Low-dose acetylsalicylic acid reduces local inflammation and tissue perfusion in dense breast tissue in postmenopausal women.

PURPOSE: One major risk factor for breast cancer is high mammographic density. It has been estimated that dense breast tissue contributes to ~ 30% of all breast cancer. Prevention targeting dense breast tissue has the potential to improve breast cancer mortality and morbidity. Anti-estrogens, which may be associated with severe side-effects, can be used for prevention of breast cancer in women with high risk of the disease per se. However, no preventive therapy targeting dense breasts is currently available. Inflammation is a hallmark of cancer. Although the biological mechanisms involved in the increased risk of cancer in dense breasts is not yet fully understood, high mammographic density has been associated with increased inflammation. We investigated whether low-dose acetylsalicylic acid (ASA) affects local breast tissue inflammation and/or structural and dynamic changes in dense breasts. METHODS: Postmenopausal women with mammographic dense breasts on their regular mammography screen were identified. A total of 53 women were randomized to receive ASA 160 mg/day or no treatment for 6 months. Magnetic resonance imaging (MRI) was performed before and after 6 months for a sophisticated and continuous measure breast density by calculating lean tissue fraction (LTF). Additionally, dynamic quantifications including tissue perfusion were performed. Microdialysis for sampling of proteins in vivo from breasts and abdominal subcutaneous fat, as a measure of systemic effects, before and after 6 months were performed. A panel of 92 inflammatory proteins were quantified in the microdialysates using proximity extension assay. RESULTS: After correction for false discovery rate, 20 of the 92 inflammatory proteins were significantly decreased in breast tissue after ASA treatment, whereas no systemic effects were detected. In the no-treatment group, protein levels were unaffected. Breast density, measured by LTF on MRI, were unaffected in both groups. ASA significantly decreased the perfusion rate. The perfusion rate correlated positively with local breast tissue concentration of VEGF. CONCLUSIONS: ASA may shape the local breast tissue microenvironment into an anti-tumorigenic state. Trials investigating the effects of low-dose ASA and risk of primary breast cancer among postmenopausal women with maintained high mammographic density are warranted. Trial registration EudraCT: 2017-000317-22.

Fatty infiltrate and neck muscle volume in individuals with chronic whiplash associated disorders compared to healthy controls - a cross sectional case-control study.

BACKGROUND: The underlying pathophysiological mechanisms of chronic Whiplash Associated Disorders (WAD) are not fully understood. More knowledge of morphology is needed to better understand the disorder, improve diagnostics and treatments. The aim was to investigate dorsal neck muscle volume (MV) and muscle fat infiltration (MFI) in relation to self-reported neck disability among 30 participants with chronic WAD grade II-III compared to 30 matched healthy controls. METHODS: MV and MFI at spinal segments C4 through C7 in both sexes with mild- to moderate chronic WAD (n = 20), severe chronic WAD (n = 10), and age- and sex matched healthy controls (n = 30) was compared. Muscles: trapezius, splenius, semispinalis capitis and semispinalis cervicis were segmented by a blinded assessor and analyzed. RESULTS: Higher MFI was found in right trapezius (p = 0.007, Cohen's d = 0.9) among participants with severe chronic WAD compared to healthy controls. No other significant difference was found for MFI (p = 0.22-0.95) or MV (p = 0.20-0.76). CONCLUSIONS: There are quantifiable changes in muscle composition of right trapezius on the side of dominant pain and/or symptoms, among participants with severe chronic WAD. No other statistically significant differences were shown for MFI or MV. These findings add knowledge of the association between MFI, muscle size and self-reported neck disability in chronic WAD. TRIAL REGISTRATION: NA. This is a cross-sectional case-control embedded in a cohort study.

Morphology and composition of the ventral neck muscles in individuals with chronic whiplash related disorders compared to matched healthy controls: a cross-sectional case-control study.

