Detection properties of indium-111 and IRDye800CW for intraoperative molecular imaging use across tissue phantom models.

Significance: Intraoperative molecular imaging (IMI) enables the detection and visualization of cancer tissue using targeted radioactive or fluorescent tracers. While IMI research has rapidly expanded, including the recent Food and Drug Administration approval of a targeted fluorophore, the limits of detection have not been well-defined. Aim: The ability of widely available handheld intraoperative tools (Neoprobe and SPY-PHI) to measure gamma decay and fluorescence intensity from IMI tracers was assessed while varying characteristics of both the signal source and the intervening tissue or gelatin phantoms. Approach: Gamma decay signal and fluorescence from tracer-bearing tumors (TBTs) and modifiable tumor-like inclusions (TLIs) were measured through increasing thicknesses of porcine tissue and gelatin in custom 3D-printed molds. TBTs buried beneath porcine tissue were used to simulate IMI-guided tumor resection. Results: Gamma decay from TBTs and TLIs was detected through significantly thicker tissue and gelatin than fluorescence, with at least 5% of the maximum signal observed through up to 5 and 0.5 cm, respectively, depending on the overlying tissue type or gelatin. Conclusions: We developed novel systems that can be fine-tuned to simulate variable tumor characteristics and tissue environments. These were used to evaluate the detection of fluorescent and gamma signals from IMI tracers and simulate IMI surgery.

Dual-labeled anti-GD2 targeted probe for intraoperative molecular imaging of neuroblastoma.

BACKGROUND: Surgical resection is integral for the treatment of neuroblastoma, the most common extracranial solid malignancy in children. Safely locating and resecting primary tumor and remote deposits of disease remains a significant challenge, resulting in high rates of complications and incomplete surgery, worsening outcomes. Intraoperative molecular imaging (IMI) uses targeted radioactive or fluorescent tracers to identify and visualize tumors intraoperatively. GD2 was selected as an IMI target, as it is highly overexpressed in neuroblastoma and minimally expressed in normal tissue. METHODS: GD2 expression in neuroblastoma cell lines was measured by flow cytometry. DTPA and IRDye® 800CW were conjugated to anti-GD2 antibody to generate DTPA-αGD2-IR800. Binding affinity (Kd) of the antibody and the non-radiolabeled tracer were then measured by ELISA assay. Human neuroblastoma SK-N-BE(2) cells were surgically injected into the left adrenal gland of 3.5-5-week-old nude mice and the orthotopic xenograft tumors grew for 5 weeks. 111In-αGD2-IR800 or isotype control tracer was administered via tail vein injection. After 4 and 6 days, mice were euthanized and gamma and fluorescence biodistributions were measured using a gamma counter and ImageJ analysis of acquired SPY-PHI fluorescence images of resected organs (including tumor, contralateral adrenal, kidneys, liver, muscle, blood, and others). Organ uptake was compared by one-way ANOVA (with a separate analysis for each tracer/day combination), and if significant, Sidak's multiple comparison test was used to compare the uptake of each organ to the tumor. Handheld tools were also used to detect and visualize tumor in situ, and to assess for residual disease following non-guided resection. RESULTS: 111In-αGD2-IR800 was successfully synthesized with 0.75-2.0 DTPA and 2-3 IRDye® 800CW per antibody and retained adequate antigen-binding (Kd = 2.39 nM for aGD2 vs. 21.31 nM for DTPA-aGD2-IR800). The anti-GD2 tracer demonstrated antigen-specific uptake in mice with human neuroblastoma xenografts (gamma biodistribution tumor-to-blood ratios of 3.87 and 3.88 on days 4 and 6 with anti-GD2 tracer), while isotype control tracer did not accumulate (0.414 and 0.514 on days 4 and 6). Probe accumulation in xenografts was detected and visualized using widely available operative tools (Neoprobe® and SPY-PHI camera) and facilitated detection ofputative residual disease in the resection cavity following unguided resection. CONCLUSIONS: We have developed a dual-labeled anti-GD2 antibody-based tracer that incorporates In-111 and IRDye® 800CW for radio- and fluorescence-guided surgery, respectively. The tracer adequately binds to GD2, specifically accumulates in GD2-expressing xenograft tumors, and enables tumor visualization with a hand-held NIR camera. These results encourage the development of 111In-αGD2-IR800 for future use in children with neuroblastoma, with the goal of improving patient safety, completeness of resection, and overall patient outcomes.

