Does spinopelvic alignment affect femoral head cartilage and the proximal femoral physis in slipped capital femoral epiphysis? A finite element analysis.

BACKGROUND: Slipped capital femoral epiphysis is a prevalent pediatric hip disorder. Recent studies suggest the spine's sagittal profile may influence the proximal femoral growth plate's slippage, an aspect not extensively explored. This study utilizes finite element analysis to investigate how various spinopelvic alignments affect shear stress and growth plate slip. METHODS: A finite element model was developed from CT scans of a healthy adult male lumbar spine, pelvis, and femurs. The model was subjected to various sagittal alignments through reorientation. Simulations of two-leg stance, one-leg stance, walking heel strike, ascending stairs heel strike, and descending stairs heel strike were conducted. Parameters measured included hip joint contact area, stress, and maximum growth plate Tresca (shear) stress. FINDINGS: Posterior pelvic tilt cases indicated larger shear stresses compared to the anterior pelvic tilt variants except in two leg stance. Two leg stance resulted in decreases in the posterior tilted pelvi variants hip contact and growth plate Tresca stress compared to anterior tilted pelvi, however a combination of posterior pelvic tilt and high pelvic incidence indicated larger shear stresses on the growth plate. One leg stance and heal strike resulted in higher shear stress on the growth plate in posterior pelvic tilt variants compared to anterior pelvic tilt, with a combination of posterior pelvic tilt and high pelvic incidence resulting in the largest shear. INTERPRETATION: Our findings suggest that posterior pelvic tilt and high pelvic incidence may lead to increased shear stress at the growth plate. Activities performed in patients with these alignments may predispose to biomechanical loading that shears the growth plate, potentially leading to slip.

Biomechanical analysis of a trans-discal, multi-level stabilization screw (MLSS) at the upper instrumented vertebra (UIV) of long posterior thoracolumbar instrumentations.

PURPOSE: To evaluate proximal junctional biomechanics of a MLSS relative to traditional pedicle screw fixation at the proximal extent of T10-pelvis posterior instrumentation constructs (T10-p PSF). METHODS: A previously validated three-dimensional osseoligamentous spinopelvic finite element (FE) model was used to compare proximal junctional range-of-motion (ROM), vertebral body stresses, and discal biomechanics between two groups: (1) T10-p with a T10-11 MLSS ("T10-11 MLSS") and (2) T10-p with a traditional T10 pedicle screw ("Traditional T10-PS"). RESULTS: The T10-11 MLSS had a 5% decrease in T9 cortical bone stress compared to Traditional T10-PS. Conversely, the T10 and T11 bone stresses increased by 46% and 98%, respectively, with T10-11 MLSS compared to Traditional T10-PS. Annular stresses and intradiscal pressures (IDP) were similar at T9-T10 between constructs. At the T10-11 disc, T10-11 MLSS decreased annular stresses by 29% and IDP by 48% compared to Traditional T10-PS. Adjacent ROM (T8-9 & T9-10) were similar between T10-11 MLSS and Traditional T10-PS. T10-11 MLSS had 39% greater ROM at T10-11 and 23% less ROM at T11-12 compared to Traditional T10-PS. CONCLUSIONS: In this FE analysis, a T10-11 MLSS at the proximal extent of T10-pelvis posterior instrumentation resulted in increased T10 and T11 cortical bone stresses, decreased discal annular stress and IDP and increased ROM at T10-11, and no change in ROM at the adjacent level. Given the complex and multifactorial nature of proximal junctional kyphosis, these results require additional biomechanical and clinical evaluations to determine the clinical utility of MLSS on the proximal junctions of thoracolumbar posterior instrumented fusions.

Identification of novel peptide inhibitors of Plasmodium falciparum dihydrofolate reductase (PfDHFR): molecular docking and MD simulation studies.

