A Novel Hands-on Approach Towards Teaching Diagnostic Radiology Residents MRI Scanning and Physics.

RATIONALE AND OBJECTIVES: Traditional approaches towards teaching magnetic resonance imaging (MRI) scanning and physics have limitations that a hands-on course may help overcome. A dedicated week of MRI instruction may help improve radiology resident confidence and competence. Additional benefits may include improved physician-technologist communication and accelerated mastery of MRI safety. MATERIALS AND METHODS: Surveys and tests were approved by our Program Evaluation Committee and administered at the beginning and at the end of this one-week course. The course consisted of protected reading time as well as practice scanning with a research magnet and assisting with clinical scanning under the close supervision of a licensed MRI technologist. Eighteen senior residents (nine third-year and nine fourth-year) participated in this course during its first year. RESULTS: Few residents had previous experience with MRI physics, scanning, or research prior to residency. After this course, mean resident confidence increased by 0.47 points (3.33 vs 2.86; p=0.01) on a five-point Likert scale. Understanding of MRI physics, as measured by pre- and post-tests, increased by 22% (0.72 vs 0.50; p<0.01), corresponding to a large effect size of 1.29 (p<0.001). Resident feedback reported that this course was efficacious (5/5), engaging (4.9/5), and had optimal faculty oversight. The most highly rated component of the course was the opportunity to experiment with the research MR scanner (5/5). CONCLUSION: A dedicated week of MRI education was highly rated by residents and associated with improvements in confidence and understanding, suggesting a positive correlation between confidence and competence. Additional metrics, such as trends in scores on the American Board of Radiology's Core Examination over the next several years, may further support the apparent benefits of this hands-on MR course.

Diffusion-weighted MRI of total hip arthroplasty for classification of synovial reactions: A pilot study.

BACKGROUND: Conventional quantitative diffusion-weighted imaging (DWI) is sensitive to changes in tissue microstructure, but its application to evaluating patients with orthopaedic hardware has generally been limited due to metallic susceptibility artifacts. The apparent diffusion coefficient (ADC) and T2-values from a multi-spectral imaging (MSI) DWI combined with 2D multi-spectral imaging with a 2D periodically rotated overlapping parallel lines with enhanced reconstruction (2D-MSI PROPELLER DWI) based sequence and a MAVRIC based T2 mapping sequence, respectively, may mitigate the artifact and provide additional quantitative information on synovial reactions in individuals with total hip arthroplasty (THA). The aim of this pilot study is to utilize a 2D-MSI PROPELLER DWI and a MAVRIC-based T2 mapping to evaluate ADC and T2-values of synovial reactions in patients with THA. METHODS: Coronal morphologic MRIs from THA patients underwent evaluation of the synovium and were assigned a synovial classification of 'normal', or 'grouped abnormal' (consisting of sub-groups 'infection', 'polymeric', 'metallosis', 'adverse local tissue reaction' [ALTR], or 'non-specific') and type of synovial reaction present (fluid-like, solid-like, or mixed). Regions of interest (ROIs) were placed in synovial reactions for measurement of ADC and T2-values, obtained from the 2D-MSI PROPELLER DWI and T2-MAVRIC sequences, respectively. A one-way analysis of variance (ANOVA) and Kruskal-Wallis rank sum tests were used to compare the differences in ADC and T2-values across the different synovial reaction classifications. A Kruskal-Wallis test was used to compare the ROI areas for the ADC and T2-values. A principal component analysis (PCA) was performed to evaluate the possible effects of ADC values, size of the ADC ROI, T2-values, and size of the T2 ROI with respect to synovial reaction classification. RESULTS: Differences of ADC and T2 among the individual synovial reactions were not found. A difference of ADC between 'normal' and 'grouped abnormal' synovial reactions was also not detected even as the ADC area of 'grouped abnormal' synovial reactions were significantly larger (p = 0.02). The 'grouped abnormal' synovial reactions had significantly shorter T2-values than 'normal' synovial reactions (p = 0.02), and that the T2 area of 'grouped abnormal' synovial reactions were significantly larger (p = 0.01). A larger ROI area on the T2-maps was observed in the mixed synovial reaction type as compared to the fluid-like reaction type area (p = 0.01). Heterogeneity was noted in calculated ADC and T2 maps. PCA analysis revealed obvious clustering by the 'normal' and 'grouped abnormal' classifications. CONCLUSIONS: 2D-MSI PROPELLER DWI and MAVRIC-T2 generate quantitative images of periprosthetic tissues within clinically feasible scan times. The combination of derived ADC and T2-values with area of synovial reaction may aid in differentiating normal from abnormal synovial reactions between types of synovial reactions in patients with THA.

