Peri-operative zoledronic acid attenuates peri-prosthetic osteolysis in a rat model of cemented knee replacement.

Progressive osteolysis can occur at the cement-bone interface of joint replacements and the associated loss of fixation can lead to clinical loosening. We previously developed a rat hemiarthroplasty model that exhibited progressive loss of fixation with the development of cement-bone gaps under the tibial tray that mimicked patterns found in human arthroplasty retrievals. Here we explored the ability of a bisphosphonate (zoledronic acid, ZA) to attenuate cement-bone osteolysis and maintain implant stability. Sprague-Dawley rats (n = 59) received a poly(methylmethacrylate) cemented tibial component and were followed for up to 12 weeks. Treatment groups included peri-operative administration of ZA (ZA group), administration of ZA at 6 weeks postop (late ZA group), or vehicle (Veh group). There was a 60% reduction in the rate of cement-bone gap formation for the ZA group (0.15 mm3/week) compared to Veh group (0.38 mm3/week, p = 0.016). Late ZA prevented further progression of gap formation but did not reverse bone loss to the level achieved in the ZA group. Micromotion from five times body weight toggle loading was positively correlated with cement-bone gap volume (p = 0.009) and negatively correlated with the amount of cement in the metaphysis (p = 0.005). Reduced new bone formation and enduring nonviable bone in the epiphysis for the ZA group were found. This suggests that low bone turnover in the epiphysis may suppress the early catabolic response due to implantation, thereby maintaining better fixation in the epiphysis. This preclinical model presents compelling supporting data documenting improved maintenance of the cement-bone fixation with the use of peri-operative bisphosphonates.

An integrated metagenomic, metabolomic and transcriptomic survey of Populus across genotypes and environments.

Bridging molecular information to ecosystem-level processes would provide the capacity to understand system vulnerability and, potentially, a means for assessing ecosystem health. Here, we present an integrated dataset containing environmental and metagenomic information from plant-associated microbial communities, plant transcriptomics, plant and soil metabolomics, and soil chemistry and activity characterization measurements derived from the model tree species Populus trichocarpa. Soil, rhizosphere, root endosphere, and leaf samples were collected from 27 different P. trichocarpa genotypes grown in two different environments leading to an integrated dataset of 318 metagenomes, 98 plant transcriptomes, and 314 metabolomic profiles that are supported by diverse soil measurements. This expansive dataset will provide insights into causal linkages that relate genomic features and molecular level events to system-level properties and their environmental influences.

Partitioning into phosphatidylcholine-cholesterol membranes: liposome measurements, coarse-grained simulations, and implications for bioaccumulation.

Membrane-water partitioning is an important physical property for the assessment of bioaccumulation and environmental impact. Here, we advance simulation methodology for predicting the partitioning of small molecules into lipid membranes and compare the computational predictions to experimental measurements in liposomes. As a step towards high-throughput screening, we present an automated mapping and parametrization procedure to produce coarse-grained models compatible with the Martini 3 force field. The methodology is general and can also be used for other applications where coarse-grained simulations are appropriate. This article addresses the effect on membrane-water partitioning of adding cholesterol to POPC (1-palmitoyl-2-oleoyl-sn-glycero-3-phosphocholine) membranes. Nine contrasting neutral, zwitterionic and charged solutes are tested. Agreement between experiment and simulation is generally good, with the most challenging cases being permanently charged solutes. For all solutes, partitioning is found to be insensitive to membrane cholesterol concentration up to 25% mole fraction. Hence, for assessment of bioaccumulation into a range of membranes (such as those found in fish), partitioning data measured in pure lipid membranes are still informative.

Modification to Mirels scoring system location component improves fracture prediction for metastatic disease of the proximal femur.