The presence of drug-resistant variants of Plasmodium parasites within the population has presented a substantial obstacle to the eradication of Malaria. As a result, numerous research groups have directed their efforts towards creating new medication candidates that specifically target parasites. In this study, our main objective was to identify tri-peptide inhibitors for Plasmodium falciparum Dihydrofolate Reductase (PfDHFR) with the aim of finding a new peptide that exhibits superior binding properties compared to the current inhibitor, WR99210. In order to achieve this objective, a virtual library consisting of 8000 tripeptides was generated and subjected to computational screening against wild-type PfDHFR. The purpose of this screening was to discover the most effective binders at the active site. The four most optimal tripeptides identified (Trp-Trp-Glu, Trp-Phe-Tyr, Phe-Trp-Trp, Tyr-Trp-Trp) exhibited significant non-covalent interactions inside the active site of PfDHFR and had binding energies ranging from -9.5 to -9.0 kcal/mol and WR99210 had a binding energy of -6.2 kcal/mol. A 250 ns Molecular Dynamics (MD) simulation was performed to investigate the kinetic and thermodynamic characteristics of the protein-ligand complexes. The Root Mean Square Deviation (RMSD) values for the optimal tripeptides fell within the allowed range, indicating the stability of the ligands inside the protein complex. The Ki value for the most effective tripeptide was 0.3482 µM, whereas WR99210 had a Ki value of 1.02 µM. This article presents the initial discovery of peptide inhibitors targeting PfDHFR. In this text, we provide a comprehensive explanation of the interactions that occur between peptides and the enzyme.Communicated by Ramaswamy H. Sarma.

Pelvic Ring Fractures: A Biomechanical Comparison of Sacral and Lumbopelvic Fixation Techniques.

BACKGROUND CONTEXT: Pelvic ring fractures are becoming more common in the aging population and can prove to be fatal, having mortality rates between 10% and 16%. Stabilization of these fractures is challenging and often require immediate internal fixation. Therefore, it is necessary to have a biomechanical understanding of the different fixation techniques for pelvic ring fractures. METHODS: A previously validated three-dimensional finite element model of the lumbar spine, pelvis, and femur was used for this study. A unilateral pelvic ring fracture was simulated by resecting the left side of the sacrum and pelvis. Five different fixation techniques were used to stabilize the fracture. A compressive follower load and pure moment was applied to compare different biomechanical parameters including range of motion (contralateral sacroiliac joint, L1-S1 segment, L5-S1 segment), and stresses (L5-S1 nucleus stresses, instrument stresses) between different fixation techniques. RESULTS: Trans-iliac-trans-sacral screw fixation at S1 and S2 showed the highest stabilization for horizontal and vertical displacement at the sacral fracture site and reduction of contralateral sacroiliac joint for bending and flexion range of motion by 165% and 121%, respectively. DTSF (Double transiliac rod and screw fixation) model showed highest stabilization in horizontal displacement at the pubic rami fracture site, while the L5_PF_W_CC (L5-Ilium posterior screw fixation with cross connectors) and L5_PF_WO_CC (L5-Ilium posterior screw fixation without cross connectors) showed higher rod stresses, reduced L1-S1 (approximately 28%), and L5-S1 (approximately 90%) range of motion. CONCLUSIONS: Longer sacral screw fixations were superior in stabilizing sacral and contralateral sacroiliac joint range of motion. Lumbopelvic fixations displayed a higher degree of stabilization in the horizontal displacement compared to vertical displacement of pubic rami fracture, while also indicating the highest rod stresses. When determining the surgical approach for pelvic ring fractures, patient-specific factors should be accounted for to weigh the advantages and disadvantages for each technique.

Validation of a patient-specific finite element analysis framework for identification of growing rod-failure regions in early onset scoliosis patients.

