Reproducibility of 3D pH-weighted chemical exchange saturation transfer contrast in the healthy cervical spinal cord.

Spinal cord ischemia and hypoxia can be caused by compression, injury, and vascular alterations. Measuring ischemia and hypoxia directly in the spinal cord noninvasively remains challenging. Ischemia and hypoxia alter tissue pH, providing a physiologic parameter that may be more directly related to tissue viability. Chemical exchange saturation transfer (CEST) is an MRI contrast mechanism that can be made sensitive to pH. More specifically, amine/amide concentration independent detection (AACID) is a recently developed endogenous CEST contrast that has demonstrated sensitivity to intracellular pH at 9.4 T. The goal of this study was to evaluate the reproducibility of AACID CEST measurements at different levels of the healthy cervical spinal cord at 3.0 T incorporating B1 correction. Using a 3.0 T MRI scanner, two 3D CEST scans (saturation pulse train followed by a 3D snapshot gradient-echo readout) were performed on 12 healthy subjects approximately 10 days apart, with the CEST volume centered at the C4 level for all subjects. Scan-rescan reproducibility was evaluated by examining between and within-subject coefficients of variation (CVs) and absolute AACID value differences. The C4 level of the spinal cord demonstrated the lowest within-subject CVs (4.1%-4.3%), between-subject CVs (5.6%-6.3%), and absolute AACID percent difference (5.8-6.1%). The B1 correction scheme significantly improved reproducibility (adjusted p-value = 0.002) compared with the noncorrected data, suggesting that implementing B1 corrections in the spinal cord is beneficial. It was concluded that pH-weighted AACID measurements, incorporating B1-inhomogeneity correction, were reproducible within subjects along the healthy cervical spinal cord and that optimal image quality was achieved at the center of the 3D CEST volume.

Characterizing mJOA-defined post-surgical recovery patterns in patients with degenerative cervical myelopathy.

Background: Degenerative cervical myelopathy is a spinal disorder resulting in progressive cord compression and neurological deficits that are assessed using the modified Japanese Orthopedic Association (mJOA) questionnaire. It is difficult to predict which patients will recover neurological function after surgery, making it challenging for clinicians to set postoperative patient expectations. In this study, we used mJOA subscores to identify patterns of recovery and recovery timelines in patients with moderate and severe myelopathy. Methods: Fifty-three myelopathy patients were enrolled and completed the mJOA questionnaire both pre-surgery, and six weeks and six months post-surgery. Pearson chi-square tests were performed to assess relationships of both recovery patterns and recovery timelines with severity of disease. Results: Moderate myelopathy patients were significantly more likely than severe myelopathy patients to experience full recovery of upper extremity, lower extremity, and sensory domains. Disease severity did not significantly impact the timeline during which recovery occurs. Overall, >90% of patients experienced at least partial recovery by six months post surgery, 80% of which demonstrated it within the first six weeks. Conclusions: This study shows the more severe the disease experienced by myelopathy patients, the more likely they will be left with permanent disabilities despite surgery. Early identification and treatment are therefore necessary to prevent worsening quality of life and increased costs of functional dependence. The recovery timelines for each subscore are similar and provide new values to guide patient expectations in their potential post-operative recovery. The overall recovery timeline is more generalizable though potentially lacking the specificity patients seek.

X-ray dose delivered during a longitudinal micro-CT study has no adverse effect on cardiac and pulmonary tissue in C57BL/6 mice.