BACKGROUND: OBJECTIVE: Studies of cross-sectional area (CSA) (morphology) and muscle fat infiltration (MFI) (composition) in ventral neck muscles is scarce in patients with chronic whiplash associated disorders (WAD), especially for men and those with severe WAD compared with matched healthy controls. The aim was to compare CSA and MFI of sternocleidomastoid (SCM), longus capitis (LCA) and longus colli (LCO) in patients with chronic right-sided dominant moderate (Neck Disability Index: NDI < 40) or severe WAD (NDI ≥ 40), compared to age- and sex-matched healthy controls. METHODS: Cross-sectional case-control study with blinded investigators. Thirty-one patients with chronic WAD (17 women and 14 men, mean age 40 years) (SD 12.6, range 20-62)) and 31 age- and sex-matched healthy controls underwent magnetic resonance imaging of ventral neck muscles segmental level C4. RESULTS: Unique to the severe group was a larger magnitude of MFI in right SCM (p = 0.02) compared with healthy controls. There was no significant difference between the groups with regards to the other muscles and measures. CONCLUSIONS: Individuals with severe right-sided dominant WAD have a higher MFI in the right SCM compared to healthy controls. No other differences were found between the groups. The present study indicates that there are changes in the composition of muscles on the side of greatest pain.

The effect on precision and T1 bias comparing two flip angles when estimating muscle fat infiltration using fat-referenced chemical shift-encoded imaging.

Investigation of the effect on accuracy and precision of different parameter settings is important for quantitative MRI. The purpose of this study was to investigate T1 bias and precision for muscle fat infiltration (MFI) measurements using fat-referenced chemical shift MFI measurements at flip angles of 5° and 10°. The fat-referenced measurements were compared with fat fractions, which is a more commonly used measure of MFI. This retrospective study was performed on data from a clinical intervention study including 40 postmenopausal women. Test and retest images were acquired with a 3-T scanner using four-point 3D spoiled gradient multiecho acquisition. Postprocessing included T2* correction and fat-referenced calibration, where the fat signal was calibrated using adipose tissue as reference. The mean MFI was calculated in six different muscle regions using both the fat-referenced fat signal and the fat fraction, defined as the fat signal divided by the sum of the fat and water signals. Both methods used the same fat and water images as input. The variance of the difference between mean MFI from test and retest was used as the measure of precision. The signal-to-noise ratio (SNR) characteristics were analyzed by measuring the full width at half maximum (FWHM) of the fat signal distribution. There was no difference in the mean MFI at different flip angles for the fat-referenced technique (p = 0.66), while the measured fat fractions were 3.3 percentage points larger for 10° compared with 5° (p < 0.001). No significant difference in the precision was found in any of the muscles analyzed. However, the FWHM of the fat signal distribution was significantly (p = 0.01) lower at 10°. This strenghtens the hypothesis that fat-referenced MFI is insensitive to flip angle-induced T1 bias in CSE-MRI, enabling usage of a higher and more SNR-effective flip angle. The lower FWHM in fat-referenced MFI at 10° indicates that high flip angle acquisition is advantageous even although no significant differences in precision were observed comparing 5° and 10°.

The relation between local and distal muscle fat infiltration in chronic whiplash using magnetic resonance imaging.

The objective of this study was to investigate the relationship between fat infiltration in the cervical multifidi and fat infiltration measured in the lower extremities to move further into understanding the complex signs and symptoms arising from a whiplash trauma. Thirty-one individuals with chronic whiplash associated disorders, stratified into a mild/moderate group and a severe group, together with 31 age- and gender matched controls were enrolled in this study. Magnetic resonance imaging was used to acquire a 3D volume of the neck and of the whole-body. Cervical multifidi was used to represent muscles local to the whiplash trauma and all muscles below the hip joint, the lower extremities, were representing widespread muscles distal to the site of the trauma. The fat infiltration was determined by fat fraction in the segmented images. There was a linear correlation between local and distal muscle fat infiltration (p<0.001, r2 = 0.28). The correlation remained significant when adjusting for age and WAD group (p = 0.009) as well as when correcting for age, WAD group and BMI (p = 0.002). There was a correlation between local and distal muscle fat infiltration within the severe WAD group (p = 0.0016, r2 = 0.69) and in the healthy group (p = 0.022, r2 = 0.17) but not in the mild/moderate group (p = 0.29, r2 = 0.06). No significant differences (p = 0.11) in the lower extremities' MFI between the different groups were found. The absence of differences between the groups in terms of lower extremities' muscle fat infiltration indicates that, in this particular population, the whiplash trauma has a local effect on muscle fat infiltration rather than a generalized.

