Purpose: Improving soft-tissue contrast resolution beyond the capability of current cone-beam CT (CBCT) systems is essential to a growing range of image guidance and diagnostic imaging scenarios. We present a framework for CBCT model-based image reconstruction (MBIR) combining artifact corrections with multi-resolution reconstruction and multi-region motion compensation and apply the method for the first time in a clinical study of CBCT for high-quality imaging of head injury. Methods: A CBCT prototype was developed for mobile point-of-care imaging in the neuro-critical care unit (NCCU). Projection data were processed via poly-energetic gain correction and an artifacts correction pipeline treating scatter, beam hardening, and motion compensation. The scatter correction was modified to use a penalized weighted least-squares (PWLS) image in the Monte-Carlo (MC) object model for better uniformity in truncated data. The PWLS method included: (1) multi-resolution reconstruction to mitigate lateral truncation from the head-holder; (2) multi-motion compensation allowing separate motion of the head and head-holder; and (3) modified statistical weights to account for electronics noise and fluence modulation by the bowtie filter. Imaging performance was evaluated in simulation and in the first clinical study (N = 54 patients) conducted with the system. Results: Using a PWLS object model in the final iteration of the MC scatter estimate improved image uniformity by 40.4% for truncated datasets. The multi-resolution, multi-motion PWLS method greatly reduced streak artifacts and non-uniformity both in simulation (RMSE reduced by 65.5%) and in the clinical study (visual image quality assessed by a neuroradiologist). Up to 15% reduction in variance was achieved using statistical weights modified according to a model for electronic noise from the detector. Each component was important for improved contrast resolution in the patient data. Conclusion: An integrated pipeline for artifacts correction and PWLS reconstruction mitigated artifacts and noise to a level supporting visualization of low-contrast brain lesions and warranting future studies of diagnostic performance in the NCCU.

Purpose: Cone-beam CT (CBCT) systems with a flat-panel detector (FPD) have advanced in a variety of specialty diagnostic imaging scenarios, with fluence modulation and multiple-gain detectors playing important roles in extending dynamic range and improving image quality. We present a penalized weighted least-squares (PWLS) reconstruction approach with a noise model that includes the effects of fluence modulation and electronic readout noise, and we show preliminary results that tests the concept with a CBCT head scanner prototype. Methods: Statistical weights in PWLS were modified using a realistic noise model for the FPD that considers factors such as system blur and spatially varying electronic noise in multiple-gain readout detectors (PWLSe). A spatially varying gain term was then introduced in the calculation of statistical weights to account for the change in quantum noise due to fluence modulation (e.g. bowtie filter) (PWLS∗). The methods were tested in phantom experiments involving an elliptical phantom specially designed to stress dual-gain readout, and a water phantom and an anthropomorphic head phantom to quantify improvements in noise-resolution characteristics for the new PWLS methods (PWLS𝑒 and PWLS∗, and combined PWLS∗e). The proposed methods were further tested using a high-quality, low-dose CBCT head scanner prototype in a clinical study involving patients with head injury. Results: Preliminary results show that the PWLSe method demonstrated superior noise-resolution tradeoffs compared to conventional PWLS, with variance reduced by ~15-25% at matched resolution of 0.65 mm edge-spread-function (ESF) width. Clinical studies confirmed these findings, with variance reduced by ~15% in peripheral regions of the head without loss in spatial resolution, improving visual image quality in detection of peridural hemorrhage. A bowtie filter and polyenergetic gain correction improved image uniformity, and early results demonstrated that the proposed PWLS∗ method showed a ~40% reduction in variance compared to conventional PWLS when used with a bowtie filter. Conclusion: A more accurate noise model incorporated in PWLS statistical weights to account for fluence modulation and electronic readout noise reduces image noise and improves soft-tissue imaging performance in CBCT for clinical applications requiring a high degree of contrast resolution.