Tibial acceleration alone is not a valid surrogate measure of tibial load in response to stride length manipulation.

PURPOSE: This study aimed to evaluate the relationship between peak tibial acceleration and peak ankle joint contact forces in response to stride length manipulation during level-ground running. METHODS: Twenty-seven physically active participants ran 10 trials at preferred speed in each of 5 stride length conditions: preferred, ±5 %, and ±10 % of preferred stride length. Motion capture, force platform, and tibial acceleration data were directly measured, and ankle joint contact forces were estimated using an inverse-dynamics-based static optimization routine. RESULTS: In general, peak axial tibial accelerations (p < 0.001) as well as axial (p < 0.001) and resultant (p < 0.001) ankle joint contact forces increased with stride length. When averaged within the 10 strides of each stride condition, moderate positive correlations were observed between peak axial acceleration and joint contact force (r = 0.49) as well as peak resultant acceleration and joint contact force (r = 0.51). However, 37% of participants illustrated either no relationship or negative correlations. Only weak correlations across participants existed between peak axial acceleration and joint contact force (r = 0.12) as well as peak resultant acceleration and ankle joint contact force (r = 0.18) when examined on a step-by-step basis. CONCLUSION: These results suggest that tibial acceleration should not be used as a surrogate for ankle joint contact force on a step-by-step basis in response to stride length manipulations during level-ground running. A 10-step averaged tibial acceleration metric may be useful for some runners, but an initial laboratory assessment would be required to identify these individuals.

Effects of Foot-Strike Pattern on Neuromuscular Function During a Prolonged Graded Run.

PURPOSE: To study whether, during typical-level running, non-rear-foot strikers (non-RFS) or rear-foot strikers (RFS) presented a similar or different extent of neuromuscular fatigue after a prolonged graded run. METHODS: Sixteen experienced male trail runners (8 non-RFS and 8 RFS) performed a 2.5-hour treadmill graded running exercise. Before and after exercise, neuromuscular tests were performed to assess neuromuscular fatigue of the plantar flexors. Biomechanical gait parameters were acquired with an instrumented treadmill, and electromyographic activity of the lower-limb muscles was collected as an index of muscle activation. RESULTS: There were no significant time × foot strike interactions for neuromuscular (all P ≥ .742), muscle activation (all P ≥ .157), or biomechanical (all P ≥ .096) variables. CONCLUSIONS: A dominant level running foot-strike pattern did not directly affect the extent of neuromuscular fatigue during a prolonged graded run. This suggests that no ideal running foot-strike pattern exists to minimize neuromuscular fatigue during prolonged-duration races wherein cumulative uphill and downhill segments are high, such as in trail running.

Monthly treatment with romosozumab for 1 year increases bone mineral at the hip, but not the knee, in women with chronic spinal cord injury.

Bone loss below the level of neurological lesion is a well-known complication of spinal cord injury (SCI). To date, most research has focused on pharmaceutical intervention using antiresorptives to prevent bone loss during the acute phase of SCI; however, limited research has investigated treatments for established osteoporosis during chronic SCI. Romosozumab, a monoclonal antibody with both antiresorptive and anabolic effects, has demonstrated significant increases in BMD for women with established PMO. Therefore, the purpose of this study was to examine the efficacy of monthly treatment with romosozumab to improve DXA-derived areal BMD at the hip, and CT-derived BMC and strength at the hip and knee in women with chronic SCI and an inability to ambulate. Twelve female participants with chronic SCI were recruited to receive 1 yr of monthly subcutaneous injections of romosozumab (210 mg). DXA and CT scans were taken at baseline, and months 3, 6, and 12 to quantify bone mineral, and finite element (FE) analysis was used to predict bone strength. Longitudinal mixed effects models were employed to determine the impact of treatment on bone properties. After 12 mo of treatment, areal BMD at the lumbar spine and total hip were significantly increased with median changes of 10.2% (IQR: 8.3-15.2%, p<.001) and 4.2% (IQR: 3.4-7.7%, p = .009), respectively. Improvements at the hip were primarily due to increases in trabecular, not cortical, bone and effects were sufficient to significantly increase FE-predicted strength by 20.3% (IQR: 9.5-37.0%, p = .004). Treatment with romosozumab did not lead to any significant improvement in bone mineral at the distal femur or proximal tibia. These findings provide promising results for romosozumab treatment to improve bone mineral and reduce fracture risk at the hip, but not the knee, in women with chronic SCI.