Pathophysiology behind prolonged whiplash associated disorders: study protocol for an experimental study.

BACKGROUND: There is insufficient knowledge of pathophysiological parameters to understand the mechanism behind prolonged whiplash associated disorders (WAD), and it is not known whether or not changes can be restored by rehabilitation. The aims of the projects are to investigate imaging and molecular biomarkers, cervical kinaesthesia, postural sway and the association with pain, disability and other outcomes in individuals with longstanding WAD, before and after a neck-specific exercise intervention. Another aim is to compare individuals with WAD with healthy controls. METHODS: Participants are a sub-group (n = 30) of individuals recruited from an ongoing randomized controlled study (RCT). Measurements in this experimental prospective study will be carried out at baseline (before intervention) and at a three month follow-up (end of physiotherapy intervention), and will include muscle structure and inflammation using magnetic resonance imaging (MRI), brain structure and function related to pain using functional MRI (fMRI), muscle function using ultrasonography, biomarkers using samples of blood and saliva, cervical kinaesthesia using the "butterfly test" and static balance test using an iPhone app. Association with other measures (self-reported and clinical measures) obtained in the RCT (e.g. background data, pain, disability, satisfaction with care, work ability, quality of life) may be investigated. Healthy volunteers matched for age and gender will be recruited as controls (n = 30). DISCUSSION: The study results may contribute to the development of improved diagnostics and improved rehabilitation methods for WAD. TRIAL REGISTRATION: Clinicaltrial.gov Protocol ID: NCT03664934, initial release 09/11/2018.

Precision of MRI-based body composition measurements of postmenopausal women.

OBJECTIVES: To determine precision of magnetic resonance imaging (MRI) based fat and muscle quantification in a group of postmenopausal women. Furthermore, to extend the method to individual muscles relevant to upper-body exercise. MATERIALS AND METHODS: This was a sub-study to a randomized control trial investigating effects of resistance training to decrease hot flushes in postmenopausal women. Thirty-six women were included, mean age 56 ± 6 years. Each subject was scanned twice with a 3.0T MR-scanner using a whole-body Dixon protocol. Water and fat images were calculated using a 6-peak lipid model including R2*-correction. Body composition analyses were performed to measure visceral and subcutaneous fat volumes, lean volumes and muscle fat infiltration (MFI) of the muscle groups' thigh muscles, lower leg muscles, and abdominal muscles, as well as the three individual muscles pectoralis, latissimus, and rhomboideus. Analysis was performed using a multi-atlas, calibrated water-fat separated quantification method. Liver-fat was measured as average proton density fat-fraction (PDFF) of three regions-of-interest. Precision was determined with Bland-Altman analysis, repeatability, and coefficient of variation. RESULTS: All of the 36 included women were successfully scanned and analysed. The coefficient of variation was 1.1% to 1.5% for abdominal fat compartments (visceral and subcutaneous), 0.8% to 1.9% for volumes of muscle groups (thigh, lower leg, and abdomen), and 2.3% to 7.0% for individual muscle volumes (pectoralis, latissimus, and rhomboideus). Limits of agreement for MFI was within ± 2.06% for muscle groups and within ± 5.13% for individual muscles. The limits of agreement for liver PDFF was within ± 1.9%. CONCLUSION: Whole-body Dixon MRI could characterize a range of different fat and muscle compartments with high precision, including individual muscles, in the study-group of postmenopausal women. The inclusion of individual muscles, calculated from the same scan, enables analysis for specific intervention programs and studies.

Intramuscular fat infiltration evaluated by magnetic resonance imaging predicts the extensibility of the supraspinatus muscle.

