, and to help with the identification and segmentation of images. FINDINGS: Here we survey the latest research in the AI application to the prediction of osteoporosis, published between January 2017 and March 2019. Around half of the articles covered predict (by classification or regression) an indicator of osteoporosis, such as bone mass or fragility fractures; the other half of studies use tools for automatic segmentation of the images of patients with or at risk of osteoporosis. The data for these studies includes diverse signal sources: acoustics, MRI, CT and of course X-rays. SUMMARY: New methods for automatic image segmentation, and prediction of fracture risk show promising clinical value. Though these recent developments have had a successful initial application to osteoporosis research, their development is still under improvements, such as accounting for positive-negative class bias. We urge care when reporting accuracy metrics, and when comparing between different studies. We also call for data transparency from study authors.

Currently, clinical determination of pathologic fracture risk in the hip is conducted using measures of defect size and shape in the stance loading condition. However, these measures often do not consider how changing lesion locations or how various loading conditions impact bone strength. The goal of this study was to determine the impact of defect location on bone strength parameters in both the sideways fall and stance-loading conditions. We recruited 20 female subjects aged 48–77 years for this study and performed MRI of the proximal femur. Using these images, we simulated 10-mm pathologic defects in greater trochanter, superior, middle, and inferior femoral head, superior, middle, and inferior femoral neck, and lateral, middle, and medial proximal diaphysis to determine the effect of defect location on change in bone strength by performing finite element analysis. We compared the effect of each osteolytic lesion on bone stiffness, strength, resilience, and toughness. For the sideways fall loading, defects in the inferior femoral head (12.21%) and in the greater trochanter (6.43%) resulted in the greatest overall reduction in bone strength. For the stance loading, defects in the mid femoral head (−7.91%) and superior femoral head (−7.82%) resulted in the greatest overall reduction in bone strength. Changes in stiffness, yield force, ultimate force, resilience, and toughness were not found to be significantly correlated between the sideways fall and stance-loading for the majority of defect locations, suggesting that calculations based on the stance-loading condition are not predictive of the change in bone strength experienced in the sideways fall condition. While stiffness was significantly related to yield force (R2 > 0.82), overall force (R2 > 0.59), and resilience (R2 > 0.55), in both, the stance-loading and sideways fall conditions for most defect locations, stiffness was not significantly related to toughness. Therefore, structure-dependent measure such as stiffness may not fully explain the post-yield measures, which depend on material failure properties. The data showed that MRI-based models have the sensitivity to determine the effect of pathologic lesions on bone strength.

BACKGROUND: In addition to the articular cartilage, osteoarthritis (OA) affects several other tissues such as tendons, ligaments, and subchondral bone. T(1ρ) relaxation study of these short T(2) tissues may provide a more comprehensive evaluation of OA. PURPOSE: To develop a 3D spin-lattice relaxation in the rotating frame (T(1ρ)) prepared zero echo time (ZTE)-based pointwise encoding time reduction with radial acquisition (3D-T(1ρ)-PETRA) sequence for relaxation mapping of semisolid short-T(2) tissues on a clinical 3 T scanner. STUDY TYPE: Prospective. POPULATION: Phantom, two bovine whole knee joint and Achilles tendon specimens, 10 healthy volunteers with no known inflammation, trauma or pain in the knee or ankle. FIELD STRENGTH/SEQUENCE: A customized PETRA sequence to acquire fat-suppressed 3D T(1ρ)-weighted images tissues with semisolid short [Formula: see text] relaxation times in the knee and ankle joints at 3 T. ASSESSMENT: Mono- and biexponential T(1ρ) relaxation components were assessed in the patellar tendon (PT), anterior cruciate ligament (ACL), posterior cruciate ligament (PCL), and Achilles tendon (AT). STATISTICAL TESTS: Kruskal–Wallis with post-hoc Dunn’s test for multiple pairwise comparisons. RESULTS: Phantom and ex vivo studies showed the feasibility of T(1ρ) relaxation mapping using the proposed 3D-T(1ρ)-PETRA sequence. The in vivo study demonstrated an averaged mono-T(1ρ) relaxation of (median [IQR]) 15.9 [14.5] msec, 23.6 [9.4] msec, 17.4 [7.4] msec, and 5.8 [10.2] msec in the PT, ACL, PCL, and AT, respectively. The bicomponent analysis showed the short and long components (with their relative fractions) of 0.65 [1.0] msec (46.9 [15.3]%) and 37.3 [18.4] msec (53.1 [15.3]%) for PT, 1.7 [2.1] msec (42.5 [12.5]%) and 43.7 [17.8] msec (57.5 [12.5]%) for ACL, and 1.2 [1.9] msec (42.6 [14.0]%) and 27.7 [14.7] msec (57.3 [14.0]%) for PCL and 0.4 [0.02] msec (58.8 [13.3]%/) and 31.3 [10.8] msec (41.2 [13.3]%) for AT. Statistically significant (P≤ 0.05) differences were observed in the mono- and biexponential relaxation between several regions. DATA CONCLUSION: The 3D-T(1ρ)-PETRA sequence allows volumetric, isotropic (0.78 × 0.78 × 0.78 mm), biexponential T(1ρ) assessment with corresponding fractions of the tissues with semisolid short [Formula: see text].