A disease-associated gene desert directs macrophage inflammation through ETS2.

Increasing rates of autoimmune and inflammatory disease present a burgeoning threat to human health1. This is compounded by the limited efficacy of available treatments1 and high failure rates during drug development2, highlighting an urgent need to better understand disease mechanisms. Here we show how functional genomics could address this challenge. By investigating an intergenic haplotype on chr21q22-which has been independently linked to inflammatory bowel disease, ankylosing spondylitis, primary sclerosing cholangitis and Takayasu's arteritis3-6-we identify that the causal gene, ETS2, is a central regulator of human inflammatory macrophages and delineate the shared disease mechanism that amplifies ETS2 expression. Genes regulated by ETS2 were prominently expressed in diseased tissues and more enriched for inflammatory bowel disease GWAS hits than most previously described pathways. Overexpressing ETS2 in resting macrophages reproduced the inflammatory state observed in chr21q22-associated diseases, with upregulation of multiple drug targets, including TNF and IL-23. Using a database of cellular signatures7, we identified drugs that might modulate this pathway and validated the potent anti-inflammatory activity of one class of small molecules in vitro and ex vivo. Together, this illustrates the power of functional genomics, applied directly in primary human cells, to identify immune-mediated disease mechanisms and potential therapeutic opportunities.

Tibial strains are sensitive to speed perturbations, but not grade perturbations, during running.

A fatigue-failure process is hypothesized to govern the development of tibial stress fractures, where bone damage is highly dependent on the peak strain magnitude. To date, much of the work examining tibial strain during running has ignored uphill and downhill running despite the prevalence of this terrain. This study examined the sensitivity of tibial strain to changes in running grade and speed using a combined musculoskeletal-finite element modelling routine. Seventeen participants ran on a treadmill at ±10, ±5 and 0 deg; at each grade, participants ran at 3.33 m s-1 and at a grade-adjusted speed of 2.50 and 4.17 m s-1 for uphill and downhill grades, respectively. Force and motion data were recorded in each grade and speed combination. Muscle and joint contact forces were estimated using inverse-dynamics-based static optimization. These forces were applied to a participant-adjusted finite element model of the tibia. None of the strain variables (50th and 95th percentile strain and strained volume ≥4000 µÎµ) differed as a function of running grade; however, all strain variables were sensitive to running speed (F1≥9.59, P≤0.03). In particular, a 1 m s-1 increase in speed resulted in a 9% (∼260 µÎµ) and 155% (∼600 mm3) increase in peak strain and strained volume, respectively. Overall, these findings suggest that faster running speeds, but not changes in running grade, may be more deleterious to the tibia.

Adapting the Intensity Gradient for Use with Count-Based Accelerometry Data in Children and Adolescents.

The intensity gradient is a new cutpoint-free metric that was developed to quantify physical activity (PA) measured using accelerometers. This metric was developed for use with the ENMO (Euclidean norm minus one) metric, derived from raw acceleration data, and has not been validated for use with count-based accelerometer data. In this study, we determined whether the intensity gradient could be reproduced using count-based accelerometer data. Twenty participants (aged 7-22 years) wore a GT1M, an ActiGraph (count-based), and a GT9X, ActiGraph (raw accelerations) accelerometer during both in-lab and at-home protocols. We found strong agreement between GT1M and GT9X counts during the combined in-lab activities (mean bias = 2 counts) and between minutes per day with different intensities of activity (e.g., sedentary, light, moderate, and vigorous) classified using cutpoints (mean bias < 5 min/d at all intensities). We generated bin sizes that could be used to generate IGs from the count data (mean bias = -0.15; 95% LOA [-0.65, 0.34]) compared with the original IG. Therefore, the intensity gradient could be used to analyze count data. The count-based intensity gradient metric will be valuable for re-analyzing historical datasets collected using older accelerometer models, such as the GT1M.

Predicting Tibia-Fibula Geometry and Density From Anatomical Landmarks Via Statistical Appearance Model: Influence of Errors on Finite Element-Calculated Bone Strain.

