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.

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 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.

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.

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.

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.

Zoledronic acid after spinal cord injury mitigates losses in proximal femoral strength independent of ambulation ability.

Rapid bone loss can occur after spinal cord injury (SCI) and a standard of care to prevent or treat this phenomenon is an active area of research. Using advanced analysis techniques, this study demonstrates that zoledronic acid, a possible treatment, prevented loss of bone strength at the hip following SCI. INTRODUCTION: Bone loss below the level of neurological lesion is a well-known complication of spinal cord injury (SCI), and effective preventive treatment for this phenomenon is an active area of research. Zoledronic acid has demonstrated efficacy to attenuate bone loss at the hip after SCI, but previous studies relied on measurements from dual-energy X-ray absorptiometry. The purpose of this investigation was to more thoroughly characterize changes to bone mineral and strength at the proximal femur in individuals receiving zoledronic acid in the acute SCI stage; we also examined the influence of ambulatory ability on bone outcomes. METHODS: Participants randomized to either zoledronic acid (n = 29) or placebo (n = 30) received computed tomography (CT) scans and ambulatory assessments at baseline and 6 and 12 months following drug infusion. CT-based finite element (FE) modeling was used to predict changes in proximal femoral strength associated with treatment. RESULTS: After 12 months, FE-predicted bone strength was reduced by a mean (SD) of 9.6 (17.9)% in the zoledronic acid group versus 24.6 (24.5)% in the placebo group (p = 0.007). These differences in strength were explained by reductions in CT measurements of both trabecular (p < 0.001) and cortical (p ≤ 0.021) bone at the femoral neck and trochanteric region. Ambulation ability influenced select trabecular and cortical parameters, but we were unable to detect an impact on FE-predicted bone strength. CONCLUSION: These findings demonstrate that treatment with zoledronic acid in acute SCI attenuates losses in proximal femoral strength, which may reduce the risk of hip fractures across patients with varying degrees of ambulatory abilities.

Challenges in management of invasive fungal infections in stem cell transplant.

Invasive fungal infections cause significant morbidity and mortality in hematopoietic stem cell transplant recipients. In order to minimize these infections, prophylaxis has become routine, although the agents used have changed over time. This presents new challenges as we consider an approach to breakthrough infections and recognize the epidemiologic shift toward isolates with higher rates of drug resistance. This review outlines the management of the most common pathogens (Candida, Aspergillus, Mucorales) as well as rarer pathogens that have higher rates of resistance (Trichosporon, Fusarium, Scedosporium, and Lomentospora). We discuss potential approaches to proven or possible breakthrough infections with yeast and pulmonary mold disease. Finally, we outline the role for combination therapy and newer antifungals, acknowledging current knowledge gaps and areas for future exploration.

Bone Mineral Loss at the Distal Femur and Proximal Tibia Following Spinal Cord Injury in Men and Women.

PURPOSE: Spinal cord injury (SCI) causes rapid bone loss and increases risk of fragility fractures in the lower extremities. The majority of individuals with SCI are men, and few studies have investigated sex as a biological variable in SCI-induced osteoporosis. This cross-sectional study aimed to quantify sex-specific differences in bone mineral following SCI. METHODS: Quantitative computed tomography (QCT) scans of the distal femur and proximal tibia were obtained at baseline of one of four clinical trials enrolling people who sustained SCI 1 month to 50 years prior to recruitment. Bone volume (BV), bone mineral content (BMC), bone mineral density (BMD), and bending strength index (BSI) were quantified in the integral, trabecular, and cortical bone in the epiphysis, metaphysis and diaphysis. Scans from 106 men and 31 women were analyzed to measure sex-specific effects on bone loss over time post-SCI. RESULTS: BMC and BSI declined exponentially as a function of time post-SCI and were best described by separate decay curves for men and women. Women had BV, BMC, and BSI at 58-77% that of men in the acute and plateau phases, with both sexes showing similar rates of loss as a function of time post-SCI. Trabecular BMD was best described as an exponential decay versus time post-SCI, with no sex-specific differences. CONCLUSIONS: Due to consistently lower BV, BMC, and BSI, women may be more susceptible to fractures after SCI than men.

Sensitivity of Internal Tibial Forces and Moments to Static Optimization Moment Constraints at the Subtalar and Ankle Joints.