BACKGROUND: Correctly identifying patients at risk of femoral fracture due to metastatic bone disease remains a clinical challenge. Mirels criteria remains the most widely referenced method with the advantage of being easily calculated but it suffers from poor specificity. The purpose of this study was to develop and evaluate a modified Mirels scoring system through scoring modification of the original Mirels location component within the proximal femur. METHODS: Computational (finite element) experiments were performed to quantify strength reduction in the proximal femur caused by simulated lytic lesions at defined locations. Virtual spherical defects representing lytic lesions were placed at 32 defined locations based on axial (4 axial positions: neck, intertrochanteric, subtrochanteric or diaphyseal) and circumferential (8 circumferential: 45-degree intervals) positions. Finite element meshes were created, material property assignment was based on CT mineral density, and femoral head/greater trochanter loading consistent with stair ascent was applied. The strength of each femur with a simulated lesion divided by the strength of the intact femur was used to calculate the Location-Based Strength Fraction (LBSF). A modified Mirels location score was next defined for each of the 32 lesion locations with an assignment of 1 (LBSF > 75%), 2 (LBSF: 51-75%), and 3 (LBSF: 0-50%). To test the new scoring system, data from 48 patients with metastatic disease to the femur, previously enrolled in a Musculoskeletal Tumor Society (MSTS) cross-sectional study was used. The lesion location was identified for each case based on axial and circumferential location from the CT images and assigned an original (2 or 3) and modified (1,2, or 3) Mirels location score. The total score for each was then calculated. Eight patients had a fracture of the femur and 40 did not over a 4-month follow-up period. Logistic regression and decision curve analysis were used to explore relationships between clinical outcome (Fracture/No Fracture) and the two Mirels scoring methods. RESULTS: The location-based strength fraction (LBSF) was lowest for lesions in the subtrochanteric and diaphyseal regions on the lateral side of the femur; lesions in these regions would be at greatest risk of fracture. Neck lesions located at the anterior and antero-medial positions were at the lowest risk of fracture. When grouped, neck lesions had the highest LBSF (83%), followed by intertrochanteric (72%), with subtrochanteric (50%) and diaphyseal lesions (49%) having the lowest LBSF. There was a significant difference (p < 0.0001) in LBSF between each axial location, except subtrochanteric and diaphyseal which were not different from each other (p = 0.96). The area under the receiver operator characteristic (ROC) curve using logistic regression was greatest for modified Mirels Score using site specific location of the lesion (Modified Mirels-ss, AUC = 0.950), followed by a modified Mirels Score using axial location of lesion (Modified Mirels-ax, AUC = 0.941). Both were an improvement over the original Mirels score (AUC = 0.853). Decision curve analysis was used to quantify the relative risks of identifying patients that would fracture (TP, true positives) and those erroneously predicted to fracture (FP, false positives) for the original and modified Mirels scoring systems. The net benefit of the scoring system weighed the benefits (TP) and harms (FP) on the same scale. At a threshold probability of fracture of 10%, use of the modified Mirels scoring reduced the number of false positives by 17-20% compared to Mirels scoring. CONCLUSIONS: A modified Mirels scoring system, informed by detailed analysis of the influence of lesion location, improved the ability to predict impending pathological fractures of the proximal femur for patients with metastatic bone disease. Decision curve analysis is a useful tool to weigh costs and benefits concerning fracture risk and could be combined with other patient/clinical factors that contribute to clinical decision making.

Potential for supraphysiologic fluid shear stresses in a rat cemented knee replacement model.

The mechano-biologic environment associated with aseptic loosening of cemented joint replacements is not fully understood. The goal of this study was to use a preclinical rat knee arthroplasty model to explore the changes in cement-bone morphology and micromotion that occur with in vivo service. Narrow gaps between cement and bone under the tibial tray were present at early time points, and with even small magnitude micromotion, resulted in large micromotion-to-gap width ratios. These data were then used to develop models of fluid flow in the cement-bone gaps to estimate potential for high fluid shear stress (FSS). Modeling results revealed supraphysiologic (>4 Pa) FSS were possible, particularly for cases in which eccentric loading applied to the implant and if the fluid in the gap consisted of marrow or synovial fluid. The early, high FSS environment, could cause fluid-induced periprosthetic osteolysis locally, resulting in progressive loss of cement-bone fixation.

Automated Coarse-Grained Mapping Algorithm for the Martini Force Field and Benchmarks for Membrane-Water Partitioning.

With a view to high-throughput simulations, we present an automated system for mapping and parameterizing organic molecules for use with the coarse-grained Martini force field. The method scales to larger molecules and a broader chemical space than existing schemes. The core of the mapping process is a graph-based analysis of the molecule's bonding network, which has the advantages of being fast, general, and preserving symmetry. The parameterization process pays special attention to coarse-grained beads in aromatic rings. It also includes a method for building efficient and stable frameworks of constraints for molecules with structural rigidity. The performance of the method is tested on a diverse set of 87 neutral organic molecules and the ability of the resulting models to capture octanol-water and membrane-water partition coefficients. In the latter case, we introduce an adaptive method for extracting partition coefficients from free-energy profiles to take into account the interfacial region of the membrane. We also use the models to probe the response of membrane-water partitioning to the cholesterol content of the membrane.