Timely evaluation of neurovasculature via CT angiography (CTA) is critical to the detection of pathology such as ischemic stroke. Cone-beam CTA (CBCT-A) systems provide potential advantages in the timely use at the point-of-care, although challenges of a relatively slow gantry rotation speed introduce tradeoffs among image quality, data consistency and data sparsity. This work describes and evaluates a new reconstruction-of-difference (RoD) approach that is robust to such challenges. A fast digital simulation framework was developed to test the performance of the RoD over standard reference reconstruction methods such as filtered back-projection (FBP) and penalized likelihood (PL) over a broad range of imaging conditions, grouped into three scenarios to test the trade-off between data consistency, data sparsity and peak contrast. Two experiments were also conducted using a CBCT prototype and an anthropomorphic neurovascular phantom to test the simulation findings in real data. Performance was evaluated primarily in terms of normalized root mean square error (NRMSE) in comparison to truth, with reconstruction parameters chosen to optimize performance in each case to ensure fair comparison. The RoD approach reduced NRMSE in reconstructed images by up to 50%-53% compared to FBP and up to 29%-31% compared to PL for each scenario. Scan protocols well suited to the RoD approach were identified that balance tradeoffs among data consistency, sparsity and peak contrast-for example, a CBCT-A scan with 128 projections acquired in 8.5 s over a 180°  +  fan angle half-scan for a time attenuation curve with ~8.5 s time-to-peak and 600 HU peak contrast. With imaging conditions such as the simulation scenarios of fixed data sparsity (i.e. varying levels of data consistency and peak contrast), the experiments confirmed the reduction of NRMSE by 34% and 17% compared to FBP and PL, respectively. The RoD approach demonstrated superior performance in 3D angiography compared to FBP and PL in all simulation and physical experiments, suggesting the possibility of CBCT-A on low-cost, mobile imaging platforms suitable to the point-of-care. The algorithm demonstrated accurate reconstruction with a high degree of robustness against data sparsity and inconsistency.

Cone-beam CT (CBCT) systems commonly incorporate a flat-panel detector (FPD) with multiple-gain readout capability to reduce electronic noise and extend dynamic range. In this work, we report a penalized weighted least-squares (PWLS) method for CBCT image reconstruction with a system model that includes the electronic noise characteristics of FPDs, including systems with dynamic-gain or dual-gain (DG) readout in which the electronic noise is spatially varying. Statistical weights in PWLS were modified to account for the contribution of the electronic noise (algorithm denoted ), and the method was combined with a certainty-based approach that improves the homogeneity of spatial resolution (algorithm denoted ). The methods were tested in phantom studies designed to stress DG readout characteristics and translated to a clinical study for CBCT of patients with head traumas. The method demonstrated superior noise-resolution tradeoffs compared to filtered back-projection (FBP) and conventional PWLS. For example, with spatial resolution (edge-spread function width) matched at 0.65 mm, reduced variance by 28%–39% and 15%–25% compared to FBP and PWLS, respectively. The method achieved more homogeneous spatial resolution than while maintaining similar variance reduction. These findings were confirmed in clinical studies, which showed ~20% variance reduction in peripheral regions of the brain, potentially improving visual image quality in detection of epidural and/or subdural intracranial hemorrhage. The results are consistent with the general notion that incorporating a more accurate system model improves performance in optimization-based statistical CBCT reconstruction—in this case, a more accurate model for (spatially varying) electronic noise to improve detectability of low-contrast lesions.

