ForMAX - a beamline for multiscale and multimodal structural characterization of hierarchical materials.

The ForMAX beamline at the MAX IV Laboratory provides multiscale and multimodal structural characterization of hierarchical materials in the nanometre to millimetre range by combining small- and wide-angle X-ray scattering with full-field microtomography. The modular design of the beamline is optimized for easy switching between different experimental modalities. The beamline has a special focus on the development of novel fibrous materials from forest resources, but it is also well suited for studies within, for example, food science and biomedical research.

Use of antiosteoporotic medication in the Danish ROSE population-based screening study.

Use of antiosteoporotic medication in the population-based, risk-stratified osteoporosis strategy evaluation (ROSE) screening study, comparing the use of FRAX followed by DXA with usual care, was examined. Screening increased the overall use of medication. Being recommended treatment by the hospital and higher age increased the likelihood of starting medication, but, nevertheless, a large percentage opted not to start treatment. INTRODUCTION: The aim of the study was to examine the impact on medication prescription, adherence, and persistence of osteoporotic medicine in the randomized population-based ROSE screening study for osteoporosis. METHODS: The Danish ROSE study included a population-based random sample of women aged 65-81 years randomized to either a two-step screening program consisting of FRAX followed by DXA for high-risk participants or opportunistic screening for osteoporosis (usual care). This sub-study on the intention-to-treat population examined the impact of the screening program on antiosteoporotic medication redemption rates, adherence, and persistence using Danish registers. RESULTS: A total of 30,719 of 34,229 women were treatment-naïve. Significantly more participants in the screening group started on antiosteoporotic medication, but no differences in adherence and persistence rates were found. Higher age was associated with a higher likelihood of starting medication. A low Charlson comorbidity score (= 1) was associated with higher treatment initiation but lower adherence and persistence of antiosteoporotic treatment. A total of 31.7% of participants advised to initiate treatment did not follow the advice. CONCLUSIONS: Screening for osteoporosis using FRAX followed by DXA increased the overall use of antiosteoporotic medication in the screening group without differences in adherence and persistence rates. A large percentage of participants advised to initiate treatment did nevertheless fail to do so.

Socioeconomic status and risk of osteoporotic fractures and the use of DXA scans: data from the Danish population-based ROSE study.

There is a need of studies exploring the link between socioeconomic status and DXA scans and osteoporotic fracture, which was the aim of the present study. No differences in socioeconomic status and risk of osteoporotic fractures were found. However, women with further/higher education and higher income are more often DXA-scanned. INTRODUCTION: Lower socioeconomic status is known to be associated with a range of chronic conditions and with access to health care services. The link between socioeconomic status and the use of DXA scans and osteoporotic fracture, however, needs to be explored more closely. Therefore, the aim of this study was to examine the relationship between socioeconomic status and both DXA scan utilization and major osteoporotic fractures (MOF) using a population-based cohort of Danish women and national registers. METHODS: The study included 17,155 women (65-81 years) sampled from the Risk-stratified Osteoporosis Strategy Evaluation study (ROSE). Information on socioeconomic background, DXA scans, and MOFs was retrieved from national registers. Competing-risk regression analyses were performed. Mean follow-up was 4.8 years. RESULTS: A total of 4245 women had a DXA scan (24.7%) and 1719 (10.0%) had an incident MOF during follow-up. Analyses showed that women with basic education had a lower probability of undergoing DXA scans than women with further or higher education (greater than upper secondary education and vocational training education) (subhazard ratio (SHR) = 0.82; 95% CI 0.75-0.89, adjusted for age and comorbidity). Moreover, women with disposable income in the low and medium tertiles had a lower probability of undergoing DXA scans than women in the high-income tertile (SHR = 0.90; 95% CI 0.84-0.97 and SHR = 0.88, 95% CI 0.82-0.95, respectively, adjusted for age and comorbidity). No association between socioeconomic background and probability of DXA was found in adjusted analyses. CONCLUSION: The study found no differences in risk of osteoporotic fractures depending on socioeconomic status. However, women with further or higher education as well as higher income are more often DXA-scanned.