PURPOSE: Growing rods are the gold-standard for treatment of early onset scoliosis (EOS). However, these implanted rods experience frequent fractures, requiring additional surgery. A recent study by the U.S. Food and Drug Administration (FDA) identified four common rod fracture locations. Leveraging this data, Agarwal et al. were able to correlate these fractures to high-stress regions using a novel finite element analysis (FEA) framework for one patient. The current study aims to further validate this framework through FEA modeling extended to multiple patients. METHODS: Three patient-specific FEA models were developed to match the pre-operative patient data taken from both registry and biplanar radiographs. The surgical procedure was then simulated to match the post-operative deformity. Body weight and flexion bending (1 Nm) loads were then applied and the output stress data on the rods were analyzed. RESULTS: Radiographic data showed fracture locations at the mid-construct, adjacent to the distal and tandem connector across the patients. Stress analysis from the FEA showed these failure locations matched local high-stress regions for all fractures observed. These results qualitatively validate the efficacy of the FEA framework by showing a decent correlation between localized high-stress regions and the actual fracture sites in the patients. CONCLUSIONS: This patient-specific, in-silico framework has huge potential to be used as a surgical tool to predict sites prone to fracture in growing rod implants. This prospective information would therefore be vital for surgical planning, besides helping optimize implant design for reducing rod failures.

Biomechanical Effects of Thoracic Flexibility and Stiffness on Lumbar Spine Loading: A Finite Element Analysis Study.

OBJECTIVE: To determine the effects of thoracic stiffness on mechanical stress in the lumbar spine during motion. METHODS: To evaluate the effect of preoperative thoracic flexibility, stiff and flexible spine models were created by changing the material properties of ligaments and discs in the thoracic spine. Total laminectomy was performed at L4/5 in stiff and flexible models. A biomechanical investigation and finite element analysis were performed preoperatively and postoperatively. A hybrid loading condition was applied, and the range of motion (ROM) at each segment and maximum stress in the discs and pars interarticularis were computed. RESULTS: In the preoperative model with the stiff thoracic spine, lumbar disc stress, lumbar ROM, and pars interarticularis stress at L5 increased. In contrast, as the thoracic spine became more flexible, lumbar disc stress, lumbar ROM, and pars interarticularis stress at L5 decreased. All L4/5 laminectomy models had increased instability and ROM at L4/5. To evaluate the effect of thoracic flexibility on the lumbar spine, differences between the stiff and flexible thoracic spine were examined: Differences in ROM and intervertebral disc stress at L4/5 in flexion between the stiff and flexible thoracic spine were respectively 0.7° and 0.0179 MPa preoperatively and 1.5° and 0.0367 MPa in the L4/5 laminectomy model. CONCLUSIONS: Biomechanically, disc stress and pars interarticularis stress decrease in the flexible thoracic spine. Flexibility of the thoracic spine reduces lumbar spine loading and could help to prevent stress-related disorders.

Two-to-three times increase in natural hip and lumbar non-sagittal plane kinematics can lead to anterior cruciate ligament injury and cartilage failure scenarios during single-leg landings.

BACKGROUND: Analyzing sports injuries is essential to mitigate risk for injury, but inherently challenging using in vivo approaches. Computational modeling is a powerful engineering tool used to access biomechanical information on tissue failure that cannot be obtained otherwise using traditional motion capture techniques. METHODS: We extrapolated high-risk kinematics associated with ACL strain and cartilage load and stress from a previous motion analysis of 14 uninjured participants. Computational simulations were used to induce ACL failure strain and cartilage failure load, stress, and contact pressure in two age- and BMI-matched participants, one of each biological sex, during single-leg cross drop and single-leg drop tasks. The high-risk kinematics were exaggerated in 20% intervals, within their physiological range of motion, to determine if injury occurred in the models. Where injury occurred, we reported the kinematic profiles that led to tissue failure. FINDINGS: Our findings revealed ACL strains up to 9.99%, consistent with reported failure values in existing literature. Cartilage failure was observed in all eight analyzed conditions when increasing each high-risk kinematic parameter by 2.61 ± 0.67 times the participants' natural landing values. The kinematics associated with tissue failure included peak hip internal rotation of 22.48 ± 19.04°, peak hip abduction of 22.51 ± 9.09°, and peak lumbar rotation away from the stance limb of 11.56 ± 9.78°. INTERPRETATION: Our results support the ability of previously reported high-risk kinematics in the literature to induce injury and add to the literature by reporting extreme motion limits leading to injurious cases. Therefore, training programs able to modify these motions during single-leg landings may reduce the risk of ACL injury and cartilage trauma.