Magnetic resonance imaging (MRI) has been proposed as a complimentary method to measure bone quality and assess fracture risk. However, manual segmentation of MR images of bone is time-consuming, limiting the use of MRI measurements in the clinical practice. The purpose of this paper is to present an automatic proximal femur segmentation method that is based on deep convolutional neural networks (CNNs). This study had institutional review board approval and written informed consent was obtained from all subjects. A dataset of volumetric structural MR images of the proximal femur from 86 subject were manually-segmented by an expert. We performed experiments by training two different CNN architectures with multiple number of initial feature maps and layers, and tested their segmentation performance against the gold standard of manual segmentations using four-fold cross-validation. Automatic segmentation of the proximal femur achieved a high dice similarity score of 0.94$\pm$0.05 with precision = 0.95$\pm$0.02, and recall = 0.94$\pm$0.08 using a CNN architecture based on 3D convolution exceeding the performance of 2D CNNs. The high segmentation accuracy provided by CNNs has the potential to help bring the use of structural MRI measurements of bone quality into clinical practice for management of osteoporosis., This is a pre-print of an article published in Scientific Reports. The final authenticated version is available online at: https://doi.org/10.1038/s41598-018-34817-6

Extensive efforts, through cell line-based models, have been made to characterize the androgen receptor (AR) signaling pathway in triple-negative breast cancer (TNBC). However, these efforts have not yet reached a consensus with regards to the mechanism of AR in TNBC. Considering that patient-derived xenografts (PDXs) are more appropriate than cell line-based models for recapitulating the structural and molecular features of a patient's tumor, we have identified and molecularly characterized two new AR-positive TNBC PDX models and assessed the impacts of AR agonist [dihydrotestosterone (DHT)] and antagonist (enzalutamide) on tumor growth and gene expression profiles by utilizing immunohistochemistry, western blots, and RNA-Seq analyses. Two PDX models, termed TN1 and TN2, were derived from two grade-3 TNBC tumors, each harboring 1∼5% of AR nuclear positive cancer cells. DHT activated AR in both PDX tumors by increasing nuclear localization and AR protein levels. However, the endpoint tumor volume of DHT-treated TN1 was 3-folds smaller than that of non-treated TN1 tumors. Conversely, the endpoint tumor volume of DHT-treated TN2 was 2-folds larger than that of non-treated TN2. Moreover, enzalutamide failed to antagonize DHT-induced tumor growth in TN2. The RNA-Seq analyses revealed that DHT mainly suppressed gene expression in TN1 (961 down-regulated genes versus 149 up-regulated genes), while DHT promoted gene expression in TN2 (673 up-regulated genes versus 192 down-regulated genes). RNA-Seq data predicted distinct TNBC molecular subtypes for TN1 and TN2. TN1 correlated to a basal-like 1 (BL1) subtype, and TN2 correlated to a basal-like 2 (BL2) subtype. These analyses suggest that TN1 and TN2, which both express functional AR, are two molecularly distinct PDX models. The molecular characterization of these PDX models expands our current knowledge on AR-positive TNBC. Our results do not support that AR is a suitable therapeutic target in TNBC. To our best knowledge, the molecular mechanisms of AR in TNBC are equivocal and should be evaluated using clinically relevant models, considering both the heterogeneous expression of AR in TNBC and the general complexities of AR signaling.