Purpose: Timely detection of neurovascular pathology such as ischemic stroke is essential to effective treatment, and systems for cone-beam CT (CBCT) could provide CT angiography (CTA) assessment in a timely manner close to the point of care. CBCT systems suffer from slow rotation speed and readout speed, which leads to inconsistent or sparse dataset. This work describes a new reconstruction method using a reconstruction of difference (RoD) approach that is robust against such factors. Methods: Important aspects of CBCT angiography were investigated, weighting tradeoffs among the magnitude of iodine enhancement (peak contrast), the degree of data consistency, and the degree of data sparsity. Simulation studies were performed across a range of CBCT half-scan acquisition speed ranging similar to 3-17 s. Experiments were conducted using a CBCT prototype and an anthropomorphic neurovascular phantom incorporating a vessel with contrast injection with a time-attenuation (TAC) injection giving low data consistency but high peak contrast. Images were reconstructed using filtered back-projection (FBP), penalized likelihood (PL), and the RoD algorithm. Data were evaluated in terms of root mean square error (RMSE) in image enhancement as well as overall image noise and artifact. Results: Feasibility was demonstrated for 3D angiographic assessment in CBCT images acquired across a range of data consistency and sparsity. Compared to FBP, the RoD method reduced the RMSE in reconstructed images by 50.0% in simulation studies (fixed peak contrast; variable data consistency and sparsity). The improvement in RMSE compared to PL reconstruction was 28.8%. The phantom experiments investigated conditions of low data consistency, RoD provided a 15.6% reduction in RMSE compared to FBP and a 16.3% reduction compared to PL, showing the feasibility of RoD method for slow-rotating CBCT-A system. Conclusions: Simulations and phantom experiments show the feasibility and improved performance of the RoD approach compared to FBP and PL reconstruction, enabling 3D neuro-angiography on a slowly rotating CBCT system (e.g., 17.1s for a half-scan). The algorithm is relatively robust against data sparsity and is sensitive in detecting low levels of contrast enhancement from the baseline (mask) scan. Tradeoffs among peak contrast, data consistency, and data sparsity are demonstrated clearly in each experiment and help to guide the development of optimal contrast injection protocols for future preclinical and clinical studies.

Purpose: A number of cone-beam CT (CBCT) applications demand increasingly compact system designs for smaller footprint and improved portability. Such compact geometries can be achieved via reduction of air gap and integration of novel, curved detectors; however, the increased x-ray scatter in presents a major challenge to soft-tissue image quality in such compact arrangements. This work investigates pre-patient modulation (bowtie filters) and antiscatter grids to mitigate such effects for compact geometries with curved detectors. Methods: The effects of bowtie filters on dose and x-ray scatter were investigated in a compact geometry (180 mm air gap), for three detector curvatures: Flat, Focused at source, and Compact focused at isocenter. Experiments used bowtie filters of varying curvature combined with antiscatter grids (GR: 8:1, 80 1pmm). Scatter was estimated via GPU-accelerated Monte Carlo simulation in an anthropomorphic head phantom. Primary fluence was estimated with a polychromatic Siddon projector. Realistic Poisson noise (total dose: 20 mGy) was added to the total signal. Scatter magnitude and distribution were evaluated in projection data, and CT image quality was assessed in PWLS reconstructions. Results were validated in physical experiments on an x-ray test-bench for CBCT. Results: Moderate bowties combined with grids reduced average scatter magnitude and SPR, reduced cupping from 90 to 5 HU, and yielded net benefit to CNR despite attenuation of primary fluence. Dose to sensitive organs (eye lens) was reduced by 27%. More aggressive bowties showed further potential for dose reduction (35%) but increased peripheral SPR and increased non-uniformity and artifacts at the periphery of the image. Curved detector geometry exhibited slightly improved uniformity but a slight reduction in CNR compared to conventional flat detector geometry. Conclusion: Highly portable, soft-tissue imaging, CBCT systems with very compact geometry and curved detectors appear feasible, despite elevated x-ray scatter, through combination of moderate pre-patient collimation and antiscatter grids.

Few studies have investigated the effects of exercise on modulation of host factors in cancer patients. We investigated the efficacy of chronic aerobic training on multiple host-related effector pathways in patients with solid tumours. Paired peripheral blood samples were obtained from 44 patients with solid tumours receiving cytotoxic therapy and synthetic erythropoietin (usual care; n=21) or usual care plus supervised aerobic training (n=23) for 12 weeks. Samples were characterised for changes in immune, cytokine and angiogenic factors, and metabolic intermediates. Aerobic training consisted of three supervised cycle ergometry sessions per week at 60% to 100% of peak oxygen consumption (VO2peak), 30–45 min per session, for 12 weeks following a nonlinear prescription. The between-group delta change in cardiopulmonary function was +4.1 ml kg −1 min−1, favouring aerobic training (P<0.05). Significant pre–post between-group differences for five cytokine and angiogenic factors (HGF, IL-4, macrophage inflammatory protein-1β (MIP-1β), vascular endothelial growth factor (VEGF), and TNF-α) also favour the aerobic training group (P’s<0.05). These reductions occurred in conjunction with nonsignificant group differences for T lymphocytes CD4+, CD8+, and CD8+/CD45RA (P<0.10). For these factors, circulating concentrations generally increased from baseline to week 12 in the aerobic training group compared with decreases or no change in the usual care group. No significant changes in any metabolic intermediates were observed. Aerobic training alters host availability of select immune–inflammatory effectors in patients with solid tumours; larger confirmatory studies in more homogenous samples are warranted.