INTRODUCTION: Rotator cuff (RC) tears result in muscle atrophy and fat infiltration within the RC muscles. An estimation of muscle quality and deformation, or extensibility, is useful in selecting the most appropriate surgical procedure. We determined if noninvasive quantitative assessment of intramuscular fat using MRI could be used to predict extensibility of the supraspinatus muscle. METHODS: Seventeen cadaveric shoulders were imaged to assess intramuscular fat infiltration. Extensibility and histological evaluations were then performed. RESULTS: Quantitative fat infiltration positively correlated with histological findings and presented a positive correlation with muscle extensibility (r = 0.69; P = 0.002). Extensibility was not significantly different between shoulders graded with a higher fat content versus those with low fat when implementing qualitative methods. DISCUSSION: A noninvasive prediction of whole-muscle extensibility may directly guide pre-operative planning to determine if the torn edge could efficiently cover the original footprint while aiding in postoperative evaluation of RC repair. Muscle Nerve 57: 129-135, 2018.

The qualitative grading of muscle fat infiltration in whiplash using fat and water magnetic resonance imaging.

BACKGROUND CONTEXT: The development of muscle fat infiltration (MFI) in the neck muscles is associated with poor functional recovery following whiplash injury. Custom software and time-consuming manual segmentation of magnetic resonance imaging (MRI) is required for quantitative analysis and presents as a barrier for clinical translation. PURPOSE: The purpose of this work was to establish a qualitative MRI measure for MFI and evaluate its ability to differentiate between individuals with severe whiplash-associated disorder (WAD), mild or moderate WAD, and healthy controls. STUDY DESIGN/SETTING: This is a cross-sectional study. PATIENT SAMPLE: Thirty-one subjects with WAD and 31 age- and sex-matched controls were recruited from an ongoing randomized controlled trial. OUTCOME MEASURES: The cervical multifidus was visually identified and segmented into eighths in the axial fat/water images (C4-C7). Muscle fat infiltration was assessed on a visual scale: 0 for no or marginal MFI, 1 for light MFI, and 2 for distinct MFI. The participants with WAD were divided in two groups: mild or moderate and severe based on Neck Disability Index % scores. METHODS: The mean regional MFI was compared between the healthy controls and each of the WAD groups using the Mann-Whitney U test. Receiver operator characteristic (ROC) analyses were carried out to evaluate the validity of the qualitative method. RESULTS: Twenty (65%) patients had mild or moderate disability and 11 (35%) were considered severe. Inter- and intra-rater reliability was excellent when grading was averaged by level or when frequency of grade II was considered. Statistically significant differences (p<.05) in regional MFI were particularly notable between the severe WAD group and healthy controls. The ROC curve, based on detection of distinct MFI, showed an area-under-the curve of 0.768 (95% confidence interval 0.59-0.94) for discrimination of WAD participants. CONCLUSIONS: These preliminary results suggest a qualitative MRI measure for MFI is reliable and valid, and may prove useful toward the classification of WAD in radiology practice.

An Investigation of Fat Infiltration of the Multifidus Muscle in Patients With Severe Neck Symptoms Associated With Chronic Whiplash-Associated Disorder.

Study Design Cross-sectional study. Background Findings of fat infiltration in cervical spine multifidus, as a sign of degenerative morphometric changes due to whiplash injury, need to be verified. Objectives To develop a method using water/fat magnetic resonance imaging (MRI) to investigate fat infiltration and cross-sectional area of multifidus muscle in individuals with whiplash-associated disorders (WADs) compared to healthy controls. Methods Fat infiltration and cross-sectional area in the multifidus muscles spanning the C4 to C7 segmental levels were investigated by manual segmentation using water/fat-separated MRI in 31 participants with WAD and 31 controls, matched for age and sex. Results Based on average values for data spanning C4 to C7, participants with severe disability related to WAD had 38% greater muscular fat infiltration compared to healthy controls (P = .03) and 45% greater fat infiltration compared to those with mild to moderate disability related to WAD (P = .02). There were no significant differences between those with mild to moderate disability and healthy controls. No significant differences between groups were found for multifidus cross-sectional area. Significant differences were observed for both cross-sectional area and fat infiltration between segmental levels. Conclusion Participants with severe disability after a whiplash injury had higher fat infiltration in the multifidus compared to controls and to those with mild/moderate disability secondary to WAD. Earlier reported findings using T1-weighted MRI were reproduced using refined imaging technology. The results of the study also indicate a risk when segmenting single cross-sectional slices, as both cross-sectional area and fat infiltration differ between cervical levels. J Orthop Sports Phys Ther 2016;46(10):886-893. Epub 2 Sep 2016. doi:10.2519/jospt.2016.6553.