Osteoporosis is associated with increased risk of fractures, which is clinically defined by low bone mineral density. Increasing evidence suggests that trabecular bone (TB) micro-architecture is an important determinant of bone strength and fracture risk. We present an improved volumetric topological analysis algorithm based on fuzzy skeletonization, results of its application on in vivo MR imaging, and compare its performance with digital topological analysis. The new VTA method eliminates data loss in the binarization step and yields accurate and robust measures of local plate-width for individual trabeculae, which allows classification of TB structures on the continuum between perfect plates and rods. The repeat-scan reproducibility of the method was evaluated on in vivo MRI of distal femur and distal radius, and high intra-class correlation coefficients between 0.93 and 0.97 were observed. The method's ability to detect treatment effects on TB micro-architecture was examined in a 2 years testosterone study on hypogonadal men. It was observed from experimental results that average plate-width and plate-to-rod ratio significantly improved after 6 months and the improvement was found to continue at 12 and 24 months. The bone density of plate-like trabeculae was found to increase by 6.5% (p = 0.06), 7.2% (p = 0.07) and 16.2% (p = 0.003) at 6, 12, 24 months, respectively. While the density of rod-like trabeculae did not change significantly, even at 24 months. A comparative study showed that VTA has enhanced ability to detect treatment effects in TB micro-architecture as compared to conventional method of digital topological analysis for plate/rod characterization in terms of both percent change and effect-size.

Automating the process of femoroacetabular cartilage identification from magnetic resonance imaging (MRI) images has important implications to guiding clinical care by providing a temporal metric that allows for optimizing the timing for joint preservation surgery. In this paper, we evaluate a new automated cartilage segmentation method using a time trial, segmented volume comparison, overlap metrics, and Euclidean distance mapping. We report interrater overlap metrics using the true fast imaging with steady-state precession MRI sequence of 0.874, 0.546, and 0.704 for the total overlap, union overlap, and mean overlap, respectively. This method was 3.28× faster than manual segmentation. This technique provides clinicians with volumetric cartilage information that is useful for optimizing the timing for joint preservation procedures.

Half of the women who sustain a hip fracture would not qualify for osteoporosis treatment based on current DXA-estimated bone mineral density criteria. Therefore, a better approach is needed to determine if an individual is at risk of hip fracture from a fall. The objective of this study was to determine the association between radiation-free MRI-derived bone strength and strain simulations compared to results from direct mechanical testing of cadaveric femora. Imaging was conducted on a 3-Tesla MRI scanner using two sequences: one balanced steady-state free precession sequence with 300 μm isotropic voxel size and one spoiled gradient echo with anisotropic voxel size of 234 × 234 × 1500 μm. Femora were dissected free of soft-tissue and 4350-ohm strain-gauges were securely applied to surfaces at the femoral shaft, inferior neck, greater trochanter, and superior neck. Cadavers were mechanically tested with a hydraulic universal test frame to simulate loading in a sideways fall orientation. Sideways fall forces were simulated on MRI-based finite element meshes and bone stiffness, failure force, and force for plastic deformation were computed. Simulated bone strength metrics from the 300 μm isotropic sequence showed strong agreement with experimentally obtained values of bone strength, with stiffness (r = 0.88, p = 0.0002), plastic deformation point (r = 0.89, p 0.0001), and failure force (r = 0.92, p 0.0001). The anisotropic sequence showed similar trends for stiffness, plastic deformation point, and failure force (r = 0.68, 0.70, 0.84; p = 0.02, 0.01, 0.0006, respectively). Surface strain-gauge measurements showed moderate to strong agreement with simulated magnitude strain values at the greater trochanter, superior neck, and inferior neck (r = -0.97, -0.86, 0.80; p ≤0.0001, 0.003, 0.03, respectively). The findings from this study support the use of MRI-based FE analysis of the hip to reliably predict the mechanical competence of the human femur in clinical settings.

MR imaging is an indispensable instrument for the diagnosis of musculoskeletal diseases. In vivo MR imaging at 7T offers many advantages, including increased signal-to-noise ratio, higher spatial resolution, improved spectral resolution for spectroscopy, improved sensitivity for X-nucleus imaging, and decreased image acquisition times. There are also however technical challenges of imaging at a higher field strength compared with 1.5 and 3T MR imaging systems. We discuss the many potential opportunities as well as the challenges presented by 7T MR imaging systems and highlight recent developments in in vivo research imaging of musculoskeletal applications in general and cartilage, skeletal muscle, and bone in particular.