In-silico molecular modelling studies of some camphor imine based compounds as anti-influenza A (H1N1) pdm09 virus agents.

The advent of influenza A (H1N1) drug-resistant strains led to the search quest for more potent inhibitors of the influenza A virus, especially in this devastating COVID-19 pandemic era. Hence, the present research utilized some molecular modelling strategies to unveil new camphor imine-based compounds as anti-influenza A (H1N1) pdm09 agents. The 2D-QSAR results revealed GFA-MLR (R2train = 0.9158, Q2=0.8475) and GFA-ANN (R2train = 0.9264, Q2=0.9238) models for the anti-influenza A (H1N1) pdm09 activity prediction which have passed the QSAR model acceptability thresholds. The results from the 3D-QSAR studies also revealed CoMFA (R2train =0.977, Q2=0.509) and CoMSIA_S (R2train =0.976, Q2=0.527) models for activity predictions. Based on the notable information derived from the 2D-QSAR, 3D-QSAR, and docking analysis, ten (10) new camphor imine-based compounds (22a-22j) were designed using the most active compound 22 as the template. Furthermore, the high predicted activity and binding scores of compound 22j were further justified by the high reactive sites shown in the electrostatic potential maps and other quantum chemical calculations. The MD simulation of 22j in the active site of the influenza hemagglutinin (HA) receptor confirmed the dynamic stability of the complex. Moreover, the appraisals of drug-likeness and ADMET properties of the proposed compounds showed zero violation of Lipinski's criteria with good pharmacokinetic profiles. Hence, the outcomes in this work recommend further in-depth in vivo and in-vitro investigations to validate these theoretical findings.Communicated by Ramaswamy H. Sarma.

In silico and structure-based evaluation of deleterious mutations identified in human Chk1, Chk2, and Wee1 protein kinase.

Checkpoint kinases Chk1, Chk2, Wee1 are playing a key role in DNA damage response and genomic integrity. Cancer-associated mutations identified in human Chk1, Chk2, and Wee1 were retrieved to understand the function associated with the mutation and also alterations in the folding pattern. Therefore, an attempt has been made to identify deleterious effect of variants using in silico and structure-based approach. Variants of uncertain significance for Chk1, Chk2, and Wee1 were retrieved from different databases and four prediction servers were employed to predict pathogenicity of mutations. Further, Interpro, I-Mutant 3.0, Consurf, TM-align, and have (y)our protein explained were used for comprehensive study of the deleterious effects of variants. The sequences of Chk1, Chk2, and Wee1 were analyzed using Clustal Omega, and the three-dimensional structures of the proteins were aligned using TM-align. The molecular dynamics simulations were performed to explore the differences in folding pattern between Chk1, Chk2, Wee1 wild-type, and mutant protein and also to evaluate the structural integrity. Thirty-six variants in Chk1, 250 Variants in Chk2, and 29 in Wee1 were categorized as pathogenic using in silico prediction tools. Furthermore, 25 mutations in Chk1, 189 in Chk2, and 14 in Wee1 were highly conserved, possessing deleterious effect and also influencing the protein structure and function. These identified mutations may provide underlying genetic intricacies to serve as potential targets for therapeutic inventions and clinical management.

Biomechanical evaluation of multi-rod constructs to stabilize an S1 pedicle subtraction osteotomy (PSO): a finite element analysis.