BACKGROUND: Micro-computed tomography (micro-CT) offers numerous advantages for small animal imaging, including the ability to monitor the same animals throughout a longitudinal study. However, concerns are often raised regarding the effects of X-ray dose accumulated over the course of the experiment. PURPOSE: To scan C57BL/6 mice multiple times per week for 6 weeks, in order to determine the effect of the cumulative dose on pulmonary and cardiac tissue at the end of the study. MATERIAL AND METHODS: C57BL/6 male mice were split into two groups (irradiated group = 10, control group = 10). The irradiated group was scanned (80 kVp/50 mA) three times weekly for 6 weeks, resulting in a weekly dose of 0.84 Gy, and a total study dose of 5.04 Gy. The control group was scanned on the final week. Scans from week 6 were reconstructed and the lungs and heart were analyzed. RESULTS: Overall, there was no significant difference in lung volume or lung density or in left ventricular volume or ejection fraction between the control group and the irradiated group. Histological samples taken from excised lung and myocardial tissue also showed no evidence of inflammation or fibrosis in the irradiated group. CONCLUSION: This study demonstrated that a 5 Gy X-ray dose accumulated over 6 weeks during a longitudinal micro-CT study had no significant effects on the pulmonary and myocardial tissue of C57BL/6 mice. As a result, the many advantages of micro-CT imaging, including rapid acquisition of high-resolution, isotropic images in free-breathing mice, can be taken advantage of in longitudinal studies without concern for negative dose-related effects.

Least-error projection sorting to optimize retrospectively gated cardiac micro-CT of free-breathing mice.

PURPOSE: To develop and characterize a technique for optimizing image quality by eliminating streaking artifacts in retrospectively gated microcomputed tomography (micro-CT) images of mice caused by insufficient and irregular angular sampling. METHODS: A least-error sorting technique was developed to minimize streak artifacts in retrospectively gated cardiac micro-CT images. To ensure complete filling of projection space, for each angular position, the projection acquired closest to the desired cardiac phase is used to reconstruct a volumetric image. An acrylic slanted-edge phantom undergoing cyclic motion was used to characterize the system's resolution. The phantom was scanned using a volumetric micro-CT scanner equipped with a flat-panel detector mounted on a slip-ring gantry. Projection images of the moving phantom were collected over a period of 60 s using a variety of acquisition protocols with the rotation period of the gantry ranging from 1 to 5 s. The modulation transfer function (MTF) of the reconstructed images was measured for many combinations of acquisition and reconstruction parameters. The use of the least-error technique was also demonstrated in vivo. RESULTS: The motion blurring introduced into the images at physiologically significant velocities of 6 cm∕s agreed well with predicted values; limiting resolution (frequency at 10% MTF) degraded from 2.5 to 1.0 mm(-1) for a velocity of 6 cm∕s and 5 s∕rotation gantry speed. Faster gantry rotation speeds led to improved temporal resolution but the scanner's data storage and transfer rates and field of view limitations made scanning at gantry speeds faster than 2 s∕rotation impractical. CONCLUSIONS: The least-error technique effectively eliminates streaking artifact caused by missing views and allows for optimization of image quality in retrospectively gated micro-CT.

Spinal cord compression is associated with brain plasticity in degenerative cervical myelopathy.

The impact of spinal cord compression severity on brain plasticity and prognostic determinates is not yet fully understood. We investigated the association between the severity of spinal cord compression in patients with degenerative cervical myelopathy, a progressive disease of the spine, and functional plasticity in the motor cortex and subcortical areas using functional magnetic resonance imaging. A 3.0 T MRI scanner was used to acquire functional images of the brain in 23 degenerative cervical myelopathy patients. Patients were instructed to perform a structured finger-tapping task to activate the motor cortex to assess the extent of cortical activation. T2-weighted images of the brain and spine were also acquired to quantify the severity of spinal cord compression. The observed blood oxygen level-dependent signal increase in the contralateral primary motor cortex was associated with spinal cord compression severity when patients tapped with their left hand (r = 0.49, P = 0.02) and right hand (r = 0.56, P = 0.005). The volume of activation in the contralateral primary motor cortex also increased with spinal cord compression severity when patients tapped with their left hand (r = 0.55, P = 0.006) and right hand (r = 0.45, P = 0.03). The subcortical areas (cerebellum, putamen, caudate and thalamus) also demonstrated a significant relationship with compression severity. It was concluded that degenerative cervical myelopathy patients with severe spinal cord compression recruit larger regions of the motor cortex to perform finger-tapping tasks, which suggests that this adaptation is a compensatory response to neurological injury and tissue damage in the spinal cord.