PURPOSE OF REVIEW: Hip fractures have catastrophic consequences. The purpose of this article is to review recent developments in high resolution magnetic resonance imaging (MRI) guided finite element analysis (FEA) of the hip as a means to determine subject-specific bone strength. RECENT FINDINGS: Despite the ability of DXA to predict hip fracture, the majority of fractures occur in patients who do not have BMD T-scores < −2.5. Therefore, without other detection methods, these individuals go undetected and untreated. Of methods available to image the hip, MRI is currently the only one capable of depicting bone microstructure in vivo. Availability of microstructural MRI allows generation of patient-specific micro finite element models that can be used to simulate real-life loading conditions and determine bone strength. SUMMARY: MRI-based FEA enables radiation-free approach to assess hip fracture strength. With further validation, this technique could become a potential clinical tool in managing hip fracture risk.

BACKGROUND: Measuring T(1ρ) in the knee menisci can potentially be used as noninvasive biomarkers in detecting early-stage osteoarthritis (OA). PURPOSE: To demonstrate the feasibility of biexponential T(1ρ) relaxation mapping of human knee menisci. STUDY TYPE: Prospective. POPULATION: Eight healthy volunteers with no known inflammation, trauma, or pain in the knee and three symptomatic subjects with early knee OA. FIELD STRENGTH/SEQUENCE: Customized Turbo-FLASH sequence to acquire 3D-T(1ρ)-weighted images on a 3 T MRI scanner. ASSESSMENT: T(1ρ) relaxation values were assessed in 11 meniscal regions of interest (ROIs) using monoexponential and biexponential models. STATISTICAL TESTS: Nonparametric rank-sum tests, Kruskal–Wallis test, and coefficient of variation. RESULTS: The mean monoexponential T(1ρ) relaxation in the lateral menisci were 28.05 ± 4.2 msec and 37.06 ± 10.64 msec for healthy subjects and early knee OA patients, respectively, while the short and long components were 8.07 ± 0.5 msec and 72.35 ± 3.2 msec for healthy subjects and 2.63 ± 2.99 msec and 55.27 ± 24.76 msec for early knee OA patients, respectively. The mean monoexponential T(1ρ) relaxation in the medial menisci were 34.30 ± 3.8 msec and 37.26 ± 11.38 msec for healthy and OA patients, respectively, while the short and long components were 7.76 ± 0.7 msec and 72.19± 4.2 msec for healthy subjects and 3.06 ± 3.24 msec and 55.27 ± 24.59 msec for OA patients, respectively. Statistically significant (P≤ 0.05) differences were observed in the monoexponential relaxation between some of the ROIs. The T(1ρ,short) was significantly lower (P = 0.02) in the patients than controls. The rmsCV% ranges were 1.51–16.6%, 3.59–14.3%, and 4.91–15.6% for T(1ρ)-mono, T(1ρ)-short, and T(1ρ)-long, respectively. DATA CONCLUSION: Our results showed that in all ROIs, T(1ρ) relaxation times of outer zones (red zones) were less than inner zones (white zones). Monoexponential T(1ρ) was increased in medial, lateral, and body menisci of early OA while the biexponential numbers were decreased in early OA patients. LEVEL OF EVIDENCE: 2 TECHNICAL EFFICACY STAGE: 1

