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These studies test, using intravital microscopy (IVM), the hypotheses that perfusion effects on insulin-stimulated muscle glucose uptake (MGU) are ) capillary recruitment independent and ) mediated through the dispersion of glucose rather than insulin. For , capillary perfusion was visualized before and after intravenous insulin. No capillary recruitment was observed. For , mice were treated with vasoactive compounds (sodium nitroprusside, hyaluronidase, and lipopolysaccharide), and dispersion of fluorophores approximating insulin size (10-kDa dextran) and glucose (2-NBDG) was measured using IVM. Subsequently, insulin and 2[C]deoxyglucose were injected and muscle phospho-2[C]deoxyglucose (2[C]DG) accumulation was used as an index of MGU. Flow velocity and 2-NBDG dispersion, but not perfused surface area or 10-kDa dextran dispersion, predicted phospho-2[C]DG accumulation. For , microspheres of the same size and number as are used for contrast-enhanced ultrasound (CEU) studies of capillary recruitment were visualized using IVM. Due to their low concentration, microspheres were present in only a small fraction of blood-perfused capillaries. Microsphere-perfused blood volume correlated to flow velocity. These findings suggest that ) flow velocity rather than capillary recruitment controls microvascular contributions to MGU, ) glucose dispersion is more predictive of MGU than dispersion of insulin-sized molecules, and ) CEU measures regional flow velocity rather than capillary recruitment.

PURPOSE - Brain shift during tumor resection can progressively invalidate the accuracy of neuronavigation systems and affect neurosurgeons' ability to achieve optimal resections. This paper compares two methods that have been presented in the literature to compensate for brain shift: a thin-plate spline deformation model and a finite element method (FEM). For this comparison, both methods are driven by identical sparse data. Specifically, both methods are driven by displacements between automatically detected and matched feature points from intraoperative 3D ultrasound (iUS). Both methods have been shown to be fast enough for intraoperative brain shift correction (Machado et al. in Int J Comput Assist Radiol Surg 13(10):1525-1538, 2018; Luo et al. in J Med Imaging (Bellingham) 4(3):035003, 2017). However, the spline method requires no preprocessing and ignores physical properties of the brain while the FEM method requires significant preprocessing and incorporates patient-specific physical and geometric constraints. The goal of this work was to explore the relative merits of these methods on recent clinical data.
METHODS - Data acquired during 19 sequential tumor resections in Brigham and Women's Hospital's Advanced Multi-modal Image-Guided Operating Suite between December 2017 and October 2018 were considered for this retrospective study. Of these, 15 cases and a total of 24 iUS to iUS image pairs met inclusion requirements. Automatic feature detection (Machado et al. in Int J Comput Assist Radiol Surg 13(10):1525-1538, 2018) was used to detect and match features in each pair of iUS images. Displacements between matched features were then used to drive both the spline model and the FEM method to compensate for brain shift between image acquisitions. The accuracies of the resultant deformation models were measured by comparing the displacements of manually identified landmarks before and after deformation.
RESULTS - The mean initial subcortical registration error between preoperative MRI and the first iUS image averaged 5.3 ± 0.75 mm. The mean subcortical brain shift, measured using displacements between manually identified landmarks in pairs of iUS images, was 2.5 ± 1.3 mm. Our results showed that FEM was able to reduce subcortical registration error by a small but statistically significant amount (from 2.46 to 2.02 mm). A large variability in the results of the spline method prevented us from demonstrating either a statistically significant reduction in subcortical registration error after applying the spline method or a statistically significant difference between the results of the two methods.
CONCLUSIONS - In this study, we observed less subcortical brain shift than has previously been reported in the literature (Frisken et al., in: Miller (ed) Biomechanics of the brain, Springer, Cham, 2019). This may be due to the fact that we separated out the initial misregistration between preoperative MRI and the first iUS image from our brain shift measurements or it may be due to modern neurosurgical practices designed to reduce brain shift, including reduced craniotomy sizes and better control of intracranial pressure with the use of mannitol and other medications. It appears that the FEM method and its use of geometric and biomechanical constraints provided more consistent brain shift correction and better correction farther from the driving feature displacements than the simple spline model. The spline-based method was simpler and tended to give better results for small deformations. However, large variability in the spline results and relatively small brain shift prevented this study from demonstrating a statistically significant difference between the results of the two methods.