PURPOSE: To develop and validate a finite element (FE) model of a sacral pedicle subtraction osteotomy (S1-PSO) and to compare biomechanical properties of various multi-rod configurations to stabilize S1-PSOs. METHODS: A previously validated FE spinopelvic model was used to develop a 30° PSO at the sacrum. Five multi-rod techniques spanning the S1-PSO were made using 4 iliac screws and a variety of primary rods (PR) and accessory rods (AR; lateral: Lat-AR or medial: Med-AR). All constructs, except one, utilized a horizontal rod (HR) connecting the iliac bolts to which PRs and Med-ARs were connected. Lat-ARs were connected to proximal iliac bolts. The simulation was performed in two steps with the acetabula fixed. For each model, PSO ROM and maximum stress on the PRs, ARs, and HRs were recorded and compared. The maximum stress on the L5-S1 disc and the PSO forces were captured and compared. RESULTS: Highest PSO ROMs were observed for 4-Rods (HR + 2 Med-AR). Constructs consisting of 5-Rods (HR + 2 Lat-ARs + 1 Med-AR) and 6-Rods (HR + 2 Lat-AR + 2 Med-AR) had the lowest PSO ROM. The least stress on the primary rods was seen with 6-Rods, followed by 5-Rods and 4-Rods (HR + 2 Lat-ARs). Lowest PSO forces and lowest L5-S1 disc stresses were observed for 4-Rod (Lat-AR), 5-Rod, and 6-Rod constructs, while 4-Rods (HR + Med-AR) had the highest. CONCLUSION: In this first FE analysis of an S1-PSO, the 4-Rod construct (HR + Med-AR) created the least rigid environment and highest PSO forces anteriorly. While 5- and 6-Rods created the stiffest constructs and lowest stresses on the primary rods, it also jeopardized load transfer to the anterior column, which may not be favorable for healing anteriorly. A balance between the construct's rigidity and anterior load sharing is essential.

Molecular modelling studies of substituted indole derivatives as novel influenza a virus inhibitors.

The emergence of drug-resistant strains motivate researchers to find new innovative anti-IAV candidates with a different mode of action. In this work, molecular modelling strategies, such as 2D-QSAR, 3D-QSAR, molecular docking, molecular dynamics, FMOs, and ADMET were applied to some substituted indoles as IAV inhibitors. The best-developed 2D-QSAR models, MLR (Q2 = 0.7634, R2train = 0.8666) and ANN[4-3-1] (Q2 = 0.8699, R2train = 0.8705) revealed good statistical validation for the inhibitory response predictions. The 3D-QSAR models, CoMFA (Q2 = 0.504, R2train = 0.805) and CoMSIA/SEDHA (Q2 = 0.619, R2train = 0.813) are selected as the best 3D models following the global thresholds. In addition, the contour maps generated from the CoMFA and CoMSIA models illustrate the relationship between the molecular fields and the inhibitory effects of the studied molecules. The results of the studies led to the design of five new molecules (24a-e) with enhanced anti-IAV activities and binding potentials using the most active molecule (24) as the template scaffold. The conformational stability of the best-designed molecules with the NA protein showed hydrophobic and H-bonds with the key residues from the molecular dynamics simulations of 100 ns. Furthermore, the global reactivity indices from the DFT calculations portrayed the relevance of 24c in view of its smaller band gap as also justified by our QSAR and molecular simulation studies.Communicated by Ramaswamy H. Sarma.

Effect of Whole Body Parameters on Knee Joint Biomechanics: Implications for ACL Injury Prevention During Single-Leg Landings.

BACKGROUND: Previous studies have examined the effect of whole body (WB) parameters on anterior cruciate ligament (ACL) strain and loads, as well as knee joint kinetics and kinematics. However, articular cartilage damage occurs in relation to ACL failure, and the effect of WB parameters on ACL strain and articular cartilage biomechanics during dynamic tasks is unclear. PURPOSES: (1) To investigate the effect of WB parameters on ACL strain, as well as articular cartilage stress and contact force, during a single-leg cross drop (SLCD) and single-leg drop (SLD). (2) To identify WB parameters predictive of high ACL strain during these tasks. STUDY DESIGN: Descriptive laboratory study. METHODS: Three-dimensional motion analysis data from 14 physically active men and women were recorded during an SLCD and SLD. OpenSim was used to obtain their kinematics, kinetics, and muscle forces for the WB model. Using these data in kinetically driven finite element simulations of the knee joint produced outputs of ACL strains and articular cartilage stresses and contact forces. Spearman correlation coefficients were used to assess relationships between WB parameters and ACL strain and cartilage biomechanics. Moreover, receiver operating characteristic curve analyses and multivariate binary logistic regressions were used to find the WB parameters that could discriminate high from low ACL strain trials. RESULTS: Correlations showed that more lumbar rotation away from the stance limb at peak ACL strain had the strongest overall association (ρ = 0.877) with peak ACL strain. Higher knee anterior shear force (ρ = 0.895) and lower gluteus maximus muscle force (ρ = 0.89) at peak ACL strain demonstrated the strongest associations with peak articular cartilage stress or contact force in ≥1 of the analyzed tasks. The regression model that used muscle forces to predict high ACL strain trials during the dominant limb SLD yielded the highest accuracy (93.5%), sensitivity (0.881), and specificity (0.952) among all regression models. CONCLUSION: WB parameters that were most consistently associated with and predictive of high ACL strain and poor articular cartilage biomechanics during the SLCD and SLD tasks included greater knee abduction angle at initial contact and higher anterior shear force at peak ACL strain, as well as lower gracilis, gluteus maximus, and medial gastrocnemius muscle forces. CLINICAL RELEVANCE: Knowledge of which landing postures create a high risk for ACL or cartilage injury may help reduce injuries in athletes by avoiding those postures and practicing the tasks with reduced high-risk motions, as well as by strengthening the muscles that protect the knee during single-leg landings.