MAVRIC based T2 mapping assessment of infrapatellar fat pad scarring in patients with total knee arthroplasty.

The infrapatellar fat pad (IPFP) has been implicated as a source of postoperative knee pain. Imaging the IPFP is challenging in patients with total knee arthroplasty (TKA) due to metallic susceptibility artifact. Multi-Acquisition Variable-Resonance Image Combination (MAVRIC)-based T2 Mapping has been developed to mitigate this artifact and can generate quantitative T2 data. Objectives of this study were to (1) measure T2 values of the IPFP in patients with TKAs using a MAVRIC based T2 mapping technique and (2) determine if IPFP T2 values are related to the degree of fat pad scarring or clinical magnetic resonance imaging (MRI) findings. Twenty-eight subjects (10 males, 18 females, Age: 66 + 7.2 years [Mean ± standard deviations]) undergoing clinical MRIs were sequentially recruited. Morphological imaging and quantitative T2 mapping sequences were performed on a clinical 1.5 T scanner. The morphologic images were graded for the presence and severity of fat pad scarring and clinical outcomes. T2 values were calculated in the total fat pad volume, a normal regions of interest (ROI), and an abnormal ROI. T2 values were shortened in the total IPFP volume (p = 0.001) and within abnormal regions (p = 0.003) in subjects with more severe IPFP scarring. The difference between T2 values in normal-abnormal regions was greater in subjects with severe versus no scarring (+1426.1%, p = 0.008). T2 values were elevated in patients with MRI findings of osteolysis (+32.3%, p = 0.02). These findings indicate that MAVRIC-based T2 Mapping may be used as a quantitative biomarker of postoperative IPFP scarring in individuals following TKA.

Alcohol induced hepatic retinoid depletion is associated with the induction of multiple retinoid catabolizing cytochrome P450 enzymes.

Chronic alcohol consumption leads to a spectrum of liver disease that is associated with significant global mortality and morbidity. Alcohol is known to deplete hepatic vitamin A content, which has been linked to the pathogenesis of alcoholic liver disease. It has been suggested that induction of Cytochrome P450 2E1 (CYP2E1) contributes to alcohol-induced hepatic vitamin A depletion, but the possible contributions of other retinoid-catabolizing CYPs have not been well studied. The main objective of this study was to better understand alcohol-induced hepatic vitamin A depletion and test the hypothesis that alcohol-induced depletion of hepatic vitamin A is due to CYP-mediated oxidative catabolism. This hypothesis was tested in a mouse model of chronic alcohol consumption, including wild type and Cyp2e1 -/- mice. Our results show that chronic alcohol consumption is associated with decreased levels of hepatic retinol, retinyl esters, and retinoic acid. Moreover, the depletion of hepatic retinoid is associated with the induction of multiple retinoid catabolizing CYPs, including CYP26A1, and CYP26B1 in alcohol fed wild type mice. In Cyp2e1 -/- mice, alcohol-induced retinol decline is blunted but retinyl esters undergo a change in their acyl composition and decline upon alcohol exposure like WT mice. In conclusion, the alcohol induced decline in hepatic vitamin A content is associated with increased expression of multiple retinoid-catabolizing CYPs, including the retinoic acid specific hydroxylases CYP26A1 and CYP26B1.

Reproducibility of pathologic scoring systems for periprosthetic adverse local tissue reactions: A cross-sectional study.