PURPOSE - Transcranial focused ultrasound (FUS) is increasingly being explored to modulate neuronal activity. To target neuromodulation, researchers often localize the FUS beam onto the brain region(s) of interest using spatially tracked tools overlaid on pre-acquired images. Here, we quantify the accuracy of optically tracked image-guided FUS with magnetic resonance imaging (MRI) thermometry, evaluate sources of error and demonstrate feasibility of these procedures to target the macaque somatosensory region.
METHODS - We developed an optically tracked FUS system capable of projecting the transducer focus onto a pre-acquired MRI volume. To measure the target registration error (TRE), we aimed the transducer focus at a desired target in a phantom under image guidance, heated the target while imaging with MR thermometry and then calculated the TRE as the difference between the targeted and heated locations. Multiple targets were measured using either an unbiased or bias-corrected calibration. We then targeted the macaque S1 brain region, where displacement induced by the acoustic radiation force was measured using MR acoustic radiation force imaging (MR-ARFI).
RESULTS - All calibration methods enabled registration with TRE on the order of 3 mm. Unbiased calibration resulted in an average TRE of 3.26 mm (min-max: 2.80-4.53 mm), which was not significantly changed by prospective bias correction (TRE of 3.05 mm; 2.06-3.81 mm, p = 0.55). Restricting motion between the transducer and target and increasing the distance between tracked markers reduced the TRE to 2.43 mm (min-max: 0.79-3.88 mm). MR-ARFI images showed qualitatively similar shape and extent as projected beam profiles in a living non-human primate.
CONCLUSIONS - Our study describes methods for image guidance of FUS neuromodulation and quantifies errors associated with this method in a large animal. The workflow is efficient enough for in vivo use, and we demonstrate transcranial MR-ARFI in vivo in macaques for the first time.

BACKGROUND - Colorectal liver metastases that demonstrate a complete radiographic response during chemotherapy are increasingly common with advances in chemotherapy regimens and are described as disappearing liver metastases (DLMs). However, these DLMs often continue to harbor residual viable tumor. If these tumors are found in the operating room with ultrasound (US), they should be treated. The intraoperative sonographic visualization of these lesions, however, can be hindered by chemotherapy-associated liver parenchyma changes. The objective of this study was to evaluate the use of an intraoperative image guidance system, Explorer (Analogic Corporation, Peabody, MA), to aid surgeons in the identification of DLMs initially undetected by US alone.
STUDY DESIGN - In a single-arm prospective trial, patients with colorectal liver metastases undergoing liver resection and/or ablation with one or more DLMs during neoadjuvant chemotherapy were enrolled. Intraoperatively, DLMs were localized with conventional US. Any DLM not found by conventional US was re-evaluated with the image guidance system. The primary outcome was the proportion of sonographically occult DLMs subsequently located by image-guided US.
RESULTS - Between April 2016 and November 2017, 25 patients with 61 DLMs were enrolled. Thirty-eight DLMs (62%) in 14 patients (56%) were not identified with US alone. Six (16%) DLMs in five patients (36%) were subsequently located with assistance of the image guidance system. The image guidance changed the intraoperative surgical plan in four of these patients.
CONCLUSIONS - Image guidance can aid surgeons in the identification of initially sonographically occult DLMs and facilitate the complete surgical clearance of all sites of liver disease.