State-of-the-art participant-specific finite element models require advanced medical imaging to quantify bone geometry and density distribution; access to and cost of imaging is prohibitive to the use of this approach. Statistical appearance models may enable estimation of participants' geometry and density in the absence of medical imaging. The purpose of this study was to: (1) quantify errors associated with predicting tibia-fibula geometry and density distribution from skin-mounted landmarks using a statistical appearance model and (2) quantify how those errors propagate to finite element-calculated bone strain. Participant-informed models of the tibia and fibula were generated for thirty participants from height and sex and from twelve skin-mounted landmarks using a statistical appearance model. Participant-specific running loads, calculated using gait data and a musculoskeletal model, were applied to participant-informed and CT-based models to predict bone strain using the finite element method. Participant-informed meshes illustrated median geometry and density distribution errors of 4.39-5.17 mm and 0.116-0.142 g/cm3, respectively, resulting in large errors in strain distribution (median RMSE = 476-492 µÎµ), peak strain (limits of agreement =±27-34%), and strained volume (limits of agreement =±104-202%). These findings indicate that neither skin-mounted landmark nor height and sex-based predictions could adequately approximate CT-derived participant-specific geometry, density distribution, or finite element-predicted bone strain and therefore should not be used for analyses comparing between groups or individuals.

Dirt Track Surface Preparation and Associated Differences in Speed, Stride Length, and Stride Frequency in Galloping Horses.

In racehorses, the risk of musculoskeletal injury is linked to a decrease in speed and stride length (SL) over consecutive races prior to injury. Surface characteristics influence stride parameters. We hypothesized that large changes in stride parameters are found during galloping in response to dirt racetrack preparation. Harrowing of the back stretch of a half-mile dirt racetrack was altered in three individual lanes with decreasing depth from the inside to the outside. Track underlay compaction and water content were changed between days. Twelve horses (six on day 2) were sequentially galloped at a target speed of 16 ms-1 across the three lanes. Speed, stride frequency (SF), and SL were quantified with a GPS/GNSS logger. Mixed linear models with speed as covariate analyzed SF and SL, with track hardness and moisture content as fixed factors (p < 0.05). At the average speed of 16.48 ms-1, hardness (both p < 0.001) and moisture content (both p < 0.001) had significant effects on SF and SL. The largest difference in SL of 0.186 m between hardness and moisture conditions exceeded the 0.10 m longitudinal decrease over consecutive race starts previously identified as injury predictor. This suggests that detailed measurements of track conditions might be useful for refining injury prediction models.

Adaptive P-Splines for challenging filtering problems in biomechanics.

Suppression of noise from recorded signals is a critically important data processing step for biomechanical analyses. While a wide variety of filtering or smoothing spline methods are available, the majority of these are not well suited for the analysis of signals with rapidly changing derivatives such as the processing of motion data for impact-like events. This is because commonly used low-pass filtering approaches or smoothing splines typically assume a single fixed cut-off frequency or regularization penalty which fails to describe rapid changes in the underlying function. To overcome these limitations we examine a class of adaptive penalized splines (APS) that extend commonly used penalized spline smoothers by inferring temporal adaptations in regularization penalty from observed data. Three variations of APS are examined in which temporal variation of spline penalization is described via either a series of independent random variables, an autoregressive process or a smooth cubic spline. Comparing the performance of APS on simulated datasets is promising with APS reducing RMSE by 48%-183% compared to a widely used Butterworth filtering approach. When inferring acceleration from noisy measurements describing the position of a pendulum impacting a barrier we observe between a 13% (independent variables) to 28% (spline) reduction in RMSE when compared to a 4th order Butterworth filter with optimally selected cut-off frequency. In addition to considerable improvement in RMSE, APS can provide estimates of uncertainty for fitted curves and generated quantities such as peak accelerations or durations of stationary periods. As a result, we suggest that researchers should consider the use of APS if features such as impact peaks, rates of loading, or periods of negligible acceleration are of interest.

ImmunoPET imaging of TIGIT in the glioma microenvironment.

Glioblastoma (GBM) is the most common primary malignant brain tumor. Currently, there are few effective treatment options for GBM beyond surgery and chemo-radiation, and even with these interventions, median patient survival remains poor. While immune checkpoint inhibitors (ICIs) have demonstrated therapeutic efficacy against non-central nervous system cancers, ICI trials for GBM have typically had poor outcomes. TIGIT is an immune checkpoint receptor that is expressed on activated T-cells and has a role in the suppression of T-cell and Natural Killer (NK) cell function. As TIGIT expression is reported as both prognostic and a biomarker for anti-TIGIT therapy, we constructed a molecular imaging agent, [89Zr]Zr-DFO-anti-TIGIT (89Zr-αTIGIT), to visualize TIGIT in preclinical GBM by immunoPET imaging. PET imaging and biodistribution analysis of 89Zr-αTIGIT demonstrated uptake in the tumor microenvironment of GBM-bearing mice. Blocking antibody and irrelevant antibody tracer studies demonstrated specificity of 89Zr-αTIGIT with significance at a late time point post-tracer injection. However, the magnitude of 89Zr-αTIGIT uptake in tumor, relative to the IgG tracer was minimal. These findings highlight the features and limitations of using 89Zr-αTIGIT to visualize TIGIT in the GBM microenvironment.