We examined the sensitivity of internal tibial forces and moments during running to different subtalar/ankle moment constraints in a static optimization routine. Seventeen participants ran at 2.20, 3.33, and 4.17 ms-1 while force and motion data were collected. Ankle joint contact force was estimated using inverse-dynamics-based static optimization. Three sets of joint moment constraints were tested. All sets included the flexion-extension and abduction-adduction moments at the hip and the flexion-extension moment at the knee but differed in the constraints used at the subtalar/ankle: (1) flexion-extension at the ankle (Sag), (2) flexion-extension and inversion-eversion at ankle (Sag + Front), and (3) flexion-extension at the ankle and supination-pronation at the subtalar (Sag + SubT). Internal tibial forces and moments were quantified at the distal one-third of the tibia, by ensuring static equilibrium with applied forces and moments. No interaction was observed between running speed and constraint for internal tibial forces or moments. Sag + SubT resulted in larger internal mediolateral force (+41%), frontal (+79%), and transverse (+29%) plane moments, compared to Sag and Sag + Front. Internal axial force was greatest in Sag + Front, compared to Sag and Sag + SubT (+37%). Faster running speeds resulted in greater internal tibial forces and moments in all directions (≥+6%). Internal tibial forces and moments at the distal one-third of the tibia were sensitive to the subtalar and ankle joint moment constraints used in the static optimization routine, independent of running speed.

Tibial Strains During Prolonged Downhill Running: A Finite Element Analysis.

Bone strains in the lower extremity may be influenced by neuromuscular fatigue. In this study, we examined potential changes in finite element (FE) predicted tibial strains over the course of a fatiguing downhill-running protocol. Twelve physically active males ran for 30 min on an instrumented treadmill at a speed of 2.8 m s-1 and a grade of -11.3 deg. Motion capture and inverse-dynamic-based static optimization were used to estimate lower-extremity joint contact and muscle forces at the beginning, middle, and end stages of the downhill run. Finite element models of the tibia-fibula complex, from database-matched computed tomography images, were then used to estimate resulting 90th percentile strain (peak strain) and strained volume (volume of elements above 3000 µÎµ). In the fatigued state, peak ankle joint contact forces decreased an average of 8.1% (p < 0.002) in the axial direction, but increased an average of 7.7% (p < 0.042) in the anterior-posterior direction; consequently, finite element estimations of peak strain and strained volume were unaffected (p > 0.190). Although neuromuscular fatigue may influence ankle joint contact forces, it may not necessarily influence tibial strains due to the complex, and sometimes nonintuitive, relationship between applied load and resulting bone strain.

Effect of stride length on the running biomechanics of healthy women of different statures.

BACKGROUND: Tibial stress fracture is a debilitating musculoskeletal injury that diminishes the physical performance of individuals who engage in high-volume running, including Service members during basic combat training (BCT) and recreational athletes. While several studies have shown that reducing stride length decreases musculoskeletal loads and the potential risk of tibial injury, we do not know whether stride-length reduction affects individuals of varying stature differently. METHODS: We investigated the effects of reducing the running stride length on the biomechanics of the lower extremity of young, healthy women of different statures. Using individualized musculoskeletal and finite-element models of women of short (N = 6), medium (N = 7), and tall (N = 7) statures, we computed the joint kinematics and kinetics at the lower extremity and tibial strain for each participant as they ran on a treadmill at 3.0 m/s with their preferred stride length and with a stride length reduced by 10%. Using a probabilistic model, we estimated the stress-fracture risk for running regimens representative of U.S. Army Soldiers during BCT and recreational athletes training for a marathon. RESULTS: When study participants reduced their stride length by 10%, the joint kinetics, kinematics, tibial strain, and stress-fracture risk were not significantly different among the three stature groups. Compared to the preferred stride length, a 10% reduction in stride length significantly decreased peak hip (p = 0.002) and knee (p < 0.001) flexion angles during the stance phase. In addition, it significantly decreased the peak hip adduction (p = 0.013), hip internal rotation (p = 0.004), knee extension (p = 0.012), and ankle plantar flexion (p = 0.026) moments, as well as the hip, knee, and ankle joint reaction forces (p < 0.001) and tibial strain (p < 0.001). Finally, for the simulated regimens, reducing the stride length decreased the relative risk of stress fracture by as much as 96%. CONCLUSIONS: Our results show that reducing stride length by 10% decreases musculoskeletal loads, tibial strain, and stress-fracture risk, regardless of stature. We also observed large between-subject variability, which supports the development of individualized training strategies to decrease the incidence of stress fracture.