The time between arrest of pregnancy development and miscarriage represents a window in which the pregnancy is nonviable and not developing. In effect, the pregnancy loss has already occurred, and additional exposure cannot influence its outcome. However, epidemiologic studies of miscarriage traditionally use gestational age at miscarriage (GAM) to assign time in survival analyses, which overestimates duration of exposure and time at risk. In Right From the Start, a pregnancy cohort study (2000-2012), we characterized the gap between estimated gestational age at arrest of development (GAAD) and miscarriage using transvaginal ultrasound in 500 women recruited from 3 states (North Carolina, Tennessee, and Texas). We compared effect estimates from models using GAAD with GAM to assign time at risk through a simulation study of several exposure patterns with varying effect sizes. The median gap between GAAD and miscarriage was 23 days (interquartile range, 15-32). Use of GAAD decreased the bias and variance of the estimated association for time-varying exposures, whereas half the time using GAM led to estimates that differed from the true effect by more than 20%. Using GAAD to assign time at risk should result in more accurate and consistent characterization of miscarriage risk associated with time-varying exposures.
© The Author(s) 2019. Published by Oxford University Press on behalf of the Johns Hopkins Bloomberg School of Public Health. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.

BACKGROUND - Functional and molecular changes often precede gross anatomical changes, so early assessment of a tumor's functional and molecular response to therapy can help reduce a patient's exposure to the side effects of ineffective chemotherapeutics or other treatment strategies.
OBJECTIVE - Our intent was to test the hypothesis that an ultrasound microvascular imaging approach might provide indications of response to therapy prior to assessment of tumor size.
METHODS - Mice bearing clear-cell renal cell carcinoma xenograft tumors were treated with antiangiogenic and Notch inhibition therapies. An ultrasound measurement of microvascular density was used to serially track the tumor response to therapy.
RESULTS - Data indicated that ultrasound-derived microvascular density can indicate response to therapy a week prior to changes in tumor volume and is strongly correlated with physiological characteristics of the tumors as measured by histology ([Formula: see text]). Furthermore, data demonstrated that ultrasound measurements of vascular density can determine response to therapy and classify between-treatment groups with high sensitivity and specificity.
CONCLUSION/SIGNIFICANCE - Results suggests that future applications utilizing ultrasound imaging to monitor tumor response to therapy may be able to provide earlier insight into tumor behavior from metrics of microvascular density rather than anatomical tumor size measurements.

Focused ultrasound (FUS) has gained recognition as a technique for non-invasive neuromodulation with high spatial precision and the ability to both excite and inhibit neural activity. Here we demonstrate that MRI-guided FUS is capable of exciting precise targets within areas 3a/3b in the monkey brain, causing downstream activations in off-target somatosensory and associated brain regions which are simultaneously detected by functional MRI. The similarity between natural tactile stimulation-and FUS- evoked fMRI activation patterns suggests that FUS likely can excite populations of neurons and produce associated spiking activities that may be subsequently transmitted to other functionally related touch regions. The across-region differences in fMRI signal changes relative to area 3a/3b between tactile and FUS conditions also indicate that FUS modulated the tactile network differently. The significantly faster rising (>1 sec) fMRI signals elicited by direct FUS stimulation at the targeted cortical region suggest that a different neural hemodynamic coupling mechanism may be involved in generating fMRI signals. This is the first demonstration of imaging neural excitation effects of FUS with BOLD fMRI on a specific functional circuit in non-human primates.

BACKGROUND - The American Thyroid Association (ATA) recommends fine-needle aspiration (FNA) biopsy of nodules measuring >1.5 cm with low-suspicion sonographic patterns or >1.0 cm with high/intermediate-suspicion features. Routine biopsy of nodules <1 cm is not recommended. However, despite these recommendations, subcentimeter nodules are often referred for FNA biopsy.
METHODS - This was a retrospective chart review of consecutive thyroid FNAs during an 18-month period (1157 patients, 1491 nodules, 2016-2017) to evaluate age, sex, medical history, diagnoses, and follow-up. Radiographic information was used to identify 61 subcentimeter nodules (4%) from 57 patients. Ultrasound studies were re-evaluated using criteria according to the American College of Radiology Thyroid Imaging, Reporting, and Data System (TI-RADS).
RESULTS - Reported reasons for biopsy included a larger companion nodule (44%), a personal or family history of cancer (26%), or a suspicious sonogram, including calcification and/or irregular contours (16%). FNA diagnoses included: 69% benign (42 of 61 nodules), 10% papillary thyroid carcinoma (PTC) (6 of 61 nodules), and 15% atypia of undetermined significance/follicular lesion of undetermined significance (AUS/FLUS) (9 of 61 nodules). Seven percent of nodules were unsatisfactory/nondiagnostic (4 of 61 nodules) compared with a 3% nondiagnostic rate for all sized nodules. Fifty-one nodules had an ultrasound available for re-review using the TI-RADS scoring system. A high TI-RADS score (4-5) was indicative of PTC in 29.4% of nodules. A low TI-RADS score (1-2) was indicative of PTC in 0% of nodules (P < .01). High and intermediate TI-RADS scores (3 and 4-5, respectively) were indicative of PTC/AUS/FLUS in 32% of nodules compared with 0% in those with low TI-RADS scores (P < .01).
CONCLUSIONS - The current results demonstrate successful use of the TI-RADS scoring system in evaluation of the risk of malignancy in subcentimeter nodules. Larger studies will be necessary to determine whether biopsy is warranted for TI-RADS high-subcentimeter nodules. Cancer Cytopathol 2018. © 2018 American Cancer Society.
© 2018 American Cancer Society.