Automatic and quantitative assessment of regional muscle volume by multi-atlas segmentation using whole-body water-fat MRI.

PURPOSE: To develop and demonstrate a rapid whole-body magnetic resonance imaging (MRI) method for automatic quantification of total and regional skeletal muscle volume. MATERIALS AND METHODS: The method was based on a multi-atlas segmentation of intensity corrected water-fat separated image volumes. Automatic lean muscle tissue segmentations were achieved by nonrigid registration of atlas datasets with 10 different manually segmented muscle groups. Ten subjects scanned at 1.5 T and 3.0 T were used as atlases, initial validation and optimization. Further validation used 11 subjects scanned at 3.0 T. The automated and manual segmentations were compared using intraclass correlation, true positive volume fractions, and delta volumes. RESULTS: For the 1.5 T datasets, the intraclass correlation, true positive volume fractions (mean ± standard deviation, SD), and delta volumes (mean ± SD) were 0.99, 0.91 ± 0.02, -0.10 ± 0.70L (whole body), 0.99, 0.93 ± 0.02, 0.01 ± 0.07L (left anterior thigh), and 0.98, 0.80 ± 0.07, -0.08 ± 0.15L (left abdomen). The corresponding values at 3.0 T were 0.97, 0.92 ± 0.03, -0.17 ± 1.37L (whole body), 0.99, 0.93 ± 0.03, 0.03 ± 0.08L (left anterior thigh), and 0.89, 0.90 ± 0.04, -0.03 ± 0.42L (left abdomen). The validation datasets showed similar results. CONCLUSION: The method accurately quantified the whole-body skeletal muscle volume and the volume of separate muscle groups independent of field strength and image resolution.

Consistent intensity inhomogeneity correction in water-fat MRI.

PURPOSE: To quantitatively and qualitatively evaluate the water-signal performance of the consistent intensity inhomogeneity correction (CIIC) method to correct for intensity inhomogeneities METHODS: Water-fat volumes were acquired using 1.5 Tesla (T) and 3.0T symmetrically sampled 2-point Dixon three-dimensional MRI. Two datasets: (i) 10 muscle tissue regions of interest (ROIs) from 10 subjects acquired with both 1.5T and 3.0T whole-body MRI. (ii) Seven liver tissue ROIs from 36 patients imaged using 1.5T MRI at six time points after Gd-EOB-DTPA injection. The performance of CIIC was evaluated quantitatively by analyzing its impact on the dispersion and bias of the water image ROI intensities, and qualitatively using side-by-side image comparisons. RESULTS: CIIC significantly ( P1.5T≤2.3×10-4,P3.0T≤1.0×10-6) decreased the nonphysiological intensity variance while preserving the average intensity levels. The side-by-side comparisons showed improved intensity consistency ( Pint⁡≤10-6) while not introducing artifacts ( Part=0.024) nor changed appearances ( Papp≤10-6). CONCLUSION: CIIC improves the spatiotemporal intensity consistency in regions of a homogenous tissue type.

Strain response of thermal barrier coatings captured under extreme engine environments through synchrotron X-ray diffraction.

The mechanical behaviour of thermal barrier coatings in operation holds the key to understanding durability of jet engine turbine blades. Here we report the results from experiments that monitor strains in the layers of a coating subjected to thermal gradients and mechanical loads representing extreme engine environments. Hollow cylindrical specimens, with electron beam physical vapour deposited coatings, were tested with internal cooling and external heating under various controlled conditions. High-energy synchrotron X-ray measurements captured the in situ strain response through the depth of each layer, revealing the link between these conditions and the evolution of local strains. Results of this study demonstrate that variations in these conditions create corresponding trends in depth-resolved strains with the largest effects displayed at or near the interface with the bond coat. With larger temperature drops across the coating, significant strain gradients are seen, which can contribute to failure modes occurring within the layer adjacent to the interface.