Effectiveness of a two-step population-based osteoporosis screening program using FRAX: the randomized Risk-stratified Osteoporosis Strategy Evaluation (ROSE) study.

The Risk-stratified Osteoporosis Strategy Evaluation (ROSE) study investigated the effectiveness of a two-step screening program for osteoporosis in women. We found no overall reduction in fractures from systematic screening compared to the current case-finding strategy. The group of moderate- to high-risk women, who accepted the invitation to DXA, seemed to benefit from the program. INTRODUCTION: The purpose of the ROSE study was to investigate the effectiveness of a two-step population-based osteoporosis screening program using the Fracture Risk Assessment Tool (FRAX) derived from a self-administered questionnaire to select women for DXA scan. After the scanning, standard osteoporosis management according to Danish national guidelines was followed. METHODS: Participants were randomized to either screening or control group, and randomization was stratified according to age and area of residence. Inclusion took place from February 2010 to November 2011. Participants received a self-administered questionnaire, and women in the screening group with a FRAX score ≥ 15% (major osteoporotic fractures) were invited to a DXA scan. Primary outcome was incident clinical fractures. Intention-to-treat analysis and two per-protocol analyses were performed. RESULTS: A total of 3416 fractures were observed during a median follow-up of 5 years. No significant differences were found in the intention-to-treat analyses with 34,229 women included aged 65-80 years. The per-protocol analyses showed a risk reduction in the group that underwent DXA scanning compared to women in the control group with a FRAX ≥ 15%, in regard to major osteoporotic fractures, hip fractures, and all fractures. The risk reduction was most pronounced for hip fractures (adjusted SHR 0.741, p = 0.007). CONCLUSIONS: Compared to an office-based case-finding strategy, the two-step systematic screening strategy had no overall effect on fracture incidence. The two-step strategy seemed, however, to be beneficial in the group of women who were identified by FRAX as moderate- or high-risk patients and complied with DXA.

Non-participation in systematic screening for osteoporosis-the ROSE trial.

Population-based screening for osteoporosis is still controversial and has not been implemented. Non-participation in systematic screening was evaluated in 34,229 women age 65-81 years. Although participation rate was high, non-participation was associated with comorbidity, aging other risk factors for fractures, and markers of low social status, e.g., low income, pension, and living alone. A range of strategies is needed to increase participation, including development of targeted information and further research to better understand the barriers and enablers in screening for osteoporosis. INTRODUCTION: Participation is crucial to the success of a screening program. The objective of this study was to analyze non-participation in Risk-stratified Osteoporosis Strategy Evaluation, a two-step population-based screening program for osteoporosis. METHODS: Thirty-four thousand two hundred twenty-nine women aged 65 to 81 years were randomly selected from the background population and randomized to either a screening group (intervention) or a control group. All women received a self-administered questionnaire designed to allow calculation of future risk of fracture based on FRAX. In the intervention group, women with an estimated high risk of future fracture were invited to DXA scanning. Information on individual socioeconomic status and comorbidity was obtained from national registers. RESULTS: A completed questionnaire was returned by 20,905 (61%) women. Non-completion was associated with older age, living alone, lower education, lower income, and higher comorbidity. In the intervention group, ticking "not interested in DXA" in the questionnaire was associated with older age, living alone, and low self-perceived fracture risk. Women with previous fracture or history of parental hip fracture were more likely to accept screening by DXA. Dropping out when offered DXA, was associated with older age, current smoking, higher alcohol consumption, and physical impairment. CONCLUSIONS: Barriers to population-based screening for osteoporosis appear to be both psychosocial and physical in nature. Women who decline are older, have lower self-perceived fracture risk, and more often live alone compared to women who accept the program. Dropping out after primary acceptance is associated not only with aging and physical impairment but also with current smoking and alcohol consumption. Measures to increase program participation could include targeted information and reducing physical barriers for attending screening procedures.