Background— An unbiased systems approach was used to define energy metabolic events that occur during the pathological cardiac remodeling en route to heart failure (HF). Methods and Results— Combined myocardial transcriptomic and metabolomic profiling were conducted in a well-defined mouse model of HF that allows comparative assessment of compensated and decompensated (HF) forms of cardiac hypertrophy because of pressure overload. The pressure overload data sets were also compared with the myocardial transcriptome and metabolome for an adaptive (physiological) form of cardiac hypertrophy because of endurance exercise training. Comparative analysis of the data sets led to the following conclusions: (1) expression of most genes involved in mitochondrial energy transduction were not significantly changed in the hypertrophied or failing heart, with the notable exception of a progressive downregulation of transcripts encoding proteins and enzymes involved in myocyte fatty acid transport and oxidation during the development of HF; (2) tissue metabolite profiles were more broadly regulated than corresponding metabolic gene regulatory changes, suggesting significant regulation at the post-transcriptional level; (3) metabolomic signatures distinguished pathological and physiological forms of cardiac hypertrophy and served as robust markers for the onset of HF; and (4) the pattern of metabolite derangements in the failing heart suggests bottlenecks of carbon substrate flux into the Krebs cycle. Conclusions— Mitochondrial energy metabolic derangements that occur during the early development of pressure overload–induced HF involve both transcriptional and post-transcriptional events. A subset of the myocardial metabolomic profile robustly distinguished pathological and physiological cardiac remodeling.

OBJECTIVE:Obesity and insulin resistance (IR) predispose to type 2 diabetes mellitus. Yet only half of obese adolescents have IR and far fewer progress to type 2 diabetes mellitus. We hypothesized that amino acid and fatty acid metabolites may serve as biomarkers or determinants of IR in obese teens.RESEARCH DESIGN AND METHODS:Fasting blood samples were analyzed by tandem mass spectrometry in 82 obese adolescents. A principal components analysis and multiple linear regression models were used to correlate metabolic components with surrogate measures of IR: homeostasis model assessment index of insulin resistance (HOMA-IR), adiponectin, and triglyceride (TG) to high-density lipoprotein (HDL) ratio.RESULTS:Branched-chain amino acid (BCAA) levels and products of BCAA catabolism were higher (P < .01) in males than females with comparable body mass index (BMI) z-score. In multivariate analyses, HOMA-IR in males correlated positively with BMI z-score and a metabolic signature containing BCAA, uric acid, and long-chain acylcarnitines and negatively with byproducts of complete fatty acid oxidation (R(2) = 0.659, P < .0001). In contrast, only BMI z-score correlated with HOMA-IR in females. Adiponectin correlated inversely with BCAA and uric acid (R(2) = 0.268, P = .0212) in males but not females. TG to HDL ratio correlated with BMI z-score and the BCAA signature in females but not males.CONCLUSIONS:BCAA levels and byproducts of BCAA catabolism are higher in obese teenage boys than girls of comparable BMI z-score. A metabolic signature comprising BCAA and uric acid correlates positively with HOMA-IR in males and TG to HDL ratio in females and inversely with adiponectin in males but not females. Likewise, byproducts of fatty acid oxidation associate inversely with HOMA-IR in males but not females. Our findings underscore the roles of sex differences in metabolic function and outcomes in pediatric obesity.

