InterCarb: A Community Effort to Improve Interlaboratory Standardization of the Carbonate Clumped Isotope Thermometer Using Carbonate Standards.

Increased use and improved methodology of carbonate clumped isotope thermometry has greatly enhanced our ability to interrogate a suite of Earth-system processes. However, interlaboratory discrepancies in quantifying carbonate clumped isotope (Δ47) measurements persist, and their specific sources remain unclear. To address interlaboratory differences, we first provide consensus values from the clumped isotope community for four carbonate standards relative to heated and equilibrated gases with 1,819 individual analyses from 10 laboratories. Then we analyzed the four carbonate standards along with three additional standards, spanning a broad range of δ47 and Δ47 values, for a total of 5,329 analyses on 25 individual mass spectrometers from 22 different laboratories. Treating three of the materials as known standards and the other four as unknowns, we find that the use of carbonate reference materials is a robust method for standardization that yields interlaboratory discrepancies entirely consistent with intralaboratory analytical uncertainties. Carbonate reference materials, along with measurement and data processing practices described herein, provide the carbonate clumped isotope community with a robust approach to achieve interlaboratory agreement as we continue to use and improve this powerful geochemical tool. We propose that carbonate clumped isotope data normalized to the carbonate reference materials described in this publication should be reported as Δ47 (I-CDES) values for Intercarb-Carbon Dioxide Equilibrium Scale.

Re-conceptualizing the origins of life.

Over the last several hundred years of scientific progress, we have arrived at a deep understanding of the non-living world. We have not yet achieved an analogous, deep understanding of the living world. The origins of life is our best chance at discovering scientific laws governing life, because it marks the point of departure from the predictable physical and chemical world to the novel, history-dependent living world. This theme issue aims to explore ways to build a deeper understanding of the nature of biology, by modelling the origins of life on a sufficiently abstract level, starting from prebiotic conditions on Earth and possibly on other planets and bridging quantitative frameworks approaching universal aspects of life. The aim of the editors is to stimulate new directions for solving the origins of life. The present introduction represents the point of view of the editors on some of the most promising future directions.This article is part of the themed issue 'Reconceptualizing the origins of life'.

Dual-Energy Imaging of Bone Marrow Edema on a Dedicated Multi-Source Cone-Beam CT System for the Extremities.

PURPOSE: Arthritis and bone trauma are often accompanied by bone marrow edema (BME). BME is challenging to detect in CT due to the overlaying trabecular structure but can be visualized using dual-energy (DE) techniques to discriminate water and fat. We investigate the feasibility of DE imaging of BME on a dedicated flat-panel detector (FPD) extremities cone-beam CT (CBCT) with a unique x-ray tube with three longitudinally mounted sources. METHODS: Simulations involved a digital BME knee phantom imaged with a 60 kVp low-energy beam (LE) and 105 kVp high-energy beam (HE) (+0.25 mm Ag filter). Experiments were also performed on a test-bench with a Varian 4030CB FPD using the same beam energies as the simulation study. A three-source configuration was implemented with x-ray sources distributed along the longitudinal axis and DE CBCT acquisition in which the superior and inferior sources operate at HE (and collect half of the projection angles each) and the central source operates at LE. Three-source DE CBCT was compared to a double-scan, single-source orbit. Experiments were performed with a wrist phantom containing a 50 mg/ml densitometry insert submerged in alcohol (simulating fat) with drilled trabeculae down to ~1 mm to emulate the trabecular matrix. Reconstruction-based three-material decomposition of fat, soft tissue, and bone was performed. RESULTS: For a low-dose scan (36 mAs in the HE and LE data), DE CBCT achieved combined accuracy of ~0.80 for a pattern of BME spherical lesions ranging 2.5 - 10 mm diameter in the knee phantom. The accuracy increased to ~0.90 for a 360 mAs scan. Excellent DE discrimination of the base materials was achieved in the experiments. Approximately 80% of the alcohol (fat) voxels in the trabecular phantom was properly identified both for single and 3-source acquisitions, indicating the ability to detect edemous tissue (water-equivalent plastic in the body of the densitometry insert) from the fat inside the trabecular matrix (emulating normal trabecular bone with significant fraction of yellow marrow). CONCLUSION: Detection of BME and quantification of water and fat content were achieved in extremities DE CBCT with a longitudinal configuration of sources providing DE imaging in a single gantry rotation. The findings support the development of DE imaging capability for CBCT of the extremities in areas conventionally in the domain of MRI.