Reducing unnecessary testing in the emergency department: The case for INR and aPTT.

OBJECTIVE: Routine coagulation testing is rarely indicated in the emergency department. Our goal is to determine the combined effects of uncoupling routine coagulation testing (i.e., international normalized ratio [INR]; activated partial thromboplastin time [aPTT]), disseminating an educational module, and implementing a clinical decision support system (CDSS) on coagulation testing rates in two academic emergency departments. METHODS: A prospective pre-post study of INR-aPTT uncoupling, educational module distribution, and CDSS implementation in two academic emergency departments. All patients ages 18 years and older undergoing evaluation and treatment during the period of August 1, 2015, to November 30, 2017, were included. Primary outcome was coagulation testing utilization during the emergency department encounter. Secondary outcomes included associated costs, frequency of downstream testing, and frequency of blood transfusions. RESULTS: Uncoupling INR-aPTT testing combined with educational module distribution and CDSS implementation resulted in significantly decreased coupled INR-aPTT testing, with significantly increased selective INR and aPTT testing. Overall, the aggregate rate of coagulation testing declined for both INR and aPTT testing (48 tests/100 patients/day to 26 tests/100 patients/day). There was a significant decrease in associated daily costs (median cost per day: $1048.32 v. $601.68), realizing estimated annual savings of $163,023 Canadian dollars (CAD). There was no signal of increased downstream testing or patient blood product requirements. CONCLUSION: Compared to baseline practice patterns, our multimodal initiative significantly decreased coagulation testing, with meaningful cost savings and without evidence of patient harm. Clinicians and administrators now have a growing toolkit to target the plethora of low-value tests and treatments in emergency medicine.

Does the Neurological Examination Correlate with Patient-Perceived Outcomes in Degenerative Cervical Myelopathy?

BACKGROUND: In patients with neurological disorders, a divergence can exist between patients' perceptions regarding the outcomes and the objective neurological findings. Degenerative cervical myelopathy (DCM), a prevalent condition characterized by progressive compression of the cervical spinal cord, can produce debilitating symptoms and profound neurological findings. The purpose of the present study was to determine whether the physician-derived neurological examination findings, as recorded by American Spine Injury Association (ASIA) summary score, correlated with the patient-derived outcome measures for DCM. METHODS: A total of 78 patients underwent surgical management of DCM with completion of preoperative and 6-month follow-up assessments. Surgical management consisted of either anterior or posterior cervical decompression. All patients underwent a neurological evaluation, including an ASIA assessment before surgery and 6 months after surgery, and completed the modified Japanese Orthopaedic Association (mJOA), neck disability index (NDI), and Short-Form 36-item (SF-36) scales pre- and postoperatively to measure both disease-specific and general perceived outcomes. RESULTS: The objective physician-derived neurological testing (ASIA) did not correlate with the patient-derived scales (mJOA, NDI, and SF-36) pre- or postoperatively. Patients reported significant improvements (P < 0.001) at 6 months postoperatively in extremity functioning (mJOA), neck pain (NDI), overall physical health (SF-36), and objective strength and sensory functioning (ASIA). All patient-perceived outcome measures correlated with each other pre- and postoperatively (P < 0.01). CONCLUSIONS: Objective scoring of postoperative neurological function did not correlate with patient-perceived outcomes before and after surgery for DCM. Traditional testing of motor and sensory function as part of the neurological assessment may not be sensitive enough to assess the scope of neurological changes experienced by patients with DCM.

Current State of Point-of-care Ultrasound Usage in Canadian Emergency Departments.