BACKGROUND Osteoporosis (OP) results in weak bone and can ultimately lead to fracture. Drugs such as glucocorticoids can also induce OP (glucocorticoid-induced osteoporosis [GIO]). Bone marrow adipose tissue composition and quantity may play a role in OP pathophysiology, but has not been thoroughly studied in GIO compared to primary OP. PURPOSE/HYPOTHESIS Chemical shift-encoded (CSE) MRI allows detection of subregional differences in bone marrow adipose tissue composition and quantity in the proximal femur of GIO compared to OP subjects and has high agreement with the reference standard of magnetic resonance spectroscopy (MRS). STUDY TYPE Prospective. SUBJECTS In all, 18 OP and 13 GIO subjects. FIELDS STRENGTH 3T. SEQUENCE Multiple gradient-echo, stimulated echo acquisition mode (STEAM). ASSESSMENT Subjects underwent CSE-MRI in the proximal femurs, and for each parametric map regions of interest (ROIs) were assessed in the femoral head (fHEAD), femoral neck (fNECK), Ward's triangle (fTRIANGLE), and the greater trochanter (GTROCH). In addition, we compared CSE-MRI against the reference standard of MRS performed in the femoral neck and Ward's triangle. STATISTICAL TESTS Differences between OP/GIO were investigated using the Mann-Whitney nonparametric test. Bland-Altman methodology was used to assess measurement agreement between CSE-MRI and MRS. RESULTS GIO compared with OP subjects demonstrated: decreased monounsaturated fat fraction (MUFA) (-2.1%, P < 0.05) in fHEAD; decreased MUFA (-3.8%, P < 0.05), increased saturated fat fraction (SFA) (5.5%, P < 0.05), and decreased T2* (-3.8 msec, P < 0.05) in fNECK; decreased proton density fat fraction (PDFF) (-15.1%, P < 0.05), MUFA (-9.8%, P < 0.05), polyunsaturated fat fraction (PUFA) (-1.8%, P < 0.01), increased SFA (11.6%, P < 0.05), and decreased T2* (-5.4 msec, P < 0.05) in fTRIANGLE; and decreased T2* (-1.5 msec, P < 0.05) in GTROCH. There was high measurement agreement between MRI and MRS using the Bland-Altman test. DATA CONCLUSION 3T CSE-MRI may allow reliable assessment of subregional bone marrow adipose tissue (bMAT) quantity and composition in the proximal femur in a clinically reasonable scan time. Glucocorticoids may alter the lipid profile of bMAT and potentially result in reduced bone quality. LEVEL OF EVIDENCE 2 Technical Efficacy: Stage 2 J. Magn. Reson. Imaging 2019;50:490-496.

More than one decade after the introduction of compressed sensing (CS) in MRI, researchers are still working on ways to translate it into different research and clinical applications. The greatest advantage of CS in MRI is the reduced amount of k-space data needed to reconstruct images, which can be exploited to reduce scan time or to improve spatial resolution and volumetric coverage. Efficient data acquisition using CS is extremely important for compositional mapping of the musculoskeletal system in general and knee cartilage mapping techniques in particular. High-resolution quantitative information about tissue biochemical composition could be obtained in just a few minutes using CS MRI. However, in order to make this goal a reality, some issues still need to be addressed. In this paper, we review the current state of the art of CS methods for rapid compositional mapping of knee cartilage. Specifically, data acquisition strategies, image reconstruction algorithms, and data fitting models are discussed. Different CS studies for T(2) and T(1ρ) mapping of knee cartilage are reviewed, with illustrative results. Future directions, opportunities, and challenges of rapid compositional mapping techniques are also discussed.

Purpose To determine the proportion of women working in academic musculoskeletal (MSK) radiology divisions and how this compares to national benchmarks for women in academic medicine. Materials and methods A list of academic radiology departments in the United States was compiled using the U.S. News and World Report listing of Best Hospitals for Orthopedics and Rheumatology to aid in department selection. Faculty information for MSK radiology divisions was obtained using websites pertinent to each department. Figures were obtained from the Association of American Medical Colleges and used as a benchmark for comparison. Results The 25 top-ranked hospitals with MSK radiology divisions were identified, with a total of 215 MSK trained radiologists. Female radiologists made up 33% of the MSK trained faculty (n = 71). This compares to 38% of fulltime female faculty in academic medicine. 79 assistant professor roles were identified, of which 35% were women (n = 28). 34% of associate professors were women (n = 11). Only 23% of professors were women (n = 10); this compares with 21% of female professors in academic medicine. Six MSK radiologists held either chair or vice-chair roles and three of these were women. Of the 24 chief or director roles identified, 30% of these were held by women. Conclusion The proportions of women within various roles in academic MSK radiology are similar to and in some instances higher than corresponding national benchmarks. However, there remains a discrepancy between the sexes with an overall male majority. Awareness of this fact is the first step required to help correct this imbalance.