Purpose Grip strength predicts disability and mortality, yet few biomarkers of hand strength have been identified. We surveyed a wide array of serum cytokines, metabolites and joint tissue markers to identify novel independent predictors of grip and pinch strength. Methods Subjects were originally recruited for a longitudinal study of radiographic knee osteoarthritis (OA) progression. At three year follow up, measurement of grip strength (Jamar Hydraulic Hand Dynamometer) and key pinch strength (Jamar Hydraulic Pinch Gauge) were performed twice on each hand, and the greatest value was used for analyses. To control for hand OA, bony enlargements of the four distal and five proximal interphalangeal joints, the five metacarpophalangeal joints, and the carpometacarpal joint were summed (range 0-15) for the stronger hand. Blood (2 hour postprandial) was collected, and serum stored at -80oC. Cytokines and inflammatory markers (adiponectin; brain-derived neurotrophic factor; d dimer; granulocyte colony stimulating factor; interleukins 1, 6, and 8; regulated upon activation normal T cell expressed and secreted; tumor necrosis factor alpha, TNFα; TNFα receptors 1 and 2; TNF related apoptosis-inducing ligand, TRAIL; soluble vascular cell adhesion molecule 1; and vascular endothelial growth factor) and joint tissue markers (C2C; CPII; cartilage oligomeric matrix protein; hyaluronic acid, HA; and matrix metalloproteinase 3) were measured by immunoassay. Acylcarnitines (ACs, n=45) and amino acids (AAs, n=15) were measured using a targeted mass-spectrometry platform. Additional metabolites (glucose; α-hydroxybutyrate; total ketones; lactate; non-esterified fatty acids; and uric acid) were measured with a Hitachi 911 analyzer. Computed variables included global arginine bio-availability ratio (GABR, arginine/(ornithine + citrulline) and C2C:CPII. All variables except age, HA, MCP-1, and TRAIL were log-transformed because of non-normal distributions. Principal components analysis, with varimax rotation, reduced separately the AAs and ACs each to a 1 factor solution. Multivariable correlations were performed between grip or pinch strength and serum markers, controlling for age, sex, and height. Candidate predictors of grip or pinch strength were analyzed by linear regression, controlling for age, sex, height and sum of bony enlargements followed by multivariable modeling of significant variables by stepwise selection (p<0.05). Results The subject population (n=138) was 73% female, mean (SD) age of 65.8 (11.5) years, BMI 31.4(6.9) kg/m2, grip strength of 27.4 (10.0) kg, and pinch strength of 5.9 (1.9) kg. Grip and pinch strength correlated with age, sex, and height (p<0.05), but not weight, BMI, or sum of bony enlargements. Multivariable modeling identified sex, age, height, C2C, and the AA Factor as significant, independent predictors of grip strength; the model predicted 55% of the variability of grip strength and was significant at p<0.0001. For pinch strength, multivariable modeling identified sex, age, height, the ratio C2C:CPII, GABR, and the AC Factor as significant, independent predictors; the model predicted 49% of the variability of pinch strength and was significant at p<0.0001. Conclusion This exploratory analysis identified several novel, independent predictors of both grip and pinch strength. As seen previously, age, sex, and height were the strongest predictors of hand strength. AA factor predicted grip strength, perhaps reflecting sarcopenia status. The association of C2C or the ratio of C2C and CPII, markers of collagen breakdown and synthesis, respectively, with grip and pinch strength suggests the involvement of joint tissue turnover with hand function. The significant associations of GABR and the AC factor implicate metabolic pathways in pinch strength. Acknowledgements: This study was supported by Claude D Pepper OAIC P30 AG028716 and P01 AR050245.