Background Point-of-care ultrasound (POCUS) has many applications in emergency medicine, which have been proven to improve patient outcomes. Training programs and well-established guidelines for its use are available, but Canadian adoption rates and attitudes toward this technology have not been recently assessed. Objectives This study aimed to provide a national assessment of the current use of POCUS in Canadian emergency departments (ED) including patterns of use, attitudes towards its role, descriptors of training experience, as well as barriers to increased utilization. Methods An electronic survey was sent to physician members of the Canadian Association of Emergency Physicians. The survey included questions related to demographics, attitudes towards POCUS, POCUS utilization, and barriers to POCUS use. Responses were statistically analyzed to identify significant associations. Results Responses demonstrated a strong association between POCUS training and amount of POCUS usage. Neither hospital type nor community type was associated with the degree of POCUS usage. POCUS was most widely adopted for Canadian Point of Care Ultrasound Society (CPOCUS) core applications and has increased since the last national survey. The most commonly reported barrier to increased POCUS adoption was the lack of training. Most physicians have formal POCUS training in core applications, and approximately one third have advanced training. Conclusions POCUS training and utilization appear to have increased since the last national assessment. This provides a foundation for future POCUS research.

Fast retrospectively gated quantitative four-dimensional (4D) cardiac micro computed tomography imaging of free-breathing mice.

OBJECTIVE: We sought to demonstrate retrospectively gated dynamic 3D cardiac micro computed tomography (CT) of free-breathing mice. MATERIALS AND METHODS: Five C57Bl6 mice were scanned using a cone-beam scanner with a slip-ring-mounted flat-panel detector. After the injection of an intravascular iodinated contrast agent, projection images were acquired over the course of 50 seconds, while the scanner rotated through 10 complete rotations. The mouse respiratory and electrocardiogram signals were recorder simultaneously with image acquisition. After acquisition, the projection images were retrospectively sorted into projections belonging to different cardiac time points, occurring only during expiration. RESULTS: Dynamic 3D cardiac images, with isotropic 150-microm voxel spacing, were reconstructed at 12-millisecond intervals throughout the cardiac cycle in all mice. The average ejection fraction and cardiac output were 58.2+/-4.6% and 11.4+/-1.3 mL/min, respectively. The measured entrance dose for the entire scan was 28 cGy. Repeat scans of the same animals showed that intrasubject variability was smaller than intersubject variability. CONCLUSIONS: We have developed a high-resolution micro computed tomography method for evaluating the cardiac function and morphology of free-breathing mice in acquisition times shorter than 1 minute.

Single-strand conformational polymorphism and denaturing gradient gel electrophoresis in screening for variegate porphyria: identification of two new mutations.

Single-strand conformational polymorphism and denaturing gel electrophoresis were used to screen for mutations in the protoporphyrinogen oxidase gene (PPOX) of three patients with clinically and biochemically proven variegate porphyria in order to select genomic regions for specific DNA sequence analysis. Two previously undescribed mutations were identified: PPOX1423-1426-delATCT and PPOX2272insG. Denaturing gel electrophoresis was able to discern the point mutation in exon 5 (PPOX2272insG) of the PPOX gene. Once an index individual has been identified, single-strand conformational polymorphism and denaturing gel electrophoresis techniques are useful to identify family members who may be unaffected carriers. Such identification can help potential cases to avoid medications and other triggers that could precipitate acute porphyric attacks.

Three-dimensional imaging of the mouse heart and vasculature using micro-CT and whole-body perfusion of iodine or phosphotungstic acid.

Recent studies have investigated histological staining compounds as micro-computed tomography (micro-CT) contrast agents, delivered by soaking tissue specimens in stain and relying on passive diffusion for agent uptake. This study describes a perfusion approach using iodine or phosphotungstic acid (PTA) stains, delivered to an intact mouse, to capitalize on the microvasculature as a delivery conduit for parenchymal staining and direct contact for staining artery walls. Twelve C57BL/6 mice, arterially perfused with either 25% Lugol's solution or 5% PTA solution were scanned intact and reconstructed with 26 µm isotropic voxels. The animals were fixed and the heart and surrounding vessels were excised, embedded and scanned; isolated heart images were reconstructed with 13 µm isotropic voxels. Myocardial enhancement and artery diameters were measured. Both stains successfully enhanced the myocardium and vessel walls. Interestingly, Lugol's solution provided a significantly higher enhancement of the myocardium than PTA [2502 ± 437 vs 656 ± 178 Hounsfield units (HU); p < 0.0001], delineating myofiber architecture and orientation. There was no significant difference in vessel wall enhancement (Lugol's, 1036 ± 635 HU; PTA, 738 ± 124 HU; p = 0.29), but coronary arteries were more effectively segmented from the PTA-stained hearts, enabling segmented imaging of fifth- order coronary artery branches. The combination of whole mouse perfusion delivery and use of heavy metal-containing stains affords high-resolution imaging of the mouse heart and vasculature by micro-CT. The differential imaging patterns of Lugol's- and PTA-stained tissues reveals new opportunities for micro-analyses of cardiac and vascular tissues.