BACKGROUND: The progressive loss of hyaline articular cartilage due to osteoarthritis (OA) changes the functional and biochemical properties of cartilage. Measuring the T1ρ along with the morphological assessment can potentially be used as noninvasive biomarkers in detecting early-stage OA. To correlate the biochemical and morphological data, submillimeter isotropic resolution for both studies is required. PURPOSE: To implement a high spatial resolution 3D-isotropic-MRI sequence for simultaneous assessment of morphological and biexponential T(1ρ) relaxometry of human knee cartilage in-vivo. STUDY TYPE: Prospective. POPULATION: Ten healthy volunteers with no known inflammation, trauma or pain in the knee. FIELD STRENGTH/SEQUENCE: Standard FLASH sequence and customized Turbo-FLASH sequence to acquire 3D-isotropic-T(1ρ)-weighted images on a 3T MRI scanner. ASSESSMENT: The mean volume and thickness along with mono and biexponential T1ρ relaxations were assessed in the articular cartilage of 10 healthy volunteers. STATISTICAL TESTS: Non-parametric rank-sum tests. Bland-Altman analysis and coefficient of variation RESULTS: The mean monoexponential T(1ρ) relaxation was 40.7±4.8ms while the long and short components were 58.2±3.9ms and 6.5±0.6ms, respectively. The mean fractions of long and short T(1ρ) relaxation components were 63.7±5.9% and 36.3±5.9%, respectively. Statistically significant (p ≤0.03) differences were observed in the monoexponential and long components between some of the ROIs. No gender differences between biexponential components were observed (p>0.05). Mean cartilage volume and thickness were 25.9±6.4cm(3) and 2.2±0.7mm, respectively. Cartilage volume (p=0.01) and thickness (p=0.03) were significantly higher in male than female participants across all ROIs. Bland-Altman analysis showed agreement between two morphological methods with limits of agreement between −1000mm(3) and +1100mm(3) for volume, and −0.78mm and +0.46mm for thickness, respectively. DATA CONCLUSION: Simultaneous assessment of morphological and multicomponent T1ρ relaxation of knee joint with 0.7mm×0.7mm×0.7mm isotropic spatial resolution is demonstrated in-vivo. Comparison with a standard method showed that the proposed technique is suitable for assessing the volume and thickness of articular cartilage

PURPOSE: To determine if 3-T magnetic resonance (MR) imaging of proximal femur microarchitecture can allow discrimination of subjects with and without fragility fracture who do not have osteoporotic proximal femur bone mineral density (BMD). MATERIALS AND METHODS: Sixty postmenopausal women (30 with and 30 without fragility fracture) who had BMD T scores of greater than −2.5 in the hip were recruited. All subjects underwent dual-energy x-ray absorptiometry to assess BMD and 3-T MR imaging of the same hip to assess bone microarchitecture. World Health Organization Fracture Risk Assessment Tool (FRAX) scores were also computed. We used the Mann-Whitney test, receiver operating characteristics analyses, and Spearman correlation estimates to assess differences between groups, discriminatory ability with parameters, and correlations among BMD, microarchitecture, and FRAX scores. RESULTS: Patients with versus without fracture showed a lower trabecular plate-to-rod ratio (median, 2.41 vs 4.53, respectively), lower trabecular plate width (0.556 mm vs 0.630 mm, respectively), and lower trabecular thickness (0.114 mm vs 0.126 mm) within the femoral neck, and higher trabecular rod disruption (43.5 vs 19.0, respectively), higher trabecular separation (0.378 mm vs 0.323 mm, respectively), and lower trabecular number (0.158 vs 0.192, respectively), lower trabecular connectivity (0.015 vs 0.027, respectively) and lower trabecular plate-to-rod ratio (6.38 vs 8.09, respectively) in the greater trochanter (P < .05 for all). Trabecular plate-to-rod ratio, plate width, and thickness within the femoral neck (areas under the curve [AUCs], 0.654–0.683) and trabecular rod disruption, number, connectivity, plate-to-rod ratio, and separation within the greater trochanter (AUCs, 0.662–0.694) allowed discrimination of patients with fracture from control subjects. Femoral neck, total hip, and spine BMD did not differ between and did not allow discrimination between groups. FRAX scores including and not including BMD allowed discrimination between groups (AUCs, 0.681–0.773). Two-factor models (one MR imaging microarchitectural parameter plus a FRAX score without BMD) allowed discrimination between groups (AUCs, 0.702–0.806). There were no linear correlations between BMD and microarchitectural parameters (Spearman ρ, −0.198 to 0.196). CONCLUSION: 3-T MR imaging of proximal femur microarchitecture allows discrimination between subjects with and without fragility fracture who have BMD T scores of greater than −2.5 and may provide different information about bone quality than that provided by dual-energy x-ray absorptiometry. (©) RSNA, 2018