Influence of microarchitecture on stressed volume and mechanical fatigue behaviour of equine subchondral bone.

Fractures of the equine metacarpophalangeal (MCP) joint are among the most common and fatal injuries experienced by racehorses. These bone injuries are a direct result of repetitive, high intensity loading of the skeleton during racing and training and there is consensus that they represent a mechanical fatigue phenomenon. Existing work has found the fatigue life of bone to be strongly determined by bone microarchitecture and the resulting stressed volume (i.e., the volume of bone stressed above assumed yield). The purpose of this study was to quantify the influence of bone microarchitecture on the mechanical fatigue behaviour of equine subchondral bone from the MCP joint across a wide variety of sample types. Forty-eight subchondral bone samples were prepared from the third metacarpal (MC3) and proximal phalanx (P1) of 8 horses and subsequently imaged using high resolution micro-computed tomography (µCT) to quantify microarchitectural features of interest, including bone volume fraction, tissue mineral density, pore size, pore spacing, and pore number. Samples were cyclically loaded in compression to a stress of 70 MPa, and fatigue life was defined as the number of cycles until failure. Finite element models were created from the µCT images and used to quantify stressed volume. Based on the expected log point-wise predictive density, stressed volume was a strong predictor of fatigue life in both the MC3 and P1. A regional analysis indicated fatigue life was more strongly associated with bone volume fraction in the superficial (r2 = 0.32, p < 0.001) and middle (r2 = 0.70, p < 0.001) regions of the subchondral bone, indicating the prominent role that the cortical plate played in the fatigue resistance of equine subchondral bone. By improving our understanding of the variance in fatigue life measurements, this research helps clarify the underlying mechanisms of the mechanical fatigue process and provides a basic understanding of subchondral bone injuries in the equine fetlock joint.

Integration of Swin UNETR and statistical shape modeling for a semi-automated segmentation of the knee and biomechanical modeling of articular cartilage.

Simulation studies, such as finite element (FE) modeling, provide insight into knee joint mechanics without patient involvement. Generic FE models mimic the biomechanical behavior of the tissue, but overlook variations in geometry, loading, and material properties of a population. Conversely, subject-specific models include these factors, resulting in enhanced predictive precision, but are laborious and time intensive. The present study aimed to enhance subject-specific knee joint FE modeling by incorporating a semi-automated segmentation algorithm using a 3D Swin UNETR for an initial segmentation of the femur and tibia, followed by a statistical shape model (SSM) adjustment to improve surface roughness and continuity. For comparison, a manual FE model was developed through manual segmentation (i.e., the de-facto standard approach). Both FE models were subjected to gait loading and the predicted mechanical response was compared. The semi-automated segmentation achieved a Dice similarity coefficient (DSC) of over 98% for both the femur and tibia. Hausdorff distance (mm) between the semi-automated and manual segmentation was 1.4 mm. The mechanical results (max principal stress and strain, fluid pressure, fibril strain, and contact area) showed no significant differences between the manual and semi-automated FE models, indicating the effectiveness of the proposed semi-automated segmentation in creating accurate knee joint FE models. We have made our semi-automated models publicly accessible to support and facilitate biomechanical modeling and medical image segmentation efforts ( https://data.mendeley.com/datasets/k5hdc9cz7w/1 ).

Model-Informed Precision Dosing Improves Outcomes in Patients Receiving Vancomycin for Gram-Positive Infections.