Application of 3-d echocardiography and gated micro-computed tomography to assess cardiomyopathy in a mouse model of duchenne muscular dystrophy.

The purpose of this study was to measure changes in cardiac function as cardiomyopathy progresses in a mouse model of Duchenne muscular dystrophy using 3-D ECG-gated echocardiography. This study is the first to correlate cardiac volumes acquired using 3-D echocardiography with those acquired using retrospectively gated micro-computed tomography (CT). Both were further compared with standard M-mode echocardiography and histologic analyses. We found that although each modality measures a decrease in cardiac function as disease progresses in mdx/utrn(-/-) mice (n = 5) compared with healthy C57BL/6 mice (n = 8), 3-D echocardiography has higher agreement with gold-standard measurements acquired by gated micro-CT, with little standard deviation between measurements. M-Mode echocardiography measurements, in comparison, exhibit considerably greater variability and user bias. Given the radiation dose associated with micro-CT and the geometric assumptions made in M-mode echocardiography to calculate ventricular volume, we suggest that use of 3-D echocardiography has important advantages that may allow for the measurement of early disease changes that occur before overt cardiomyopathy.

Evaluation of eXIA 160 cardiac-related enhancement in C57BL/6 and BALB/c mice using micro-CT.

Evaluation of cardiovascular function in mice using micro-CT requires that a contrast agent be administered to differentiate the blood from the myocardium. eXIA 160, an aqueous colloidal poly-disperse contrast agent with a high iodine concentration (160 mg I ml(-1)), creates strong contrast between blood and tissue with a low injection volume. In this study, the blood-pool enhancement time-course of eXIA 160 is monitored over a 48 h period to determine its optimal use during cardiac function studies in C57BL/6 and BALB/c mice. Eight-second scans were performed (80 kV(p), 110 mA) using the GE Locus Ultra micro-CT scanner. Six C57BL/6 and six BALB/c male mice (22-24 g) were injected via tail vein with 5 µl g(-1) body weight eXIA 160. A precontrast scan was performed; following injection, mice were scanned at 5, 15, 30, 45 and 60 min, and 2, 4, 8, 12, 24 and 48 h. Images were reconstructed, and enhancement-time curves were generated for each of the following tissues: left ventricle (LV), myocardium, liver, spleen, renal cortex, bladder and brown adipose tissue. The highest contrast in the LV occurred at 5 min in both strains (~670 HU above precontrast value). Uptake of the contrast agent by the myocardium was also observed: myocardial tissue showed increasing enhancement over a 4 h period in both strains, remaining even once the contrast was eliminated from the vasculature. In both C57BL/6 and BALB/c strains, eXIA 160 provided high contrast between blood and myocardial tissue for a period of 30 min following injection. Notably, this contrast agent was also taken up by the myocardium and provided continued enhancement when it was eliminated from the blood, making LV wall motion studies possible. In conclusion, eXIA 160, with its high iodine concentration and targeted tissue uptake characteristics, is an ideal agent to use when evaluating cardiovascular function in mice.

Rapid microcomputed tomography suggests cardiac enlargement occurs during conductance catheter measurements in mice.