BACKGROUND: Several previous studies have described broad histologic classifications of peri-prosthetic reactions that likely reflect the underlying mechanism of arthroplasty failure; however, a consensus has not yet been reached about the relative importance of individual observations. QUESTION/PURPOSE: The purpose of this study was to evaluate the inter-examiner repeatability of commonly used histopathologic grading methods, and to determine the utility of assigning a more simple, global categorization in patients undergoing revision THA surgery of implants with a variety of bearing combinations. METHODS: Between March 2013 and February 2020, a total of 2131 patients underwent revision hip arthroplasty surgery at a one center, of which 12% (248 of 2131) of patients were enrolled. Two pathologists independently reviewed microscope slides of periprosthetic tissue from these patients, of which 425 slides (229 hips, 222 subjects) were reviewed by both pathologists. Separate slides were used for a priori training of the pathologists. Slides were evaluated with the Campbell Aseptic Lymphocyte-dominant Vasculitis-Associated Lesion (ALVAL) score, the Oxford ALVAL score as modified by Grammatopolous, the Fujishiro and Natu scores, and a proposed simplified pattern classification, similar to that of Krenn et al., that incorporates individual factors of these existing scoring methods and was previously shown to correspond to Magnetic Resonance Imaging findings. Inter-rater agreement was assessed using Gwet's AC1 and AC2 coefficients and correspondence analysis was used to examine associations between individual factors of prior scoring methods with the proposed major pattern. RESULTS: Almost perfect inter-rater repeatability (Gwet's AC2 > 0.8) was found for 71% (15/21) of the individual factors, and substantial interrater agreement was found for the proposed major overall pattern (Gwet's AC1: 0.80, 95%CI: 0.72-0.85). Correspondence analysis was able to explain 89-91% of data variability and was able to identify individual features not commonly associated with a major pattern, but discriminatory of the major pattern, such as "Lymph Cuff Thickness 0.25-0.5″ with ALVAL. CONCLUSION: In contrast to prior examinations, excellent interrater agreement was found that may be attributable to a priori training of raters with a test set of slides or difficulty of interpreting grading criteria. The proposed simplified major pattern classification may facilitate evaluation of histopathologic tissue samples.

Clinical Feasibility of Multi-Acquisition Variable-Resonance Image Combination-Based T2 Mapping near Hip Arthroplasty.

Background: Hip arthroplasty is increasingly prevalent, and early detection of complications can improve outcomes. Quantitative magnetic resonance imaging (qMRI) methods using multi-acquisition variable-resonance image combination (MAVRIC) may allow for the assessment of soft tissues in close proximity to hip arthroplasty devices. Question/Purposes: We sought to determine the clinical feasibility of MAVRIC-based T2 mapping as a qMRI approach for assessing synovial reactions in patients with a hip arthroplasty device. We hypothesized that there would be differences in T2 metrics by synovial type, clinical impression, and clinical findings related to synovitis. Methods: We conducted a cross-sectional study of 141 subjects with 171 hip arthroplasties with greater than 1 year post-implantation. We enrolled subjects who had had a primary total hip arthroplasty or hip resurfacing arthroplasty between May 2019 and March 2020, excluding those with a revision hip arthroplasty and those with standard safety contraindications for receiving an MRI. Institutional standard 2D fast spin echo (FSE), short-tau inversion recovery (STIR), and susceptibility-reduced MAVRIC morphological MR images were acquired for each hip and followed by a dual-echo acquisition MAVRIC T2 mapping sequence. Results: While 131 subjects (81%) were classified as having a "normal" synovial reaction, significantly longer T2 values were found for fluid synovial reactions compared with mixed reactions. In addition, subjects with synovial dehiscence and decompression present had T2 prolongation. Larger synovial volumes were found in subjects with low-signal intensity deposits. Conclusions: MAVRIC-based T2 mapping is clinically feasible and there are significant quantitative differences based on type of synovial reaction. Patients undergoing hip arthroscopy revision surgery will warrant comparison of T2 values with direct histologic assessment of a tissue sample obtained intraoperatively. The approach used in this study may be used for a quantitative evaluation and monitoring of soft tissues around metal implants.

Adverse Local Tissue Reactions are Common in Asymptomatic Individuals After Hip Resurfacing Arthroplasty: Interim Report from a Prospective Longitudinal Study.