Predicting Fracture Risk in Patients with Metastatic Bone Disease of the Femur: A Pictorial Review Using Three Different Techniques.

One of the key roles of an orthopedic surgeon treating metastatic bone disease (MBD) is fracture risk prediction. Current widely used impending fracture risk tools such as Mirels scoring lack specificity. Two newer methods of fracture risk prediction, CT-based structural rigidity analysis (CTRA) and finite element analysis (FEA), have each been shown to be more accurate than Mirels. This case series illustrates comparative Mirels, CTRA, and FEA for 8 femurs in 7 subjects. These cases were selected from a much larger data set to portray examples of true positives, true negatives, false positives, and false negatives as defined by CTRA relative to the fracture outcome. Case illustrations demonstrate comparative Mirels and FEA. This series illustrates the use, efficacy, and limitations of these tools. As all current tools have limitations, further work is needed in refining and developing fracture risk prediction.

Standardization of assay representation in the Ontology for Biomedical Investigations.

The Ontology for Biomedical Investigations (OBI) underwent a focused review of assay term annotations, logic and hierarchy with a goal to improve and standardize these terms. As a result, inconsistencies in W3C Web Ontology Language (OWL) expressions were identified and corrected, and additionally, standardized design patterns and a formalized template to maintain them were developed. We describe here this informative and productive process to describe the specific benefits and obstacles for OBI and the universal lessons for similar projects.

Differing susceptibility of C57BL/6J and DBA/2J mice-parents of the murine BXD family, to severe acute respiratory syndrome coronavirus infection.

The ongoing coronavirus disease-2019 (COVID-19) pandemic, caused by a novel coronavirus termed severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) that is closely related to SARS-CoV, poses a grave threat to global health and has devastated societies worldwide. One puzzling aspect of COVID-19 is the impressive variation in disease manifestations among infected individuals, from a majority who are asymptomatic or exhibit mild symptoms to a smaller, largely age-dependent fraction who develop life-threatening conditions. Some of these differences are likely the consequence of host genetic factors. Systems genetics using diverse and replicable cohorts of isogenic mice represents a powerful way to dissect those host genetic differences that modulate microbial infections. Here we report that the two founders of the large BXD family of mice-C57BL/6J and DBA/2J, differ substantially in their susceptibility to a mouse-adapted SARS-CoV, MA15. Following intranasal viral challenge, DBA/2J develops a more severe disease than C57BL/6J as evidenced by more pronounced and sustained weight loss. Disease was accompanied by high levels of pulmonary viral replication in both strains early after infection but substantially delayed viral clearance in DBA/2J. Our data reveal that the parents of the BXD family are segregated by clear phenotypic differences during MA15 infection and support the feasibility of using this family to systemically dissect the complex virus-host interactions that modulate disease progression and outcome of infection with SARS-CoV, and provisionally also with SARS-CoV-2.

Nearest-neighbor connectedness theory: A general approach to continuum percolation.

We introduce a method to estimate continuum percolation thresholds and illustrate its usefulness by investigating geometric percolation of noninteracting line segments and disks in two spatial dimensions. These examples serve as models for electrical percolation of elongated and flat nanofillers in thin film composites. While the standard contact volume argument and extensions thereof in connectedness percolation theory yield accurate predictions for slender nanofillers in three dimensions, they fail to do so in two dimensions, making our test a stringent one. In fact, neither a systematic order-by-order correction to the standard argument nor invoking the connectedness version of the Percus-Yevick approximation yield significant improvements for either type of particle. Making use of simple geometric considerations, our new method predicts a percolation threshold of ρ_{c}l^{2}≈5.83 for segments of length l, which is close to the ρ_{c}l^{2}≈5.64 found in Monte Carlo simulations. For disks of area a we find ρ_{c}a≈1.00, close to the Monte Carlo result of ρ_{c}a≈1.13. We discuss the shortcomings of the conventional approaches and explain how usage of the nearest-neighbor distribution in our method bypasses those complications.

Control of Superselectivity by Crowding in Three-Dimensional Hosts.