Assessment of image quality in soft tissue and bone visualization tasks for a dedicated extremity cone-beam CT system.

OBJECTIVE: To assess visualization tasks using cone-beam CT (CBCT) compared to multi-detector CT (MDCT) for musculoskeletal extremity imaging. METHODS: Ten cadaveric hands and ten knees were examined using a dedicated CBCT prototype and a clinical multi-detector CT using nominal protocols (80 kVp-108mAs for CBCT; 120 kVp- 300 mAs for MDCT). Soft tissue and bone visualization tasks were assessed by four radiologists using five-point satisfaction (for CBCT and MDCT individually) and five-point preference (side-by-side CBCT versus MDCT image quality comparison) rating tests. Ratings were analyzed using Kruskal-Wallis and Wilcoxon signed-rank tests, and observer agreement was assessed using the Kappa-statistic. RESULTS: Knee CBCT images were rated "excellent" or "good" (median scores 5 and 4) for "bone" and "soft tissue" visualization tasks. Hand CBCT images were rated "excellent" or "adequate" (median scores 5 and 3) for "bone" and "soft tissue" visualization tasks. Preference tests rated CBCT equivalent or superior to MDCT for bone visualization and favoured the MDCT for soft tissue visualization tasks. Intraobserver agreement for CBCT satisfaction tests was fair to almost perfect (κ ~ 0.26-0.92), and interobserver agreement was fair to moderate (κ ~ 0.27-0.54). CONCLUSION: CBCT provided excellent image quality for bone visualization and adequate image quality for soft tissue visualization tasks. KEY POINTS: • CBCT provided adequate image quality for diagnostic tasks in extremity imaging. • CBCT images were "excellent" for "bone" and "good/adequate" for "soft tissue" visualization tasks. • CBCT image quality was equivalent/superior to MDCT for bone visualization tasks.

High-Performance Soft-Tissue Imaging in Extremity Cone-Beam CT.

PURPOSE: Clinical performance studies of an extremity cone-beam CT (CBCT) system indicate excellent bone visualization, but point to the need for improvement of soft-tissue image quality. To this end, a rapid Monte Carlo (MC) scatter correction is proposed, and Penalized Likelihood (PL) reconstruction is evaluated for noise management. METHODS: The accelerated MC scatter correction involved fast MC simulation with low number of photons implemented on a GPU (107 photons/sec), followed by Gaussian kernel smoothing in the detector plane and across projection angles. PL reconstructions were investigated for reduction of imaging dose for projections acquired at ~2 mGy. RESULTS: The rapid scatter estimation yielded root-mean-squared-errors of scatter projections of ~15% of peak scatter intensity for 5·106 photons/projection (runtime ~0.5 sec/projection) and 25% improvement in fat-muscle contrast in reconstructions of a cadaveric knee. PL reconstruction largely restored soft-tissue visualization at 2 mGy dose to that of 10 mGy FBP image. CONCLUSION: The combination of rapid (5-10 minutes/scan) MC-based, patient-specific scatter correction and PL reconstruction offers an important means to overcome the current limitations of extremity CBCT in soft-tissue imaging.

Peripheral Quantitative CT (pQCT) Using a Dedicated Extremity Cone-Beam CT Scanner.