The Effect of Posterior Lumbar Interbody Fusion in Lumbar Spine Stenosis with Diffuse Idiopathic Skeletal Hyperostosis: A Finite Element Analysis.

OBJECTIVE: Lumbar spinal canal stenosis (LSS) with diffuse idiopathic skeletal hyperostosis (DISH) can require revision surgery because of the intervertebral instability after decompression. However, there is a lack of mechanical analyses for decompression procedures for LSS with DISH. METHODS: This study used a validated, three-dimensional finite element model of an L1-L5 lumbar spine, L1-L4 DISH, pelvis, and femurs to compare the biomechanical parameters (range of motion [ROM], intervertebral disc, hip joint, and instrumentation stresses) with an L5-sacrum (L5-S) and L4-S posterior lumbar interbody fusion (PLIF). A pure moment with a compressive follower load was applied to these models. RESULTS: ROM of L5-S and L4-S PLIF models decreased by more than 50% at L4-L5, respectively, and decreased by more than 15% at L1-S compared with the DISH model in all motions. The L4-L5 nucleus stress of the L5-S PLIF increased by more than 14% compared with the DISH model. In all motions, the hip stress of DISH, L5-S, and L4-S PLIF had very small differences. The sacroiliac joint stress of L5-S and L4-S PLIF models decreased by more than 15% compared with the DISH model. The stress values of the screws and rods in the L4-S PLIF model was higher than in the L5-S PLIF model. CONCLUSIONS: The concentration of stress because of DISH may influence adjacent segment disease on the nonunited segment of PLIF. A shorter-level lumbar interbody fixation is recommended to preserve ROM; however, it should be used with caution because it could provoke adjacent segment disease.

Repurposing of drugs against methyltransferase as potential Zika virus therapies.

In recent years, the outbreak of infectious disease caused by Zika Virus (ZIKV) has posed a major threat to global public health, calling for the development of therapeutics to treat ZIKV disease. Several possible druggable targets involved in virus replication have been identified. In search of additional potential inhibitors, we screened 2895 FDA-approved compounds using Non-Structural Protein 5 (NS5) as a target utilizing virtual screening of in-silco methods. The top 28 compounds with the threshold of binding energy -7.2 kcal/mol value were selected and were cross-docked on the three-dimensional structure of NS5 using AutoDock Tools. Of the 2895 compounds screened, five compounds (Ceforanide, Squanavir, Amcinonide, Cefpiramide, and Olmesartan_Medoxomil) ranked highest based on filtering of having the least negative interactions with the NS5 and were selected for Molecular Dynamic Simulations (MDS) studies. Various parameters such as RMSD, RMSF, Rg, SASA, PCA and binding free energy were calculated to validate the binding of compounds to the target, ZIKV-NS5. The binding free energy was found to be -114.53, -182.01, -168.19, -91.16, -122.56, and -150.65 kJ mol-1 for NS5-SFG, NS5-Ceforanide, NS5-Squanavir, NS5-Amcinonide, NS5-Cefpiramide, and NS5-Ol_Me complexes respectively. The binding energy calculations suggested Cefpiramide and Olmesartan_Medoxomil (Ol_Me) as the most stable compounds for binding to NS5, indicating a strong rationale for their use as lead compounds for development of ZIKV inhibitors. As these drugs have been evaluated on pharmacokinetics and pharmacodynamics parameters only, in vitro and in vivo testing and their impact on Zika viral cell culture may suggest their clinical trials on ZIKV patients.