Conductance catheters (CC) represent an established method of determining cardiac function in mice; however, the potentially detrimental effects a catheter may have on the mouse heart have never been evaluated. The present study takes advantage of rapid three-dimensional (3D) microcomputed tomography (CT) to compare simultaneously acquired micro-CT and CC measurements of left ventricular (LV) volumes in healthy and infarcted mice and to determine changes in LV volume and function associated with CC insertion. LV volumes were measured in C57BL/6 mice (10 healthy, 10 infarcted, 2% isoflurane anesthesia) using a 1.4-Fr Millar CC. 3D micro-CT images of each mouse were acquired before CC insertion as well as during catheterization. Each CT scan produced high-resolution images throughout the entire cardiac cycle in <1 min, enabling accurate volume measurements as well as direct visualization of the CC within the LV. Bland-Altman analysis demonstrated that CC measurements underestimate volume compared with CT measurements in both healthy [bias of -18.4 and -28.9 µl for end-systolic (ESV) and end-diastolic volume (EDV), respectively] and infarcted mice (ESV = -51.6 µl and EDV = -71.7 µl); underestimation was attributed to the off-center placement of the catheter. Individual evaluation of each heart revealed LV dilation following CC insertion in 40% of mice in each group. No change in ejection fraction was observed, suggesting the enlargement was caused by volume overload associated with disruption of the papillary muscles or chords. The enlargement witnessed was not significant; however, the results suggest the potential for CC insertion to detrimentally affect mouse myocardium, necessitating further investigation.

Longitudinal follow-up of cardiac structure and functional changes in an infarct mouse model using retrospectively gated micro-computed tomography.

OBJECTIVES: Mouse models of myocardial infarction are valuable in studying the effect of genetic modifications on structural and functional remodeling of the heart. Our group recently developed a method for acquiring three-dimensional images of the beating mouse heart using micro-computed tomography (micro-CT) and retrospective gating. In this study, we evaluated cardiac function in sham and infarcted mice longitudinally, using this novel technique. MATERIALS AND METHODS: Thirteen mice (7 sham-operated, 6 infarcted; male, C57BL/6) were imaged at baseline and at weeks 1, 2, 3, and 4 postligation of the left anterior descending coronary artery. Animals were anesthetized with 1.5% isoflurane; mechanical ventilation was not used. Contrast between blood and tissue was provided by an iodinated blood-pool contrast agent (0.01 mL/g Fenestra VC). The cardiac and respiratory waveforms were recorded during the 50-second scan time, to enable retrospective gating. Once scanning was completed on week 4 postsurgery, hemodynamic measurements were performed using a Millar pressure conductance catheter. RESULTS: There were significant differences in systolic and diastolic volumes, and ejection fraction, between sham and myocardial infarction groups (P < 0.0001). A comparison of ejection fraction derived from both CT and hemodynamic measurements was not significantly different (P > 0.1). CONCLUSIONS: We have demonstrated the first use of dynamic micro-CT for monitoring cardiac remodeling, resulting from myocardial infarction, over time. The fast scan times (<1 minute) and ability to track individual animals over an entire study make this quantitative noninvasive technique a promising tool for in vivo studies of cardiac disease in mouse models.

Contrast-enhanced microcomputed tomography using intraperitoneal contrast injection for the assessment of tumor-burden in liver metastasis models.

OBJECTIVES: To determine if intraperitoneally (IP) administered contrast (iohexol), used in conjunction with a liver-specific agent (Fenestra), can improve measurement precision and accuracy when quantifying tumor volume from micro-CT images of a liver metastasis model. MATERIALS AND METHODS: We compared images acquired with Fenestra alone to images acquired with the combination of Fenestra and IP iohexol. The variability in tumor volume and tumor-burden measurement was evaluated for both techniques. The tumor-burden measurement accuracy of both in vivo techniques was determined by comparison with tumor-burden quantified from ex vivo images. RESULTS: : The addition of IP iohexol decreased measurement variability for individual tumors and overall tumor-burden by 4-8 fold and 2-3 fold, respectively. IP iohexol significantly improved the accuracy of tumor-burden measurement for both low and high tumor-burdened animals. CONCLUSIONS: The combination of IP iohexol with Fenestra provides superior delineation of liver tumors, in comparison to Fenestra alone. The complete tumor delineation provided by this imaging strategy allows for noninvasive quantification of liver tumor-burden.