The authors used DTI to study posttraumatic white matter changes over a 5-year period. Thirteen patients with severe injuries acutely showed significant fractional anisotropy decreases in the corpus callosum and corona radiata when compared with controls. These abnormalities progressed at 2 years and then remained stable until 5 years. The DTI abnormalities correlated with sequelae such as amnesia, aphasia, and dyspraxia.BACKGROUND AND PURPOSE: Extensive white matter damage has been documented in patients with severe traumatic brain injury, yet how this damage evolves in the long term is not well understood. We used DTI to study white matter changes at 5 years after traumatic brain injury.MATERIALS AND METHODS: There were 8 healthy control participants and 13 patients with severe traumatic brain injury who were enrolled in a prospective observational study, which included clinical assessment and brain MR imaging in the acute setting (< 6 weeks) and 2 years and 5 years after injury. Only subjects with mild to moderate disability or no disability at 1 year were included in this analysis. DTI parameters were measured in 20 different brain regions and were normalized to values obtained in an age-matched control group.RESULTS: In the acute setting, fractional anisotropy was significantly lower in the genu and body of the corpus callosum and in the bilateral corona radiata in patients compared with control participants, whereas radial diffusivity was significantly (P < .05) higher in these tracts. At 2 years, fractional anisotropy in these tracts had further decreased and radial diffusivity had increased. No significant changes were detected between 2 and 5 years after injury. The baseline radial diffusivity and fractional anisotropy values in the anterior aspect of the brain stem, genu and body of the corpus callosum, and the right and left corona radiata were significantly (P < .05) associated with neurocognitive sequelae (including amnesia, aphasia, and dyspraxia) at year 5.CONCLUSIONS: DTI changes in major white matter tracts persist up to 5 years after severe traumatic brain injury and are most pronounced in the corpus callosum and corona radiata. Limited structural change is noted in the interval between 2 and 5 years.

Background. Biventricular pacing has been shown to improve morbidity and mortality in patients with impaired systolic left ventricular function and congestive heart failure who have evidence of dyssynchronous ventricular contraction. However, a significant percentage of patients implanted with a biventricular pacer will not have a beneficial response. Novel molecular technologies may help identify biomarkers to better predict who will benefit most from this therapy. Methods. Individuals undergoing biventricular pacemaker implantation were selected from the ElectroPhysiology GENetics (EPGEN) biorepository (N=120). Targeted, quantitative mass-spectrometry based metabolomic profiling of 63 metabolites was performed on baseline, frozen, fasting plasma samples collected at the time of the index procedure. Positive response to pacing was defined as a 5% improvement in left ventricular ejection fraction or a ≥1 class improvement in New York Heart Association functional class at six months after device implantation. Principal components analysis (PCA) was used to reduce the large number of individual metabolites into a smaller set of uncorrelated factors. Logistic regression was used to test the association between PCA-derived factors and response. Results. A positive response to biventricular pacing was observed in 55 individuals at 6 months (N=65 showing no positive response). PCA identified 13 metabolite factors clustering in biologically plausible pathways. Of these, factor 1 (composed of medium and long chain acylcarnitines, medium and long chain dicarboxylacylcarnitines, ketones and β-hydroxybutyrate) was associated with positive response to pacing (p=0.007). Analyses of the individual metabolites composing this factor showed similar results (p=0.03-0.003). Conclusions. We have identified a cluster of metabolites, many of which are derived from mitochondrial metabolism, that predict a positive response to biventricular pacing. These novel biomarkers may assist in better risk stratification and patient selection for this therapy.

Insulin resistance (IR) improves with weight loss, but this response is heterogeneous. We hypothesised that metabolomic profiling would identify biomarkers predicting changes in IR with weight loss.

Relative to diets enriched in palmitic acid (PA), diets rich in oleic acid (OA) are associated with reduced risk of type 2 diabetes. To gain insight into mechanisms underlying these observations, we applied comprehensive lipidomic profiling to specimens collected from healthy adults enrolled in a randomized, crossover trial comparing a high-PA diet to a low-PA/high-OA (HOA) diet. Effects on insulin sensitivity (SI) and disposition index (DI) were assessed by intravenous glucose tolerance testing. In women, but not men, SI and DI were higher during HOA. The effect of HOA on SI correlated positively with physical fitness upon enrollment. Principal components analysis of either fasted or fed-state metabolites identified one factor affected by diet and heavily weighted by the PA/OA ratio of serum and muscle lipids. In women, this factor correlated inversely with SI in the fasted and fed states. Medium-chain acylcarnitines emerged as strong negative correlates of SI, and the HOA diet was accompanied by lower serum and muscle ceramide concentrations and reductions in molecular biomarkers of inflammatory and oxidative stress. This study provides evidence that the dietary PA/OA ratio impacts diabetes risk in women.