Modeling of chitosan modified PLGA atorvastatin-curcumin conjugate (AT-CU) nanoparticles, overcoming the barriers associated with PLGA: An approach for better management of atherosclerosis.

Conjugate drugs are evolving into potent techniques in the drug development process for enhancing the biopharmaceutical, physicochemical, and pharmacokinetic properties. Atorvastatin (AT) is the first line of treatment for coronary atherosclerosis; however its therapeutic efficacy is limited because of its poor solubility and fast pass metabolism. Curcumin (CU) is evidenced in several crucial signaling pathways linked to lipid regulation and inflammation. To enhance the therapeutic efficacy and physical properties of AT and CU, a new conjugate derivative (AT-CU) was synthesized and assessed by in silico, in vitro characterizations, and in vivo efficacy through mice model. Although the biocompatibility and biodegradability of Polylactic-co-Glycolic Acid (PLGA) in nanoparticles are well documented, burst release is a common issue with this polymer. Hence the current work used chitosan as a drug release modifier to the PLGA nanoparticles. The chitosan-modified PLGA AT-CU nanoparticles were prepaid by single emulsion and solvent evaporation technique. With raising the concentration of chitosan the particle size grew from 139.2 nm to 197.7 nm, the zeta potential rose from -20.57 mV to 28.32 mV, and the drug encapsulation efficiency improved from 71.81% to 90.57%. At 18 h, the burst release of AT-CU from PLGA nanoparticles was seen, hitting abruptly 70.8%. For chitosan-modified PLGA nanoparticles, the burst release pattern was significantly reduced which could be due to the adsorption of the drug on the surface of chitosan. The efficiency of the ideal formulation i.e F4 (chitosan/PLGA = 0.4) in treating atherosclerosis was further strongly evidenced by in vivo investigation.

Resisting subsidence with a truss Implant: Application of the "Snowshoe" principle for interbody fusion devices.

The primary objective was to compare the subsidence resistance properties of a novel 3D-printed spinal interbody titanium implant versus a predicate polymeric annular cage. We evaluated a 3D-printed spinal interbody fusion device that employs truss-based bio-architectural features to apply the snowshoe principle of line length contact to provide efficient load distribution across the implant/endplate interface as means of resisting implant subsidence. Devices were tested mechanically using synthetic bone blocks of differing densities (osteoporotic to normal) to determine the corresponding resistance to subsidence under compressive load. Statistical analyses were performed to compare the subsidence loads and evaluate the effect of cage length on subsidence resistance. The truss implant demonstrated a marked rectilinear increase in resistance to subsidence associated with increase in the line length contact interface that corresponds with implant length irrespective of subsidence rate or bone density. In blocks simulating osteoporotic bone, comparing the shortest with the longest length truss cage (40 vs. 60 mm), the average compressive load necessary to induce subsidence of the implant increased by 46.4% (383.2 to 561.0 N) and 49.3% (567.4 to 847.2 N) for 1 and 2 mm of subsidence, respectively. In contrast, for annular cages, there was only a modest increase in compressive load when comparing the shortest with the longest length cage at a 1 mm subsidence rate. The Snowshoe truss cages demonstrated substantially more resistance to subsidence than corresponding annular cages. Clinical studies are required to support the biomechanical findings in this work.

Effects of Sacral Slope Changes on the Intervertebral Disc and Hip Joint: A Finite Element Analysis.