14C BOMB-PULSE DATING AND STABLE ISOTOPE ANALYSIS FOR GROWTH RATE AND DIETARY INFORMATION IN BREAST CANCER?

The purpose of this study was to perform an initial investigation of the possibility to determine breast cancer growth rate with (14)C bomb-pulse dating. Tissues from 11 breast cancers, diagnosed in 1983, were retrieved from a regional biobank. The estimated average age of the majority of the samples overlapped the year of collection (1983) within 3σ Thus, this first study of tumour tissue has not yet demonstrated that (14)C bomb-pulse dating can obtain information on the growth of breast cancer. However, with further refinement, involving extraction of cell types and components, there is a possibility that fundamental knowledge of tumour biology might still be gained by the bomb-pulse technique. Additionally, δ (13)C and δ (15)N analyses were performed to obtain dietary and metabolic information, and to serve as a base for improvement of the age determination.

Grating-based X-ray Dark-field Computed Tomography of Living Mice.

Changes in x-ray attenuating tissue caused by lung disorders like emphysema or fibrosis are subtle and thus only resolved by high-resolution computed tomography (CT). The structural reorganization, however, is of strong influence for lung function. Dark-field CT (DFCT), based on small-angle scattering of x-rays, reveals such structural changes even at resolutions coarser than the pulmonary network and thus provides access to their anatomical distribution. In this proof-of-concept study we present x-ray in vivo DFCTs of lungs of a healthy, an emphysematous and a fibrotic mouse. The tomographies show excellent depiction of the distribution of structural - and thus indirectly functional - changes in lung parenchyma, on single-modality slices in dark field as well as on multimodal fusion images. Therefore, we anticipate numerous applications of DFCT in diagnostic lung imaging. We introduce a scatter-based Hounsfield Unit (sHU) scale to facilitate comparability of scans. In this newly defined sHU scale, the pathophysiological changes by emphysema and fibrosis cause a shift towards lower numbers, compared to healthy lung tissue.

Quantitative X-ray phase-contrast microtomography from a compact laser-driven betatron source.

X-ray phase-contrast imaging has recently led to a revolution in resolving power and tissue contrast in biomedical imaging, microscopy and materials science. The necessary high spatial coherence is currently provided by either large-scale synchrotron facilities with limited beamtime access or by microfocus X-ray tubes with rather limited flux. X-rays radiated by relativistic electrons driven by well-controlled high-power lasers offer a promising route to a proliferation of this powerful imaging technology. A laser-driven plasma wave accelerates and wiggles electrons, giving rise to a brilliant keV X-ray emission. This so-called betatron radiation is emitted in a collimated beam with excellent spatial coherence and remarkable spectral stability. Here we present a phase-contrast microtomogram of a biological sample using betatron X-rays. Comprehensive source characterization enables the reconstruction of absolute electron densities. Our results suggest that laser-based X-ray technology offers the potential for filling the large performance gap between synchrotron- and current X-ray tube-based sources.

Self-perceived facture risk: factors underlying women's perception of risk for osteoporotic fractures: the Risk-Stratified Osteoporosis Strategy Evaluation study (ROSE).

