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.

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.

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.

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.

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.

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.

Prevalence of risk factors for fractures and use of DXA scanning in Danish women. A regional population-based study.

SUMMARY: To determine the relationship between risk factors and use of DXA scans. Our study showed a relatively high use of DXA in low-risk women and the relatively low coverage in women with multiple risk factors. Moreover, distance to DXA clinics, age, and socio-economic factors are associated with the use of DXA. INTRODUCTION: To determine the relationship between risk factors for fracture and use of DXA scans in Danish women in relation to distance to DXA clinics and socio-economic factors. METHODS: From the Danish National Civil Register we randomly selected 5,000 women aged 40-90 years living in the region of Southern Denmark to receive a mailed questionnaire concerning risk factors for fractures. RESULTS: The respondents rate was 84% and 77% of the invited population were available for analysis. A total of 10.3% of the women without risk factors and only 36% of the women with three or more risk factors had a history of DXA. The likelihood of a history of DXA was higher with increasing FRAX(™) 10-year risk; i.e., 8.7% and 30.2% in patients with a 10-year fracture risk of 0-14.9% and 25-100%, respectively. In women with less than 10 km to nearest DXA facility, 20.2% had a history of DXA, while 11.5% of those with more than 40 km to the nearest scanner had a history of DXA. Logistic regression analysis showed that distance, fracture risk, oral glucocorticoids, low-energy fracture, conditions associated with secondary osteoporosis, low BMI, history of falls, age 65-79 years, spouse status, and income were significantly associated with having a history of DXA. CONCLUSIONS: Our study showed a relatively high use of DXA in low-risk women and the relatively low coverage in women with multiple risk factors. Moreover, distance to DXA clinics, age, and a number of socio-economic factors are associated with the use of DXA.

Hard-X-ray dark-field imaging using a grating interferometer.

Imaging with visible light today uses numerous contrast mechanisms, including bright- and dark-field contrast, phase-contrast schemes and confocal and fluorescence-based methods. X-ray imaging, on the other hand, has only recently seen the development of an analogous variety of contrast modalities. Although X-ray phase-contrast imaging could successfully be implemented at a relatively early stage with several techniques, dark-field imaging, or more generally scattering-based imaging, with hard X-rays and good signal-to-noise ratio, in practice still remains a challenging task even at highly brilliant synchrotron sources. In this letter, we report a new approach on the basis of a grating interferometer that can efficiently yield dark-field scatter images of high quality, even with conventional X-ray tube sources. Because the image contrast is formed through the mechanism of small-angle scattering, it provides complementary and otherwise inaccessible structural information about the specimen at the micrometre and submicrometre length scale. Our approach is fully compatible with conventional transmission radiography and a recently developed hard-X-ray phase-contrast imaging scheme. Applications to X-ray medical imaging, industrial non-destructive testing and security screening are discussed.

X-ray imaging with the PILATUS 100k detector.

We report on the application of the PILATUS 100K pixel detector for medical imaging. Experimental results are presented in the form of X-ray radiographs using standard X-ray absorption contrast and a recently developed phase contrast imaging method. The results obtained with the PILATUS detector are compared to results obtained with a conventional X-ray imaging system consisting of an X-ray scintillation screen, lens optics, and a charge coupled device. Finally, the results for both systems are discussed more quantitatively based on an image power spectrum analysis.

High-resolution brain tumor visualization using three-dimensional x-ray phase contrast tomography.

We report on significant advances and new results concerning a recently developed method for grating-based hard x-ray phase tomography. We demonstrate how the soft tissue sensitivity of the technique is increased and show in vitro tomographic images of a tumor bearing rat brain sample, without use of contrast agents. In particular, we observe that the brain tumor and the white and gray brain matter structure in a rat's cerebellum are clearly resolved. The results are potentially interesting from a clinical point of view, since a similar approach using three transmission gratings can be implemented with more readily available x-ray sources, such as standard x-ray tubes. Moreover, the results open the way to in vivo experiments in the near future.

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.

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.

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.

A simple procedure for quantification of neurite outgrowth based on stereological principles.

The molecular mechanisms controlling formation and remodelling of neuronal extensions are of considerable interest for the understanding of neuronal development and plasticity. Determination of neurite outgrowth in cell culture is a widely used approach to investigate these phenomena. This is generally done by a time consuming tracing of individual neurites and their branches. We have used stereological principles to determine the length of neurites. The total neuritic length per cell was estimated by counting the number of intersections between neurites and test lines of an unbiased counting frame superimposed on images of cell cultures obtained by conventional computer-assisted microscopy. The absolute length, L, of neurites per cell was subsequently estimated from the number of neurite intersections, I, per cell by means of the equation L=(pid/2)I describing the relationship between the number of neurite intersections and the vertical distance, d, between the test lines used. When measuring neurite outgrowth from PC12 cells and primary hippocampal neurons, data obtained by counting neuritic intersections correlated statistically significantly with data obtained using a conventional tracing technique. However, information was acquired more efficiently using the stereological approach. Thus, using the described set-up, the stereological procedure was approximately five times less time consuming than the conventional method based on neurite tracing. The study shows that stereological estimation of neuritic length provides a precise and efficient method for the study of neurite outgrowth in cultures of primary neurons and cell lines.

Cost implications of routine mammography screening of women 50-69 years in the county of Funen, Denmark.

In order to estimate the net costs of introducing mammography screening to women 50-69 years of age, unit costs of all relevant activities related to detection and treatment of breast cancer were estimated using activity based costing methods. In order to determine the overall impact of mammography screening, activity data collected from the second screening round (1996-1997) were compared with expected activity levels in the case no screening had taken place in this time period. The direct health care costs associated with the screening activity, excluding effects on treatment and diagnostics but including women's transport and time costs, were estimated at DKK 305 per attendee. The cost of clinical mammography decreases with the introduction of screening due to a decrease in the total number of women undergoing this introductory diagnostic activity, while surgery costs increases, whereas cost incurred by adjuvant treatment and treatment of recurrences will be significantly reduced. Overall, inclusion of effects on course of treatment decreases the net cost of screening by 30-40% to DKK 208 and DKK 128 including and excluding the women's time and transport costs, respectively.