Melanoma lacks a clinically useful blood-based biomarker of disease activity to help guide patient management. To determine whether measurements of circulating, cell-free, tumor-associated BRAF(mutant) and NRAS(mutant) DNA (ctDNA) have a higher sensitivity than LDH to detect metastatic disease prior to treatment initiation and upon disease progression we studied patients with unresectable stage IIIC/IV metastatic melanoma receiving treatment with BRAF inhibitor therapy or immune checkpoint blockade and at least 3 plasma samples obtained during their treatment course. Levels of BRAF(mutant) and NRAS(mutant) ctDNA were determined using droplet digital PCR (ddPCR) assays. Among patients with samples available prior to treatment initiation ctDNA and LDH levels were elevated in 12/15 (80%) and 6/20 (30%) (p = 0.006) patients respectively. In patients with RECIST scores

Background Bone remodels in response to mechanical loads and osteoporosis results from impaired ability of bone to remodel. Bone microarchitecture analysis provides information on bone quality beyond bone mineral density (BMD). Purpose To compare subchondral bone microarchitecture parameters in the medial and lateral tibia plateau in individuals with and without fragility fractures. Material and Methods Twelve female patients (mean age = 58 ± 15 years; six with and six without previous fragility fractures) were examined with dual-energy X-ray absorptiometry (DXA) and 7-T magnetic resonance imaging (MRI) of the proximal tibia. A transverse high-resolution three-dimensional fast low-angle shot sequence was acquired (0.234 × 0.234 × 1 mm). Digital topological analysis (DTA) was applied to the medial and lateral subchondral bone of the proximal tibia. The following DTA-based bone microarchitecture parameters were assessed: apparent bone volume; trabecular thickness; profile-edge-density (trabecular bone erosion parameter); profile-interior-density (intact trabecular rods parameter); plate-to-rod ratio; and erosion index. We compared femoral neck T-scores and bone microarchitecture parameters between patients with and without fragility fracture. Results There was no statistical significant difference in femoral neck T-scores between individuals with and without fracture (–2.4 ± 0.9 vs. −1.8 ± 0.7, P = 0.282). Apparent bone volume in the medial compartment was lower in patients with previous fragility fracture (0.295 ± 0.022 vs. 0.317 ± 0.009; P = 0.016). Profile-edge-density, a trabecular bone erosion parameter, was higher in patients with previous fragility fracture in the medial (0.008 ± 0.003 vs. 0.005 ± 0.001) and lateral compartment (0.008 ± 0.002 vs. 0.005 ± 0.001); both P = 0.025. Other DTA parameters did not differ between groups. Conclusion 7-T MRI and DTA permit detection of subtle changes in subchondral bone quality when differences in BMD are not evident.

The goal of this paper was to evaluate the possibility of bi-component T1ρ and T2 relaxation mapping of human skeletal muscle at 3 T in clinically feasible scan times. T1ρ- and T2-weighted images of calf muscle were acquired using a modified 3D-SPGR sequence on a standard 3 T clinical MRI scanner. The mono- and biexponential models were fitted pixel-wise to the series of T1ρ and T2 weighted images. The biexponential decay of T1ρ and T2 relaxations was detected in ~30% and ~40% of the pixels across all volunteers, respectively. Monoexponential and bi-exponential short and long T1ρ relaxation times were estimated to be 26.9 ms, 4.6 ms (fraction 22%) and 33.2 ms (fraction: 78%), respectively. Similarly, the mono- and bi-exponential short and long T2 relaxation times were 24.7 ms, 4.2 ms (fraction 15%) and 30.4 ms (fraction 85%) respectively. The experiments had good repeatability with RMSCV 60%. This approach could potentially be used in exercise intervention studies or in studies of inflammatory myopathies or muscle fibrosis, permitting greater sensitivity and specificity via measurement of different water compartments and their fractions.