Background: Consensus guidelines for dosing and monitoring of vancomycin recommend collection of 2 serum concentrations to estimate an area under the curve/minimum inhibitory concentration ratio (AUC/MIC). Use of Bayesian software for AUC estimation and model-informed precision dosing (MIPD) enables pre-steady state therapeutic drug monitoring using a single serum concentration; however, data supporting this approach are limited. Methods: Adult patients with culture-proven gram-positive infections treated with vancomycin ≥72 hours receiving either trough-guided or AUC-guided therapy were included in this retrospective study. AUC-guided therapy was provided using MIPD and single-concentration monitoring. Treatment success, vancomycin-associated acute kidney injury (VA-AKI), and inpatient mortality were compared using a desirability of outcome ranking analysis. The most desirable outcome was survival with treatment success and no VA-AKI, and the least desirable outcome was death. Results: The study population (N = 300) was comprised of an equal number of patients receiving AUC-guided or trough-guided therapy. More patients experienced the most desirable outcome in the AUC-guided group compared to the trough-guided group (58.7% vs 46.7%, P = .037). Rates of VA-AKI were lower (21.3% vs 32.0%, P = .037) and median hospital length of stay was shorter (10 days [interquartile range {IQR}, 8-20] vs 12 days [IQR, 8-25]; P = .025) among patients receiving AUC-guided therapy. Conclusions: AUC-guided vancomycin therapy using MIPD and single-concentration monitoring improved outcomes in patients with culture-proven gram-positive infections. Safety was improved with reduced incidence of VA-AKI, and no concerns for reduced efficacy were observed. Moreover, MIPD allowed for earlier assessment of AUC target attainment and greater flexibility in the collection of serum vancomycin concentrations.

Knowledge and awareness assessment of bone loss and fracture risk after spinal cord injury.

METHODS: A cross-sectional analysis was conducted on a convenience sample of 138 adults with SCI, who completed a survey regarding knowledge and awareness of post-SCI bone health as part of a larger study. Self-reported demographic information and assessments of bone health knowledge were analyzed. RESULTS: Approximately 20% (n = 28) of participants had never heard of bone mineral density (BMD), 25% (n = 34) only vaguely remembered that BMD was mentioned during their hospitalization/rehabilitation after SCI, 36% (n = 50) clearly remembered that BMD was mentioned during their hospitalization/rehabilitation, and 17% (n = 24) reported having an individual or group education session on causes and management of low BMD during rehabilitation. Only 30% (n = 42) of participants believed they had adequate knowledge on the subject, while 70% (n = 96) believed their knowledge was inadequate or were unsure. Most participants (73%, n = 101) reported being concerned about the risks of low BMD after SCI and were interested in learning more about prevention (76%, n = 105) and treatment options (78%, n = 108). CONCLUSIONS: While results suggest that most participants received some information regarding bone health in post-SCI care, over 70% of participants reported wanting more information about bone loss prevention and treatment, indicating bone health education is a patient priority in this population.

PRG4 deficiency in mice alters skeletal structure, mechanics, and calvarial osteoclastogenesis, and rhPRG4 inhibits in vitro osteoclastogenesis.

Osteoporosis is a chronic disease characterized by reduced bone mass and increased fracture risk, estimated to affect over 10 million people in the United States alone. Drugs used to treat bone loss often come with significant limitations and/or long-term safety concerns. Proteoglycan-4 (PRG4, also known as lubricin) is a mucin-like glycoprotein best known for its boundary lubricating function of articular cartilage. In more recent years, it has been shown that PRG4 has anti-inflammatory properties, contributes to the maintenance of subchondral bone integrity, and patients with PRG4 mutations are osteopenic. However, it remains unknown how PRG4 impacts mechanical and material properties of bone. Therefore, our objective was to perform a phenotyping study of bone in a Prg4 gene trap (GT) mouse (PRG4 deficient). We found that femurs of Prg4 GT mice have altered mechanical, structural, and material properties relative to wildtype littermates. Additionally, Prg4 GT mice have a greater number of calvarial osteoclasts than wildtype mice, but do not have a notable inflammatory serum profile. Finally, Prg4 GT mice do not have an altered rate of bone formation, and exogenous recombinant human PRG4 (rhPRG4) administration inhibited osteoclastogenesis in vitro, suggesting that the skeletal phenotype may be due to changes in bone resorption. Overall, this work demonstrates that PRG4 deficiency affects several integral properties of bone structure, mechanics, and skeletal cell activity, and provides the foundation and insight toward future work evaluating PRG4 as a potential therapeutic target in treating bone loss.

Fixed and Relative Positioning of Scans for High Resolution Peripheral Quantitative Computed Tomography.