Test-retest reliability of automated whole body and compartmental muscle volume measurements on a wide bore 3T MR system.

PURPOSE: To measure the test-retest reproducibility of an automated system for quantifying whole body and compartmental muscle volumes using wide bore 3 T MRI. MATERIALS AND METHODS: Thirty volunteers stratified by body mass index underwent whole body 3 T MRI, two-point Dixon sequences, on two separate occasions. Water-fat separation was performed, with automated segmentation of whole body, torso, upper and lower leg volumes, and manually segmented lower leg muscle volumes. RESULTS: Mean automated total body muscle volume was 19·32 L (SD9·1) and 19·28 L (SD9·12) for first and second acquisitions (Intraclass correlation coefficient (ICC) = 1·0, 95% level of agreement -0·32-0·2 L). ICC for all automated test-retest muscle volumes were almost perfect (0·99-1·0) with 95% levels of agreement 1.8-6.6% of mean volume. Automated muscle volume measurements correlate closely with manual quantification (right lower leg: manual 1·68 L (2SD0·6) compared to automated 1·64 L (2SD 0·6), left lower leg: manual 1·69 L (2SD 0·64) compared to automated 1·63 L (SD0·61), correlation coefficients for automated and manual segmentation were 0·94-0·96). CONCLUSION: Fully automated whole body and compartmental muscle volume quantification can be achieved rapidly on a 3 T wide bore system with very low margins of error, excellent test-retest reliability and excellent correlation to manual segmentation in the lower leg. KEY POINTS: Sarcopaenia is an important reversible complication of a number of diseases. Manual quantification of muscle volume is time-consuming and expensive. Muscles can be imaged using in and out of phase MRI. Automated atlas-based segmentation can identify muscle groups. Automated muscle volume segmentation is reproducible and can replace manual measurements.

Synchrotron X-ray measurement techniques for thermal barrier coated cylindrical samples under thermal gradients.

Measurement techniques to obtain accurate in situ synchrotron strain measurements of thermal barrier coating systems (TBCs) applied to hollow cylindrical specimens are presented in this work. The Electron Beam Physical Vapor Deposition coated specimens with internal cooling were designed to achieve realistic temperature gradients over the TBC coated material such as that occurring in the turbine blades of aeroengines. Effects of the circular cross section on the x-ray diffraction (XRD) measurements in the various layers, including the thermally grown oxide, are investigated using high-energy synchrotron x-rays. Multiple approaches for beam penetration including collection, tangential, and normal to the layers, along with variations in collection parameters are compared for their ability to attain high-resolution XRD data from the internal layers. This study displays the ability to monitor in situ, the response of the internal layers within the TBC, while implementing a thermal gradient across the thickness of the coated sample. The thermal setup maintained coating surface temperatures in the range of operating conditions, while monitoring the substrate cooling, for a controlled thermal gradient. Through variation in measurement location and beam parameters, sufficient intensities are obtained from the internal layers which can be used for depth resolved strain measurements. Results are used to establish the various techniques for obtaining XRD measurements through multi-layered coating systems and their outcomes will pave the way towards goals in achieving realistic in situ testing of these coatings.

Microstructural evolution of carbon nanotube fibers: deformation and strength mechanism.

A comprehensive investigation of the mechanical behavior and microstructural evolution of carbon nanotube (CNT) continuous fibers under twisting and tension is conducted using coarse-grained molecular dynamics simulations. The tensile strength of CNT fibers with random CNT stacking is found to be higher than that of fibers with regular CNT stacking. The factor dominating the mechanical response of CNT fibers is identified as individual CNT stretching. A simplified twisted CNT fiber model is studied to illustrate the structural evolution mechanisms of CNT fibers under tension. Moreover, it is demonstrated that CNT fibers can be reinforced by enhancing intertube interactions. This study would be helpful not only in the general understanding of the nano- and micro-scale factors affecting CNT fibers' mechanical behavior, but also in the optimal design of CNT fibers' architecture and performance.