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.

Internal Tibial Forces and Moments During Graded Running.

The stress experienced by the tibia has contributions from the forces and moments acting on the tibia. We sought to quantify the influence of running grade on internal tibial forces and moments. Seventeen participants ran at 3.33 m/s on an instrumented treadmill at 0 deg, ±5 deg, and ±10 deg while motion data were captured. Ankle joint contact force was estimated from an anthropometrically-scaled musculoskeletal model using inverse dynamics-based static optimization. Internal tibial forces and moments were quantified at the distal 1/3rd of the tibia, by ensuring static equilibrium with all applied forces and moments. Downhill running conditions resulted in lower peak internal axial force (range of mean differences: -9% to -16%, p < 0.001), lower peak internal anteroposterior force (-14% to -21%, p < 0.001), and lower peak internal mediolateral force (-14% to -15%, p < 0.001), compared to 0 deg and +5 deg. Furthermore, downhill conditions resulted in lower peak internal mediolateral moment (-11%to -21%, p < 0.001), lower peak internal anteroposterior moment (-13% to -14%, p < 0.001), and lower peak internal torsional moment (-9% to -21%, p < 0.001), compared to 0 deg, +5 deg, and +10 deg. The +10 deg condition resulted in lower peak internal axial force (-7% to -9%, p < 0.001) and lower peak internal mediolateral force (-9%, p = 0.004), compared to 0 deg and +5 deg. These findings suggest that downhill running may be associated with lower tibial stresses than either level or uphill running.

Preventing Bone Stress Injuries in Runners with Optimal Workload.

Bone stress injuries (BSIs) occur at inopportune times to invariably interrupt training. All BSIs in runners occur due to an "error" in workload wherein the interaction between the number and magnitude of bone tissue loading cycles exceeds the ability of the tissue to resist the repetitive loads. There is not a single optimal bone workload, rather a range which is influenced by the prevailing scenario. In prepubertal athletes, optimal bone workload consists of low-repetitions of fast, high-magnitude, multidirectional loads introduced a few times per day to induce bone adaptation. Premature sports specialization should be avoided so as to develop a robust skeleton that is structurally optimized to withstand multidirectional loading. In the mature skeleton, optimal workload enables gains in running performance but minimizes bone damage accumulation by sensibly progressing training, particularly training intensity. When indicated (e.g., following repeated BSIs), attempts to reduce bone loading magnitude should be considered, such as increasing running cadence. Determining the optimal bone workload for an individual athlete to prevent and manage BSIs requires consistent monitoring. In the future, it may be possible to clinically determine bone loads at the tissue level to facilitate workload progressions and prescriptions.

Bringing Mechanical Context to Image-Based Measurements of Bone Integrity.

PURPOSE OF REVIEW: Image-based measurements of bone integrity are used to estimate failure properties and clinical fracture risk. This paper (1) reviews recent imaging studies that have enhanced our understanding of the mechanical pathways to bone fracture and (2) discusses the influence that inter-individual differences in image-based measurements may have on the clinical assessment of fracture risk RECENT FINDINGS: Increased tissue mineralization is associated with improved bone strength but reduced fracture toughness. Trabecular architecture that is important for fatigue resistance is less important for bone strength. The influence of porosity on bone failure properties is heavily dependent on pore location and size. The interaction of various characteristics, such as bone area and mineral content, can further complicate their influence on bone failure properties. What is beneficial for bone strength is not always beneficial for bone toughness or fatigue resistance. Additionally, given the large amount of imaging data that is clinically available, there is a need to develop effective translational strategies to better interpret non-invasive measurements of bone integrity.

Validation of Bone Density and Microarchitecture Measurements of the Load-Bearing Femur in the Human Knee Obtained Using In Vivo HR-pQCT Protocol.