In a prospective cohort study, we tested the hypothesis that children with sickle cell anemia (SCA) with normal transcranial Doppler ultrasound (TCD) velocities and without silent cerebral infarcts (SCIs) would have a lower incidence rate of new neurological events (strokes, seizures or transient ischemic attacks) compared to children with normal TCD measurements and SCIs, not receiving regular blood transfusions. Nonrandomized participants from the silent cerebral infarct transfusion (SIT) Trial who had screening magnetic resonance imaging (MRI) of the brain and normal TCD measurements were included. Follow-up ended at the time of first neurological event (stroke, seizure or transient ischemic attack), start of regular blood transfusion, or loss to follow-up, whichever came first. The primary endpoint was a new neurological event. Of 421 participants included, 68 had suspected SCIs. Mean follow-up was 3.6 years. Incidence rates of new neurological events in nontransfused participants with normal TCD values with SCIs and without SCIs were 1.71 and 0.47 neurological events per 100 patient-years, respectively, P = .065. The absence of SCI(s) at baseline was associated with a decreased risk of a new neurological event (hazard ratio 0.231, 95% CI 0.062-0.858; P = .029). Local pediatric neurologists examined 67 of 68 participants with suspected SCIs and identified 2 with overt strokes classified as SCIs by local hematologists; subsequently one had a seizure and the other an ischemic stroke. Children with SCA, without SCIs, and normal TCD measurements have a significantly lower rate of new neurological events when compared to those with SCIs and normal TCD measurements. Pediatric neurology assessment may assist risk stratification.
© 2018 Wiley Periodicals, Inc.

Ultrasound imaging for kidney stones suffers from poorer sensitivity, diminished specificity, and overestimation of stone size compared to computed tomography (CT). The purpose of this study was to demonstrate in vitro feasibility of novel ultrasound imaging methods comparing traditional B-mode to advanced beamforming techniques including plane wave synthetic focusing (PWSF), short-lag spatial coherence (SLSC) imaging, mid-lag spatial coherence (MLSC) imaging with incoherent compounding, and aperture domain model image reconstruction (ADMIRE). The ultrasound techniques were evaluated using a research-based ultrasound system applied to an in vitro kidney stone model at 4 and 8 cm depths. Stone diameter sizing and stone contrast were compared among the different techniques. Analysis of variance was used to analyze the differences among group means, with p < 0.05 considered significant, and a Student's t test was used to compare each method with B-mode, with p < 0.0025 considered significant. All stones were detectable with each method. MLSC performed best with stone sizing and stone contrast compared to B-mode. On average, B-mode sizing error ± SD was > 1 mm (1.2 ± 1.1 mm), while those for PWSF, ADMIRE, and MLSC were < 1 mm (- 0.3 ± 2.9 mm, 0.6 ± 0.8, 0.8 ± 0.8, respectively). Subjectively, MLSC appeared to suppress the entire background thus highlighting only the stone. The ADMIRE and SLSC techniques appeared to highlight the stone shadow relative to the background. The detection and sizing of stones in vitro are feasible with advanced beamforming methods with ultrasound. Future work will include imaging stones at greater depths and evaluating the performance of these methods in human stone formers.