Motivated by the fine compositional control observed in membraneless droplet organelles in cells, we investigate how a sharp binding-unbinding transition can occur between multivalent client molecules and receptors embedded in a porous three-dimensional structure. In contrast to similar superselective binding previously observed at surfaces, we have identified that a key effect in a three-dimensional environment is that the presence of inert crowding agents can significantly enhance or even introduce superselectivity. In essence, molecular crowding initially suppresses binding via an entropic penalty, but the clients can then more easily form many bonds simultaneously. We demonstrate the robustness of the superselective behavior with respect to client valency, linker length, and binding interactions in Monte Carlo simulations of an archetypal lattice polymer model.

Progressive loss of implant fixation in a preclinical rat model of cemented knee arthroplasty.

Aseptic loosening of total knee arthroplasty continues to be a challenging clinical problem. The progression of the loosening process, from the initial well-fixed component, is not fully understood. In this study, loss of fixation of cemented hemiarthroplasty was explored using 9-month-old Sprague-Dawley rats with 0, 2, 6, 12, 26 week end points. Morphological and cellular changes of cement-bone fixation were determined for regions directly below the tibial tray (epiphysis) and distal to the tray (metaphysis). Loss of fixation, with a progressive increase in cement-bone gap volume was found in the epiphysis (0.162 mm3 /week), but did not progress appreciably in the metaphysis (0.007 mm3 /week). In the epiphysis, there was an early and sustained elevation of osteoclasts adjacent to the cement border and development of a fibrous tissue layer between the cement and bone. There was early formation of bone around the cement in the metaphysis, resulting in a condensed bone layer without osteoclastic bone resorption or development of a fibrous tissue layer. Implant positioning was also an important factor in the cement-bone gap formation, with greater gap formation for implants that were placed medially on the tibial articular surface. Loss of fixation in the rat model mimicked patterns found in human arthroplasty where cement-bone gaps initiate under the tibial tray, at the periphery of the implant. This preclinical model could be used to study early biological response to cemented fixation and associated contributions of mechanical instability, component alignment, and periprosthetic inflammation.

Potential COVID-19 papain-like protease PLpro inhibitors: repurposing FDA-approved drugs.

Using the crystal structure of SARS-CoV-2 papain-like protease (PLpro) as a template, we developed a pharmacophore model of functional centers of the PLpro inhibitor-binding pocket. With this model, we conducted data mining of the conformational database of FDA-approved drugs. This search identified 147 compounds that can be potential inhibitors of SARS-CoV-2 PLpro. The conformations of these compounds underwent 3D fingerprint similarity clusterization, followed by docking of possible conformers to the binding pocket of PLpro. Docking of random compounds to the binding pocket of protease was also done for comparison. Free energies of the docking interaction for the selected compounds were lower than for random compounds. The drug list obtained includes inhibitors of HIV, hepatitis C, and cytomegalovirus (CMV), as well as a set of drugs that have demonstrated some activity in MERS, SARS-CoV, and SARS-CoV-2 therapy. We recommend testing of the selected compounds for treatment of COVID-19.

Radiographic and Biomechanical Assessment of Three Implant Designs for Canine Cementless Total Hip Replacement.

OBJECTIVE: The aim of this study was to evaluate the relationship between radiographic fit/fill measurements and biomechanical performance of three canine cementless total hip implant designs using an in vitro biomechanical testing protocol that replicates compression and torsion. STUDY DESIGN: Eighteen (six/group) canine cadaveric femurs were implanted with one of three cementless total hip implant designs: (1) collarless, (2) collared or (3) lateral bolt stems. Femoral length, canal flare index (CFI), canal fill, stem fit, stem level and stem angle were measured as independent variables. Biomechanical performance was tested using physiological, non-destructive gait loading (loading protocols) and destructive testing (failure protocols). RESULTS: During loading protocols, compressive stiffness was influenced by stem level (p < 0.05) and torsional stiffness was influenced by stem level and CFI for collarless stems (p < 0.05). During failure protocols, peak load was influenced by mediolateral (ML) stem angle (p < 0.05) and CFI (p < 0.01) for collarless stems and CFI for lateral bolt stems (p < 0.05). Peak torque was influenced by ML stem angle, craniocaudal stem angle and CFI for collarless stems (p < 0.05) and average ML fill for collared stems (p < 0.05). CONCLUSION: Biomechanical performance of collarless stems in cementless hip arthroplasty is more impacted by radiographic fit/fill than lateral bolt and collared stems. As a result, collarless stems may be more dependent on preoperative fit and intraoperative precision.

Phase transitions on non-uniformly curved surfaces: coupling between phase and location.