PURPOSE: We describe the initial assessment of the peripheral quantitative CT (pQCT) imaging capabilities of a cone-beam CT (CBCT) scanner dedicated to musculoskeletal extremity imaging. The aim is to accurately measure and quantify bone and joint morphology using information automatically acquired with each CBCT scan, thereby reducing the need for a separate pQCT exam. METHODS: A prototype CBCT scanner providing isotropic, sub-millimeter spatial resolution and soft-tissue contrast resolution comparable or superior to standard multi-detector CT (MDCT) has been developed for extremity imaging, including the capability for weight-bearing exams and multi-mode (radiography, fluoroscopy, and volumetric) imaging. Assessment of pQCT performance included measurement of bone mineral density (BMD), morphometric parameters of subchondral bone architecture, and joint space analysis. Measurements employed phantoms, cadavers, and patients from an ongoing pilot study imaged with the CBCT prototype (at various acquisition, calibration, and reconstruction techniques) in comparison to MDCT (using pQCT protocols for analysis of BMD) and micro-CT (for analysis of subchondral morphometry). RESULTS: The CBCT extremity scanner yielded BMD measurement within ±2-3% error in both phantom studies and cadaver extremity specimens. Subchondral bone architecture (bone volume fraction, trabecular thickness, degree of anisotropy, and structure model index) exhibited good correlation with gold standard micro-CT (error ~5%), surpassing the conventional limitations of spatial resolution in clinical MDCT scanners. Joint space analysis demonstrated the potential for sensitive 3D joint space mapping beyond that of qualitative radiographic scores in application to non-weight-bearing versus weight-bearing lower extremities and assessment of phalangeal joint space integrity in the upper extremities. CONCLUSION: The CBCT extremity scanner demonstrated promising initial results in accurate pQCT analysis from images acquired with each CBCT scan. Future studies will include improved x-ray scatter correction and image reconstruction techniques to further improve accuracy and to correlate pQCT metrics with known pathology.

WE-G-217BCD-04: Diagnostic Image Quality Evaluation of a Dedicated Extremity Cone- Beam CT Scanner: Pre-Clinical Studies and First Clinical Results.

PURPOSE: To assess the diagnostic performance of a prototype cone-beam CT (CBCT) scanner developed for musculoskeletal extremity imaging. Studies involved controlled observer studies conducted subsequent to rigorous technical assessment as well as patient images from the first clinical trial in imaging the hand and knee. METHODS: Performance assessment included: 1.) rigorous technical assessment; 2.) controlled observer studies using CBCT images of cadaveric specimens; and 3.) first clinical images. Technical assessment included measurement of spatial resolution (MTF), constrast, and noise (SDNR) versus kVp and dose using standard CT phantoms. Diagnostic performance in comparison to multi- detector CT (MDCT) was assessed in controlled observer studies involving 12 cadaveric hands and knees scanned with and without abnormality (fracture). Observer studies involved five radiologists rating pertinent diagnostics tasks in 9-point preference and 10-point diagnostic satisfaction scales. Finally, the first clinical images from an ongoing pilot study were assessed in terms of diagnostic utility in disease assessment and overall workflow in patient setup. RESULTS: Quantitative assessment demonstrated sub-mm spatial resolution (MTF exceeding 10% out to 15-20 cm-1) and SDNR sufficient for relevant soft-tissue visualization tasks at dose <10 mGy. Observer studies confirmed optimal acquisition techniques and demonstrated superior utility of combined soft-tissue visualization and isotropic spatial resolution in diagnostic tasks. Images from the patient trial demonstrate exquisite contrast and detail and the ability to detect tissue impingement in weight-bearing exams. CONCLUSIONS: The prototype CBCT scanner provides isotropic spatial resolution superior to standard-protocol MDCT with soft-tissue visibility sufficient for a broad range of diagnostic tasks in musculoskeletal radiology. Dosimetry and workflow were advantageous in comparison to whole-body MDCT. Multi-mode and weight-bearing capabilities add valuable functionality. An ongoing clinical study further assesses diagnostic utility and defines the role of such technology in the diagnostic arsenal. - Research Grant, Carestream Health - Research Grant, National Institutes of Health 2R01-CA-112163.

A dedicated cone-beam CT system for musculoskeletal extremities imaging: design, optimization, and initial performance characterization.