BACKGROUND: The evaluation of the natural history prevalence of adverse local tissue reactions (ALTRs) using MRI has focused only on metal-on-metal (MoM) bearing surfaces without comparison to nonMoM bearing surfaces. QUESTIONS/PURPOSES: To determine (1) the longitudinal changes and differences in blood metal ion levels in patients with hip resurfacing arthroplasty (HRA), ceramic-on-ceramic (CoC) THA, and metal-on-polyethylene (MoP) THA compared with those undergoing ceramic-on-polyethylene (CoP) THA; (2) how the longitudinal change of synovial reaction classification in patients with HRA, CoC THA, and MoP THA compares with those undergoing CoP THA, and whether there is an association between the presence of an ALTR or metallosis on MRI with corresponding patient-reported outcomes, or the presence of capsular dehiscence; and (3) differences in blood metal ion levels between patients undergoing HRA with an ALTR or metallosis on MRI and those with HRA without these conditions. METHODS: Between March 2014 and February 2019, 22,723 patients underwent primary HRA and THA at one center. Patients received an HRA based on their desired athletic level after surgery and the presence of normal acetabular and proximal femoral bone morphology without osteopenia or osteoporosis. Two percent (342 of 22,723) of patients were contacted to participate, and 71% (243 of 342 hips in 206 patients) were enrolled for analysis at baseline. The patients underwent arthroplasty for degenerative joint disease, and 25 patients withdrew over the course of the study. We included patients who were more than 1 year postarthroplasty. All participants had an MRI examination and blood serum ion testing and completed a Hip Disability and Osteoarthritis Outcome Score survey annually for four years (baseline, year 1, year 2, year 3). Morphologic and susceptibility-reduced MR images were evaluated by a single radiologist not involved in the care of patients for the presence and classification of synovitis (Gwet AC1: 0.65 to 0.97), synovial thickness, and volume (coefficient of repeatability: 1.8 cm3). Linear mixed-effects models were used to compare the mean synovial thickness, synovial volume, and Hip Disability and Osteoarthritis Outcome Score subscales between bearing surfaces at each timepoint and within each bearing surface over time. Marginal Cox proportional hazards models were used to compare the time to and the risk of developing ALTR only, metallosis only, and ALTR or metallosis between bearing surfaces. All models were adjusted for age, sex, BMI, and length of implantation based on known confounders for hip arthroplasty. Adjustment for multiple comparisons was performed using the Dunnett-Hsu method. RESULTS: Patients with unilateral HRA had higher cobalt and chromium serum ion levels (baseline: 1.8 ± 0.8 ppb, year 1: 2.0 ± 1.5 ppb, year 2: 2.1 ± 1.2 ppb, year 3: 1.6 ± 0.7 ppb) than those with unilateral CoP bearings (baseline: 0.0 ± 0.1 ppb, year 1: 0.1 ± 0.3 ppb, year 2: 0.0 ± 0.2 ppb, year 3: 0.0 ± 0.0 ppb) at all timepoints (p < 0.001 for each time point). More patients who received an HRA developed ALTR or metallosis on MRI than did patients with CoP bearings (hazard ratio 4.8 [95% confidence interval 1.2 to 18.4]; p = 0.02). There was no association between the longitudinal change of synovial reaction to ALTR or metallosis on MRI with patient-reported outcomes. In addition, there was no association between the presence of dehiscence at baseline and the subsequent development of ALTR or metallosis, as seen on MRI. There were elevated cobalt (4.7 ± 3.5 ppb) and chromium (4.7 ± 2.6 ppb) serum levels in patients with unilateral HRA who had an ALTR or metallosis present on MRI at year 1 compared with patients without an ALTR or metallosis on MRI (cobalt: 1.8 ± 1.0 ppb, mean difference 4.7 ppb [95% CI 3.3 to 6.0]; p < 0.001; chromium: 2.3 ± 0.5 ppb, mean difference 3.6 ppb [95% CI 2.2 to 5.0]; p < 0.001) as well as for chromium at year 3 (3.9 ± 2.4 ppb versus 2.2 ± 1.1 ppb, mean difference 1.3 ppb [95% CI 0.3 to 2.4]; p = 0.01). CONCLUSION: We found a higher proportion of ALTR or metallosis on MRI in patients with HRA compared with patients with CoP, even when patient self-assessed symptomatology of those with an ALTR or metallosis on MRI was not different than the absence of these features. MRI detected ALTRs in high-function patients, emphasizing that an annual clinical assessment dependent on survey or blood ion testing alone may not detect soft tissue complications. The results of this study are in line with prior consensus recommendations of using MRI as part of a routine follow-up protocol for this patient population. LEVEL OF EVIDENCE: Level III, therapeutic study.

HPV Oncogene Manipulation Using Nonvirally Delivered CRISPR/Cas9 or Natronobacterium gregoryi Argonaute.

CRISPR/Cas9 technology enables targeted gene editing; yet, the efficiency and specificity remain unsatisfactory, particularly for the nonvirally delivered, plasmid-based CRISPR/Cas9 system. To tackle this, a self-assembled micelle is developed and evaluated for human papillomavirus (HPV) E7 oncogene disruption. The optimized micelle enables effective delivery of Cas9 plasmid with a transient transgene expression profile, benefiting the specificity of Cas9 recognition. Furthermore, the feasibility of using the micelle is explored for another nucleic acid-guided nuclease system, Natronobacterium gregoryi Argonaute (NgAgo). Both systems are tested in vitro and in vivo to evaluate their therapeutic potential. Cas9-mediated E7 knockout leads to significant inhibition of HPV-induced cancerous activity both in vitro and in vivo, while NgAgo does not show significant E7 inhibition on the xenograft mouse model. Collectively, this micelle represents an efficient delivery system for nonviral gene editing, adding to the armamentarium of gene editing tools to advance safe and effective precision medicine-based therapeutics.