SUMMARY: This Danish cross-sectional study (n=20,905) showed that women aged 65-81 years generally underestimated fracture risk compared to absolute risk estimated by the FRAX® algorithm. Significant association was found between risk factors (e.g., previous fracture, parental hip fracture, and self-rated heath) and self-perceived fracture risk. Although women recognized the importance of some fracture risk factors, a number of significant risk factors appeared to be less well known. INTRODUCTION: The aim of this study is to investigate women's self-perceived fracture risk and potential factors associated with this and to compare self-perceived risk with absolute fracture risk estimated by FRAX® in women aged 65-80 years. METHODS: Data from 20,905 questionnaires from the ROSE study were analyzed. The questionnaire included 25 items on osteoporosis, risk factors for fractures, and self-perceived risk of fractures and enabled calculation of absolute fracture risk by FRAX®. Data were analyzed using bivariate tests and regression models. RESULTS: Women generally underestimated their fracture risk compared to absolute risk estimated by FRAX®. Women with risk factors for facture estimated their fracture risk significantly higher than their peers. No correlation between self-perceived risk and absolute risk was found. The ordered logistic regression model showed a significant association between high self-perceived fracture risk and previous fragility fracture, parental hip fracture, falls, self-rated heath, conditions related to secondary osteoporosis, and inability to do housework. CONCLUSIONS: These women aged 65-81 years underestimated their risk of fracture. However, they did seem to have an understanding of the importance of some risk factors such as previous fractures, parental hip fracture and falls. Risk communication is a key element in fracture prevention and should have greater focus on less well-known risk factors. Furthermore, it is important to acknowledge that risk perception is not based solely on potential risk factors but is also affected by experiences from everyday life to personal history.

Three-dimensional imaging of whole mouse models: comparing nondestructive X-ray phase-contrast micro-CT with cryotome-based planar epi-illumination imaging.

In this study, we compare two evolving techniques for obtaining high-resolution 3D anatomical data of a mouse specimen. On the one hand, we investigate cryotome-based planar epi-illumination imaging (cryo-imaging). On the other hand, we examine X-ray phase-contrast micro-computed tomography (micro-CT) using synchrotron radiation. Cryo-imaging is a technique in which an electron multiplying charge coupled camera takes images of a cryo-frozen specimen during the sectioning process. Subsequent image alignment and virtual stacking result in volumetric data. X-ray phase-contrast imaging is based on the minute refraction of X-rays inside the specimen and features higher soft-tissue contrast than conventional, attenuation-based micro-CT. To explore the potential of both techniques for studying whole mouse disease models, one mouse specimen was imaged using both techniques. Obtained data are compared visually and quantitatively, specifically with regard to the visibility of fine anatomical details. Internal structure of the mouse specimen is visible in great detail with both techniques and the study shows in particular that soft-tissue contrast is strongly enhanced in the X-ray phase images compared to the attenuation-based images. This identifies phase-contrast micro-CT as a powerful tool for the study of small animal disease models.

In-vivo dark-field and phase-contrast x-ray imaging.

Novel radiography approaches based on the wave nature of x-rays when propagating through matter have a great potential for improved future x-ray diagnostics in the clinics. Here, we present a significant milestone in this imaging method: in-vivo multi-contrast x-ray imaging of a mouse using a compact scanner. Of particular interest is the enhanced contrast in regions related to the respiratory system, indicating a possible application in diagnosis of lung diseases (e.g. emphysema).

Microbubbles as a scattering contrast agent for grating-based x-ray dark-field imaging.

In clinically established-absorption-based-biomedical x-ray imaging, contrast agents with high atomic numbers (e.g. iodine) are commonly used for contrast enhancement. The development of novel x-ray contrast modalities such as phase contrast and dark-field contrast opens up the possible use of alternative contrast media in x-ray imaging. We investigate using ultrasound contrast agents, which unlike iodine-based contrast agents can also be administered to patients with renal impairment and thyroid dysfunction, for application with a recently developed novel x-ray dark-field imaging modality. To produce contrast from these microbubble-based contrast agents, our method exploits ultra-small-angle coherent x-ray scattering. Such scattering dark-field x-ray images can be obtained with a grating-based x-ray imaging setup, together with refraction-based differential phase-contrast and the conventional attenuation contrast images. In this work we specifically show that ultrasound contrast agents based on microbubbles can be used to produce strongly enhanced dark-field contrast, with superior contrast-to-noise ratio compared to the attenuation signal. We also demonstrate that this method works well with an x-ray tube-based setup and that the relative contrast gain even increases when the pixel size is increased from tenths of microns to clinically compatible detector resolutions about up to a millimetre.