PURPOSE: This paper reports on the design and initial imaging performance of a dedicated cone-beam CT (CBCT) system for musculoskeletal (MSK) extremities. The system complements conventional CT and MR and offers a variety of potential clinical and logistical advantages that are likely to be of benefit to diagnosis, treatment planning, and assessment of therapy response in MSK radiology, orthopaedic surgery, and rheumatology. METHODS: The scanner design incorporated a host of clinical requirements (e.g., ability to scan the weight-bearing knee in a natural stance) and was guided by theoretical and experimental analysis of image quality and dose. Such criteria identified the following basic scanner components and system configuration: a flat-panel detector (FPD, Varian 3030+, 0.194 mm pixels); and a low-power, fixed anode x-ray source with 0.5 mm focal spot (SourceRay XRS-125-7K-P, 0.875 kW) mounted on a retractable C-arm allowing for two scanning orientations with the capability for side entry, viz. a standing configuration for imaging of weight-bearing lower extremities and a sitting configuration for imaging of tensioned upper extremity and unloaded lower extremity. Theoretical modeling employed cascaded systems analysis of modulation transfer function (MTF) and detective quantum efficiency (DQE) computed as a function of system geometry, kVp and filtration, dose, source power, etc. Physical experimentation utilized an imaging bench simulating the scanner geometry for verification of theoretical results and investigation of other factors, such as antiscatter grid selection and 3D image quality in phantom and cadaver, including qualitative comparison to conventional CT. RESULTS: Theoretical modeling and benchtop experimentation confirmed the basic suitability of the FPD and x-ray source mentioned above. Clinical requirements combined with analysis of MTF and DQE yielded the following system geometry: a -55 cm source-to-detector distance; 1.3 magnification; a 20 cm diameter bore (20 x 20 x 20 cm3 field of view); total acquisition arc of -240 degrees. The system MTF declines to 50% at -1.3 mm(-1) and to 10% at -2.7 mm(-1), consistent with sub-millimeter spatial resolution. Analysis of DQE suggested a nominal technique of 90 kVp (+0.3 mm Cu added filtration) to provide high imaging performance from -500 projections at less than -0.5 kW power, implying -6.4 mGy (0.064 mSv) for low-dose protocols and -15 mGy (0.15 mSv) for high-quality protocols. The experimental studies show improved image uniformity and contrast-to-noise ratio (without increase in dose) through incorporation of a custom 10:1 GR antiscatter grid. Cadaver images demonstrate exquisite bone detail, visualization of articular morphology, and soft-tissue visibility comparable to diagnostic CT (10-20 HU contrast resolution). CONCLUSIONS: The results indicate that the proposed system will deliver volumetric images of the extremities with soft-tissue contrast resolution comparable to diagnostic CT and improved spatial resolution at potentially reduced dose. Cascaded systems analysis provided a useful basis for system design and optimization without costly repeated experimentation. A combined process of design specification, image quality analysis, clinical feedback, and revision yielded a prototype that is now awaiting clinical pilot studies. Potential advantages of the proposed system include reduced space and cost, imaging of load-bearing extremities, and combined volumetric imaging with real-time fluoroscopy and digital radiography.

Validation of a method for measuring the volumetric breast density from digital mammograms.

The purpose of this study was to evaluate the performance of an algorithm used to measure the volumetric breast density (VBD) from digital mammograms. The algorithm is based on the calibration of the detector signal versus the thickness and composition of breast-equivalent phantoms. The baseline error in the density from the algorithm was found to be 1.25 +/- 2.3% VBD units (PVBD) when tested against a set of calibration phantoms, of thicknesses 3-8 cm, with compositions equivalent to fibroglandular content (breast density) between 0% and 100% and under x-ray beams between 26 kVp and 32 kVp with a Rh/Rh anode/filter. The algorithm was also tested against images from a dedicated breast computed tomography (CT) scanner acquired on 26 volunteers. The CT images were segmented into regions representing adipose, fibroglandular and skin tissues, and then deformed using a finite-element algorithm to simulate the effects of compression in mammography. The mean volume, VBD and thickness of the compressed breast for these deformed images were respectively 558 cm(3), 23.6% and 62 mm. The displaced CT images were then used to generate simulated digital mammograms, considering the effects of the polychromatic x-ray spectrum, the primary and scattered energy transmitted through the breast, the anti-scatter grid and the detector efficiency. The simulated mammograms were analyzed with the VBD algorithm and compared with the deformed CT volumes. With the Rh/Rh anode filter, the root mean square difference between the VBD from CT and from the algorithm was 2.6 PVBD, and a linear regression between the two gave a slope of 0.992 with an intercept of -1.4 PVBD and a correlation with R(2) = 0.963. The results with the Mo/Mo and Mo/Rh anode/filter were similar.