INTRODUCTION: High resolution peripheral quantitative computed tomography (HR-pQCT) imaging protocol requires defining where to position the ∼1 cm thick scan along the bone length. Discrepancies between the use of two positioning methods, the relative and fixed offset, may be problematic in the comparison between studies and participants. This study investigated how bone landmarks scale linearly with length and how this scaling affects both positioning methods aimed at providing a consistent anatomical location for scan acquisition. METHODS: Using CT images of the radius (N = 25) and tibia (N = 42), 10 anatomical landmarks were selected along the bone length. The location of these landmarks was converted to a percent length along the bone, and the variation in their location was evaluated across the dataset. The absolute location of the HR-pQCT scan position using both offset methods was identified for all bones and converted to a percent length position relative to the HR-pQCT reference line for comparison. A secondary analysis of the location of the scan region specifically within the metaphysis was explored at the tibia. RESULTS: The location of landmarks deviated from a linear relationship across the dataset, with a range of 3.6 % at the radius sites, and 4.5 % at the tibia sites. The consequent variation of the position of the scan at the radius was 0.6 % and 0.3 %, and at the tibia 2.4 % and 0.5 %, for the fixed and relative offset, respectively. The position of the metaphyseal junction with the epiphysis relative to the scan position was poorly correlated to bone length, with R2 = 0.06 and 0.37, for the fixed and relative offset respectively. CONCLUSION: The variation of the scan position by either method is negated by the intrinsic variation of the bone anatomy with respect both to total bone length as well as the metaphyseal region. Therefore, there is no clear benefit of either offset method. However, the lack of difference due to the inherent variation in the underlying anatomy implies that it is reasonable to compare studies even if they are using different positioning methods.

Is Running Power a Useful Metric? Quantifying Training Intensity and Aerobic Fitness Using Stryd Running Power Near the Maximal Lactate Steady State.

We sought to determine the utility of Stryd, a commercially available inertial measurement unit, to quantify running intensity and aerobic fitness. Fifteen (eight male, seven female) runners (age = 30.2 [4.3] years; V·O2max = 54.5 [6.5] ml·kg-1·min-1) performed moderate- and heavy-intensity step transitions, an incremental exercise test, and constant-speed running trials to establish the maximal lactate steady state (MLSS). Stryd running power stability, sensitivity, and reliability were evaluated near the MLSS. Stryd running power was also compared to running speed, V·O2, and metabolic power measures to estimate running mechanical efficiency (EFF) and to determine the efficacy of using Stryd to delineate exercise intensities, quantify aerobic fitness, and estimate running economy (RE). Stryd running power was strongly associated with V·O2 (R2 = 0.84; p < 0.001) and running speed at the MLSS (R2 = 0.91; p < 0.001). Stryd running power measures were strongly correlated with RE at the MLSS when combined with metabolic data (R2 = 0.79; p < 0.001) but not in isolation from the metabolic data (R2 = 0.08; p = 0.313). Measures of running EFF near the MLSS were not different across intensities (~21%; p > 0.05). In conclusion, although Stryd could not quantify RE in isolation, it provided a stable, sensitive, and reliable metric that can estimate aerobic fitness, delineate exercise intensities, and approximate the metabolic requirements of running near the MLSS.

Survival following complete resection of neuroblastoma in novel orthotopic rat xenograft model.

Neuroblastoma accounts for 15% of pediatric cancer deaths, despite multimodal therapy including surgical resection. Current neuroblastoma rodent models are insufficient for studying the impact of surgery and combination treatments, largely due to the small size of mouse models. Human neuroblastoma SK-N-BE(2) cells were injected into the left adrenal gland of 5-6-week-old RNU homozygous nude rats. Rats were either monitored by MRI until humane endpoint was reached or after 5 weeks underwent operative tumor resection, followed by monitoring for recurrence and survival. Following neuroblastoma cell implantation, the majority of tumors grew to greater than 5000 mm3 within 5.5-6.5 weeks, meeting the humane endpoint. Surgical resection was successfully done in 8 out of 9 rats, extending survival following tumor implantation from a median of 42 days to 78 days (p < 0.005). Pathology was consistent with human neuroblastoma, showing small round blue cell tumors with Homer-Wright rosettes, high mitoses and karyorrhectic index, and strong PHOX2B staining. Thus, we have established a novel orthotopic xenograft rat model of neuroblastoma and demonstrated increased survival of rats after surgical tumor resection. This model can be used for the development of surgical techniques, such as the use of intraoperative molecular imaging or assessment of combination therapies that include surgery.