For particles confined to two dimensions, any curvature of the surface affects the structural, kinetic and thermodynamic properties of the system. If the curvature is non-uniform, an even richer range of behaviours can emerge. Using a combination of bespoke Monte Carlo, molecular dynamics and basin-hopping methods, we show that the stable states of attractive colloids confined to non-uniformly curved surfaces are distinguished not only by the phase of matter but also by their location on the surface. Consequently, the transitions between these states involve cooperative migration of the entire colloidal assembly. We demonstrate these phenomena on toroidal and sinusoidal surfaces for model colloids with different ranges of interactions as described by the Morse potential. In all cases, the behaviour can be rationalised in terms of three universal considerations: cluster perimeter, stress, and the packing of next-nearest neighbours.

Similitude of cement-bone micromechanics in cemented rat and human knee replacement.

A preclinical rat knee replacement model was recently developed to explore the biological and mechanobiological changes of trabecular resorption for cement-bone interdigitated regions. The goal here was to evaluate the relevance of this model compared with human knee replacement with regards to functional micromechanics. Eight nonsurvival, cemented knee replacement surgeries were performed, the interdigitated gap morphology was quantified, and interface micromotion between cement and bone was measured for 1 to 5 bodyweight loading. Computational fluid dynamics modeling of unit cell geometries with small gaps between trabeculae and cement was used to estimate fluid flow. Gap width (3.6 µm) was substantially smaller compared with cement-bone gaps reported in human knee replacement (11.8 µm). Micromotion at the cement-bone border was also decreased for the rat knee replacement (0.48 µm), compared with human (1.97 µm), for 1 bodyweight loading. However, the micromotion-to-gap width ratio (0.19 and 0.22 for, rat and human), and estimated fluid shear stress (6.47 and 7.13 Pa, for rat and human) were similar. Replicating the fluid dynamic characteristics of cement-bone interdigitated regions in human knee replacements using preclinical models may be important to recapitulate trabecular resorption mechanisms due to proposed supraphysiologic fluid shear stress. Statement of clinical significance: local cement-bone micromotion due to joint loading may contribute to the process of clinical loosening in total joint replacements. This work shows that while micromotion and gap morphology are diminished for the rat knee model compared to human, the motion-to-gap ratio, and corresponding fluid shear stress are of similar magnitudes.

Orthodontic Preparation for Secondary Alveolar Bone Grafting in Patients with Complete Cleft Lip and Palate.

This article provides an overview of the orthodontic preparation prior to secondary alveolar bone grafting of alveolar defects in those with complete cleft lip and palate. Use of cone beam computed tomography in diagnosis and treatment planning for addressing alveolar clefts, the rationale for maxillary expansion prior to alveolar bone grafting, key steps in differential maxillary expansion, potential adverse effects, and outcomes associated with maxillary expansion are provided in this overview.

A novel tool for standardizing clinical data in a semantically rich model.

Standardizing clinical information in a semantically rich data model is useful for promoting interoperability and facilitating high quality research. Semantic Web technologies such as Resource Description Framework can be utilized to their full potential when a model accurately reflects the semantics of the clinical situation it describes. To this end, ontologies that abide by sound organizational principles can be used as the building blocks of a semantically rich model for the storage of clinical data. However, it is a challenge to programmatically define such a model and load data from disparate sources. The PennTURBO Semantic Engine is a tool developed at the University of Pennsylvania that transforms concise RDF data into a source-independent, semantically rich model. This system sources classes from an application ontology and specifically defines how instances of those classes may relate to each other. Additionally, the system defines and executes RDF data transformations by launching dynamically generated SPARQL update statements. The Semantic Engine was designed as a generalizable data standardization tool, and is able to work with various data models and incoming data sources. Its human-readable configuration files can easily be shared between institutions, providing the basis for collaboration on a standard data model.

T-BAS Version 2.1: Tree-Based Alignment Selector Toolkit for Evolutionary Placement of DNA Sequences and Viewing Alignments and Specimen Metadata on Curated and Custom Trees.

The Tree-Based Alignment Selector (T-BAS) toolkit combines phylogenetic-based placement of DNA sequences with alignment and specimen metadata visualization tools in an integrative pipeline for analyzing microbial biodiversity. The release of T-BAS version 2.1 makes available reference phylogenies, supports multilocus sequence placements and permits uploading and downloading trees, alignments, and specimen metadata.