Monochromatic computed tomography with a compact laser-driven X-ray source.

A laser-driven electron-storage ring can produce nearly monochromatic, tunable X-rays in the keV energy regime by inverse Compton scattering. The small footprint, relative low cost and excellent beam quality provide the prospect for valuable preclinical use in radiography and tomography. The monochromaticity of the beam prevents beam hardening effects that are a serious problem in quantitative determination of absorption coefficients. These values are important e.g. for osteoporosis risk assessment. Here, we report quantitative computed tomography (CT) measurements using a laser-driven compact electron-storage ring X-ray source. The experimental results obtained for quantitative CT measurements on mass absorption coefficients in a phantom sample are compared to results from a rotating anode X-ray tube generator at various peak voltages. The findings confirm that a laser-driven electron-storage ring X-ray source can indeed yield much higher CT image quality, particularly if quantitative aspects of computed tomographic imaging are considered.

Visualization of subcutaneous insulin injections by x-ray computed tomography.

We report how the three-dimensional structure of subcutaneous injections of soluble insulin can be visualized by x-ray computed tomography using an iodine based contrast agent. The injections investigated are performed ex vivo in porcine adipose tissue. Full tomography scans carried out at a laboratory x-ray source with a total acquisition time of about 1 min yield CT-images with an effective pixel size of 109 × 109 µm². The depots are segmented using a modified Chan-Vese algorithm and we are able to observe differences in the shape of the injection depot and the position of the depot in the skin among equally performed injections. To overcome the beam hardening artefacts, which affect the quantitative prediction of the volume injected, we additionally present results concerning the visualization of two injections using synchrotron radiation. The spatial concentration distribution of iodine is calculated to show the dilution of the insulin drug inside the depot. Characterisation of the shape of the depot and the spatial concentration profile of the injected fluid is important knowledge when improving the clinical formulation of an insulin drug, the performance of injection devices and when predicting the effect of the drug through biomedical simulations.

X-ray tomography using the full complex index of refraction.

We report on x-ray tomography using the full complex index of refraction recorded with a grating-based x-ray phase-contrast setup. Combining simultaneous absorption and phase-contrast information, the distribution of the full complex index of refraction is determined and depicted in a bivariate graph. A simple multivariable threshold segmentation can be applied offering higher accuracy than with a single-variable threshold segmentation as well as new possibilities for the partial volume analysis and edge detection. It is particularly beneficial for low-contrast systems. In this paper, this concept is demonstrated by experimental results.

X-ray dark-field imaging modeling.

Dark-field images are formed from x-ray small-angle scattering signals. The small-angle scattering signals are particularly sensitive to structural variation and density fluctuation on a length scale of several tens to hundreds of nanometers, offering a unique contrast mechanism to reveal subtle structural features of an object. In this study, based on the principle of energy conservation, we develop a physical model to describe the relationship between x-ray small-angle scattering coefficients of an object and dark-field intensity images. This model can be used to reconstruct volumetric x-ray small-angle scattering images of an object using classical tomographic algorithms. We also establish a relationship between the small-angle scattering intensity and the visibility function measured with x-ray grating imaging. The numerical simulations and phantom experiments have demonstrated the accuracy and practicability of the proposed model.

Trimodal low-dose X-ray tomography.