The myth of the 50-50 breast.

PURPOSE: For dosimetry and for work in optimization of x-ray imaging of the breast, it is commonly assumed that the breast is composed of 50% fibroglandular tissue and 50% fat. The purpose of this study was to assess whether this assumption was realistic. METHODS: First, data obtained from an experimental breast CT scanner were used to validate an algorithm that measures breast density from digitized film mammograms. Density results obtained from a total of 2831 women, including 191 women receiving CT and from mammograms of 2640 women from three other groups, were then used to estimate breast compositions. RESULTS: Mean compositions, expressed as percent fibroglandular tissue (including the skin), varied from 13.7% to 25.6% among the groups with an overall mean of 19.3%. The mean compressed breast thickness for the mammograms was 5.9 cm (sigma = 1.6 cm). 80% of the women in our study had volumetric breast density less than 27% and 95% were below 45%. CONCLUSIONS: Based on the results obtained from the four groups of women in our study, the "50-50" breast is not a representative model of the breast composition.

Open problems in artificial life.

This article lists fourteen open problems in artificial life, each of which is a grand challenge requiring a major advance on a fundamental issue for its solution. Each problem is briefly explained, and, where deemed helpful, some promising paths to its solution are indicated.

Modeling experimental time series with ordinary differential equations.

Recently some methods have been presented to extract ordinary differential equations (ODE) directly from an experimental time series. Here, we introduce a new method to find an ODE which models both the short time and the long time dynamics. The experimental data are represented in a state space and the corresponding flow vectors are approximated by polynomials of the state vector components. We apply these methods both to simulated data and experimental data from human limb movements, which like many other biological systems can exhibit limit cycle dynamics. In systems with only one oscillator there is excellent agreement between the limit cycling displayed by the experimental system and the reconstructed model, even if the data are very noisy. Furthermore, we study systems of two coupled limit cycle oscillators. There, a reconstruction was only successful for data with a sufficiently long transient trajectory and relatively low noise level.

Modeling adaptive biological systems.

During the evolution of many systems found in nature, both the system composition and the interactions between components will vary. Equating the dimension with the number of different components, a system which adds or deletes components belongs to a class of dynamical systems with a finite dimensional phase space of variable dimension. We present two models of biochemical systems with a variable phase space, a model of autocatalytic reaction networks in the prebiotic soup and a model of the idiotypic network of the immune system. Each model contains characteristic meta-dynamical rules for constructing equations of motion from component properties. The simulation of each model occurs on two levels. On one level, the equations of motion are integrated to determine the state of each component. On a second level, algorithms which approximate physical processes in the real system are employed to change the equations of motion. Models with meta-dynamical rules possess several advantages for the study of evolving systems. First, there are no explicit fitness functions to determine how the components of the model rank in terms of survivability. The success of any component is a function of its relationship to the rest of the system. A second advantage is that since the phase space representation of the system is always finite but continually changing, we can explore a potentially infinite phase space which would otherwise be inaccessible with finite computer resources. Third, the enlarged capacity of systems with meta-dynamics for variation allows us to conduct true evolution experiments. The modeling methods presented here can be applied to many real biological systems. In the two studies we present, we are investigating two apparent properties of adaptive networks. With the simulation of the prebiotic soup, we are most interested in how a chemical reaction network might emerge from an initial state of relative disorder. With the study of the immune system, we study the self-regulation of the network including its ability to distinguish between species which are part of the network and those which are not.