Osteoarthritis (OA) is characterized by cartilage destruction and chondrocytes have a central role in this process. With age and inflammation chondrocytes have reduced capacity to synthesize and maintain ATP, a molecule important for cartilage homeostasis. Here we show that concentrations of ATP and adenosine, its metabolite, fall after treatment of mouse chondrocytes and rat tibia explants with IL-1β, an inflammatory mediator thought to participate in OA pathogenesis. Mice lacking A2A adenosine receptor (A2AR) or ecto-5′nucleotidase (an enzyme that converts extracellular AMP to adenosine) develop spontaneous OA and chondrocytes lacking A2AR develop an ‘OA phenotype' with increased expression of Mmp13 and Col10a1. Adenosine replacement by intra-articular injection of liposomal suspensions containing adenosine prevents development of OA in rats. These results support the hypothesis that maintaining extracellular adenosine levels is an important homeostatic mechanism, loss of which contributes to the development of OA; targeting adenosine A2A receptors might treat or prevent OA., Osteoarthritis (OA) is a debilitating and destructive joint disease for which disease modifying drugs are not available. Here the authors show that extracellular adenosine signalling via the A2AR receptor on chondrocytes is needed to prevent OA and that liposome-bound adenosine injection can treat the pathology in rats.

To evaluate the potential of sodium MRI to detect changes over time of apparent sodium concentration (ASC) in articular cartilage in patients with knee osteoarthritis (OA). The cartilage of 12 patients with knee OA were scanned twice over a period of approximately 16 months with two sodium MRI sequences at 7 T: without fluid suppression (radial 3D) and with fluid suppression by adiabatic inversion recovery (IR). Changes between baseline and follow-up of mean and standard deviation of ASC (in mM), and their rate of change (in mM/day), were measured in the patellar, femorotibial medial and lateral cartilage regions for each subject. A matched-pair Wilcoxon signed rank test was used to assess significance of the changes. Changes in mean and in standard deviation of ASC, and in their respective rate of change over time, were only statistically different when data was acquired with the fluid-suppressed sequence. A significant decrease (p = 0.001) of approximately 70 mM in mean ASC was measured between the two IR scans. Quantitative sodium MRI with fluid suppression by adiabatic IR at 7 T has the potential to detect a decrease of ASC over time in articular cartilage of patients with knee osteoarthritis. • Sodium MRI can detect apparent sodium concentration (ASC) in cartilage • Longitudinal study: sodium MRI can detect changes in ASC over time • Potential for follow-up studies of cartilage degradation in knee osteoarthritis

In this study, we demonstrated the feasibility of in-vivo biexponential T1ρ relaxation mapping of knee articular cartilage of 8 healthy volunteers using 3T MRI in clinically feasible scan times. Our preliminary results show that the biexponential model may better represents the T1ρ relaxation decay in articular cartilage. It is possible distinguish between tightly bound and loosely bound water compartments associated with macromolecules in the articular cartilage.

Introduction Difficulty determining anatomic rotation following intramedullary (IM) nailing of the femur continues to be problematic for surgeons. Clinical exam and fluoroscopic imaging of the hip and knee have been used to estimate femoral version, but are inaccurate. We hypothesize that 3D c-arm imaging can be used to accurately measure femoral version following IM nailing of femur fractures to prevent rotational malreduction. Methods A midshaft osteotomy was created in a femur Sawbone to simulate a transverse diaphyseal fracture. An intramedullary (IM) nail was inserted into the Sawbone femur without locking screws or cephalomedullary fixation. A goniometer was used to simulate four femoral version situations after IM nailing: 20° retroversion, 0° version, 15° anteversion, and 30° anteversion. In each simulated position, 3D c-arm imaging and, for comparison purposes, perfect lateral radiographs of the knee and hip were performed. The femoral version of each simulated 3D and fluoroscopic case was measured and the results were tabulated. Results The measured version from the 3D c-arm images was 22.25° retroversion, 0.66° anteversion, 19.53° anteversion, and 25.15° anteversion for the simulated cases of 20° retroversion, 0° version, 15° anteversion, and 30° anteversion, respectively. The lateral fluoroscopic views were measured to be 9.66° retroversion, 12.12° anteversion, 20.91° anteversion, and 18.77° anteversion for the simulated cases, respectively. Conclusion This study demonstrates the utility of a novel intraoperative method to evaluate femur rotational malreduction following IM nailing. The use of 3D c-arm imaging to measure femoral version offers accuracy and reproducibility.