High resolution peripheral quantitative computed tomography (HR-pQCT) was designed to study bone mineral density (BMD) and microarchitecture in peripheral sites at the distal radius and tibia. With the introduction of the second generation HR-pQCT scanner (XtremeCT II, Scanco Medical) that has a larger, longer gantry it is now possible to study the human knee in vivo using HR-pQCT. Previous validation of HR-pQCT measurements at the distal radius and tibia against micro-CT is not representative of the knee because the increased cross-sectional area, greater amount of soft tissue surrounding the scan region, and different imaging protocol result in potentially increased beam hardening effects and photon scatter and different signal-to-noise ratio. The objective of this study is to determine the accuracy of density and microarchitecture measurements in the human knee measured by HR-pQCT using an in vivo protocol. Twelve fresh-frozen cadaver knees were imaged using in vivo HR-pQCT (60.7 µm) protocol. Subsequentially, distal femurs were extracted and imaged using a higher resolution (30.3 µm) ex vivo protocol, replicating micro-CT imaging. Scans were registered so that agreement of density and bone microarchitecture measurements could be determined using linear regression and Bland-Altman plots. All density and microarchitecture outcomes were highly correlated between the 2 protocols (R2 > 0.89) albeit with statistically significant differences between absolute measures based on paired t tests. All parameters showed accuracy between 4.5% and 8.7%, and errors were highly systematic, particularly for trabecular BMD and trabecular thickness (R2 > 0.93). We found that BMD and microarchitecture measurements in the distal femur obtained using an in vivo HR-pQCT knee protocol contained systematic errors, and accurately represented measurements obtained using a micro-CT equivalent imaging protocol. This work establishes the validity and limitations of using HR-pQCT to study the BMD and microarchitecture of human knees in future clinical studies.

Effects of body size and load carriage on lower-extremity biomechanical responses in healthy women.

BACKGROUND: Musculoskeletal injuries, such as stress fractures, are the single most important medical impediment to military readiness in the U.S. Army. While multiple studies have established race- and sex-based risks associated with a stress fracture, the role of certain physical characteristics, such as body size, on stress-fracture risk is less conclusive. METHODS: In this study, we investigated the effects of body size and load carriage on lower-extremity joint mechanics, tibial strain, and tibial stress-fracture risk in women. Using individualized musculoskeletal-finite-element-models of 21 women of short, medium, and tall statures (n = 7 in each group), we computed the joint mechanics and tibial strains while running on a treadmill at 3.0 m/s without and with a load of 11.3 or 22.7 kg. We also estimated the stress-fracture risk using a probabilistic model of bone damage, repair, and adaptation. RESULTS: Under all load conditions, the peak plantarflexion moment for tall women was higher than those in short women (p < 0.05). However, regardless of the load condition, we did not observe differences in the strains and the stress-fracture risk between the stature groups. When compared to the no-load condition, a 22.7-kg load increased the peak hip extension and flexion moments for all stature groups (p < 0.05). However, when compared to the no-load condition, the 22.7-kg load increased the strains and the stress-fracture risk in short and medium women (p < 0.05), but not in tall women. CONCLUSION: These results show that women of different statures adjust their gait mechanisms differently when running with external load. This study can educate the development of new strategies to help reduce the risk of musculoskeletal injuries in women while running with external load.

Subject-Specific Finite Element Models of the Tibia With Realistic Boundary Conditions Predict Bending Deformations Consistent With In Vivo Measurement.

Understanding the structural response of bone during locomotion may help understand the etiology of stress fracture. This can be done in a subject-specific manner using finite element (FE) modeling, but care is needed to ensure that modeling assumptions reflect the in vivo environment. Here, we explored the influence of loading and boundary conditions (BC), and compared predictions to previous in vivo measurements. Data were collected from a female participant who walked/ran on an instrumented treadmill while motion data were captured. Inverse dynamics of the leg (foot, shank, and thigh segments) was combined with a musculoskeletal (MSK) model to estimate muscle and joint contact forces. These forces were applied to an FE model of the tibia, generated from computed tomography (CT). Eight conditions varying loading/BCs were investigated. We found that modeling the fibula was necessary to predict realistic tibia bending. Applying joint moments from the MSK model to the FE model was also needed to predict torsional deformation. During walking, the most complex model predicted deformation of 0.5 deg posterior, 0.8 deg medial, and 1.4 deg internal rotation, comparable to in vivo measurements of 0.5-1 deg, 0.15-0.7 deg, and 0.75-2.2 deg, respectively. During running, predicted deformations of 0.3 deg posterior, 0.3 deg medial, and 0.5 deg internal rotation somewhat underestimated in vivo measures of 0.85-1.9 deg, 0.3-0.9 deg, 0.65-1.72 deg, respectively. Overall, these models may be sufficiently realistic to be used in future investigations of tibial stress fracture.