X-ray grating interferometry is a coherent imaging technique that bears tremendous potential for three-dimensional tomographic imaging of soft biological tissue and other specimens whose details exhibit very weak absorption contrast. It is intrinsically trimodal, delivering phase contrast, absorption contrast, and scattering ("dark-field") contrast. Recently reported acquisition strategies for grating-interferometric phase tomography constitute a major improvement of dose efficiency and speed. In particular, some of these techniques eliminate the need for scanning of one of the gratings ("phase stepping"). This advantage, however, comes at the cost of other limitations. These can be a loss in spatial resolution, or the inability to fully separate the three imaging modalities. In the present paper we report a data acquisition and processing method that optimizes dose efficiency but does not share the main limitations of other recently reported methods. Although our method still relies on phase stepping, it effectively uses only down to a single detector frame per projection angle and yields images corresponding to all three contrast modalities. In particular, this means that dark-field imaging remains accessible. The method is also compliant with data acquisition over an angular range of only 180° and with a continuous rotation of the specimen.

A reconstruction method for equidistant fan beam differential phase contrast computed tomography.

We report a reconstruction method, called a back-projection filtered (BPF) algorithm, for fan beam differential phase contrast computed tomography (DPC-CT) with equidistant geometrical configuration. This work comprises a numerical study of the algorithm and its experimental verification with a three-grating interferometer and an x-ray tube source. The numerical simulation and experimental results demonstrate that the proposed method can deal with several classes of truncated datasets. It could be of interest in future medical phase contrast imaging applications.

Molecular X-ray computed tomography of myelin in a rat brain.

In this work we demonstrate the feasibility of applying small-angle X-ray scattering computed tomography (SAXS-CT) for non-invasive molecular imaging of myelin sheaths in a rat brain. Our results show that the approach yields information on several quantities, including the relative myelin concentration, its periodicity, the total thickness of the myelin sheaths, and the relative concentration of cytoskeletal neurofilaments. For example the periodicity of the myelin sheaths varied in the range from 17.0 to 18.2 nm around an average of 17.6 (±0.3) nm. We believe that imaging, i.e., spatially resolved measuring these quantities could provide general means for understanding the relation to a number of neurodegenerative diseases.

Association between passive smoking in adulthood and phalangeal bone mineral density: results from the KRAM study--the Danish Health Examination Survey 2007-2008.

UNLABELLED: The study investigates an association between phalangeal bone mineral density (BMD) and self-reported passive smoking using data on 15,038 persons (aged 18-95 years), who underwent a BMD scan in the Danish KRAM study. BMD was significantly lower in persons exposed to long-term passive smoking in their home during adulthood. INTRODUCTION: Smoking is associated with decreased bone mineral density (BMD) and increased risk of osteoporotic fractures. This study aimed to investigate a possible association between BMD at the phalangeal bones and self-reported passive smoking. METHODS: The study included a cohort of 15,544 men and women aged 18-95 years, who underwent a BMD scan in the Danish KRAM study. BMD scans of the middle phalanges of the second, third and fourth digits of the non-dominant hand were performed with a compact radiographic absorptiometry system (Alara MetriScan®). Also, height, weight and body fat percentage were measured and 96.7% (n = 15,038) of the participants answered a self-reported questionnaire with information on passive smoking, other lifestyle factors, education, etc. The association between passive smoking and BMD was examined using multiple linear regression analysis. RESULTS: A total of 39.1% (n = 5,829) of the participants had been exposed to passive smoking in adulthood at home. BMD was significantly lower in subjects exposed to passive smoking, 0.343 vs. 0.331 g/cm(2); p < 0.01 (unadjusted) and 0.339 vs. 0.337 g/cm(2); p < 0.05 (adjusted for age, gender, height and weight, and smoking). Multiple linear regression analysis showed that exposure to passive smoking for more than 20 years in adulthood at home was significantly related to BMD when adjusted for potential confounders (men, ß = -4.4 × 10(-3); r = -0.05; p < 0.01 and women, ß = -2.3 × 10 (-3); r = -0.03; p < 0.05). This relationship was also seen in the group of never smokers (ß = -3.3 × 10(-3); r = -0.03; p = 0.01). CONCLUSION: Our study supports a potential negative effect of long-term passive smoking in adulthood at home on phalangeal BMD.