CRISPR Technology for Breast Cancer: Diagnostics, Modeling, and Therapy.

Molecularly, breast cancer represents a highly heterogenous family of neoplastic disorders, with substantial interpatient variations regarding genetic mutations, cell composition, transcriptional profiles, and treatment response. Consequently, there is an increasing demand for alternative diagnostic approaches aimed at the molecular annotation of the disease on a patient-by-patient basis and the design of more personalized treatments. The clustered regularly interspaced short palindromic repeats (CRISPR)/CRISPR-associated (Cas) technology enables the development of such novel approaches. For instance, in diagnostics, the use of the RNA-specific C2c2 system allows ultrasensitive nucleic acid detection and could be used to characterize the mutational repertoire and transcriptional breast cancer signatures. In disease modeling, CRISPR/Cas9 technology can be applied to selectively engineer oncogenes and tumor-suppressor genes involved in disease pathogenesis. In treatment, CRISPR/Cas9 can be used to develop gene-therapy, while its catalytically-dead variant (dCas9) can be applied to reprogram the epigenetic landscape of malignant cells. As immunotherapy becomes increasingly prominent in cancer treatment, CRISPR/Cas9 can engineer the immune cells to redirect them against cancer cells and potentiate antitumor immune responses. In this review, CRISPR strategies for the advancement of breast cancer diagnostics, modeling, and treatment are highlighted, culminating in a perspective on developing a precision medicine-based approach against breast cancer.

Chronic alcohol consumption decreases brown adipose tissue mass and disrupts thermoregulation: a possible role for altered retinoid signaling.

Retinoic acid, an active metabolite of dietary vitamin A, acts as a ligand for nuclear receptor transcription factors with more than 500 known target genes. It is becoming increasingly clear that alcohol has a significant impact on cellular retinoic acid metabolism, with resultant effects on its function. Here, we test the hypothesis that chronic alcohol consumption impairs retinoic acid signaling in brown adipose tissue (BAT), leading to impaired BAT function and thermoregulation. All studies were conducted in age-matched, male mice consuming alcohol-containing liquid diets. Alcohol's effect on BAT was assessed by histology, qPCR, HPLC, LC/MS and measures of core body temperature. Our data show that chronic alcohol consumption decreases BAT mass, with a resultant effect on thermoregulation. Follow-up mechanistic studies reveal a decreased triglyceride content in BAT, as well as impaired retinoic acid homeostasis, associated with decreased BAT levels of retinoic acid in alcohol-consuming mice. Our work highlights a hitherto uncharacterized effect of alcohol on BAT function, with possible implications for thermoregulation and energy metabolism in drinkers. Our data indicate that alcohol's effects on brown adipose tissue may be mediated through altered retinoic acid signaling.

The Hepatic Lipidome: A Gateway to Understanding the Pathogenes is of Alcohol-Induced Fatty Liver.

Chronic alcohol consumption can lead to the development of alcoholic fatty liver disease. The underlying pathogenic mechanisms however, have not been fully elucidated. Here, we review the current state of the art regarding the application of lipidomics to study alcohol's effect on hepatic lipids. It is clear that alcohol has a profound effect on the hepatic lipidome, with documented changes in the major lipid categories (i.e. fatty acyls, glycerolipids, glycerophospholipids, sphingolipids, sterol lipids and prenol lipids). Alcohol's most striking effect is the marked change in the hepatic fatty acyl pool. This effect includes increased levels of 18-carbon fatty acyl chains incorporated into multiple lipid species, as well as a general shift toward increased unsaturation of fatty acyl moieties. In addition to our literature review, we also make several recommendations to consider when designing lipidomic studies into alcohol's effects. These recommendations include integration of lipidomic data with other measures of lipid metabolism, inclusion of multiple experimental time points, and presentation of quantitative data. We believe rigorous analysis of the hepatic lipidome can yield new insight into the pathogenesis of alcohol-induced fatty liver. While the existing literature has been largely descriptive, the field is poised to apply lipidomics to yield a new level of understanding on alcohol's effects on hepatic lipid metabolism.