OBJECTIVE: Spinopelvic parameters are vital components that must be considered when treating patients with spinal disease. Several finite element (FE) studies have explored spinopelvic parameters such as sacral slope (SS) and the impact on the lumbar spine, although no study has examined the effect on the hip and sacroiliac joint (SIJ) on varying SS angles. Therefore, it is necessary to have a biomechanical understanding of the impact on the spinopelvic complex. METHODS: An FE lumbar, pelvis, and femur model was created from computed tomography scans of a 55-year-old female patient with no abnormalities. Three models were created: a normal model (SS = 26°), a model with high SS (SS = 30°), and a model with low SS (SS = 20°). These models underwent loading for flexion, extension, lateral bending, and axial rotation. Range of motion (ROM), intradiscal pressures, hip joint, and SIJ contact stresses were analyzed. RESULTS: The high SS model (SS = 30°) indicated the highest ROM in the L5-S1 (slip angle) level and the highest intradiscal pressures. The highest average hip and SIJ contact stresses were present in this model, although the low SS model (SS = 20°) in extension had the largest stresses for the hip and SIJ. CONCLUSIONS: The results provide evidence that patients with higher SS may be more prone to increased ROM at the slip angle (L5-S1). In addition, patients with higher SS were shown to have higher contact stresses on the hip joint and SIJ, potentially leading to SIJ dysfunction. Clinically, correcting lumbar lordosis including SS is important; however, a high SS may have a negative impact on the intervertebral disc, SIJ, and hip joint.

Natural Metabolite Ursolic Acid as an Inhibitor of Dormancy Regulator DosR of Mycobacterium tuberculosis: Evidence from Molecular Docking, Molecular Dynamics Simulation and Free Energy Analysis.

BACKGROUND: DosR is a transcriptional regulator of Mycobacterium tuberculosis (MTB), governing the expression of a set of nearly 50 genes that is often referred to as 'dormancy regulon'. The inhibition of DosR expression by an appropriate inhibitor may be a crucial step against MTB. OBJECTIVE: We targeted the DosR with natural metabolites, ursolic acid (UA) and carvacrol (CV), using in silico approaches. METHODS: The molecular docking, molecular dynamics (MD) simulation for 200 ns, calculation of binding energies by MM-GBSA method, and ADMET calculation were performed to evaluate the inhibitory potential of natural metabolites ursolic acid (UA) and carvacrol (CV) against DosR of MTB. RESULTS: Our study demonstrated that UA displayed significant compatibility with DosR during the 200 ns timeframe of MD simulation. The thermodynamic binding energies by MM-GBSA also suggested UA conformational stability within the binding pocket. The SwissADME, pkCSM, and OSIRIS DataWarrior showed a drug-likeness profile of UA, where Lipinski profile was satisfied with one violation (MogP > 4.15) with no toxicities, no mutagenicity, no reproductive effect, and no irritant nature. CONCLUSION: The present study suggests that UA has the potency to inhibit the DosR expression and warrants further investigation on harnessing its clinical potential.

Lumbar Disc Degeneration Affects the Risk of Rod Fracture Following PSO; A Finite Element Study.

STUDY DESIGN: Finite element (FE) study. OBJECTIVE: Pedicle subtraction osteotomy (PSO) is a surgical method to correct sagittal plane deformities. In this study, we aimed to investigate the biomechanical effects of lumbar disc degeneration on the instrumentation following PSO and assess the effects of using interbody spacers adjacent to the PSO level in a long instrumented spinal construct. METHODS: A spinopelvic model (T10-pelvis) with PSO at the L3 level was used to generate 3 different simplified grades of degenerated lumbar discs (mild (Pfirrmann grade III), moderate (Pfirrmann grade IV), and severe (Pfirrmann grade V)). Instrumentation included eighteen pedicle screws and bilateral primary rods. To investigate the effect of interbody spacers, the model with normal disc height was modified to accommodate 2 interbody spacers adjacent to the PSO level through a lateral approach. For the models, the rods' stress distribution, PSO site force values, and the spine range of motion (ROM) were recorded. RESULTS: The mildly, moderately, and severely degenerated models indicated approximately 10%, 26%, and 40% decrease in flexion/extension motion, respectively. Supplementing the instrumented spinopelvic PSO model using interbody spacers reduced the ROM by 22%, 21%, 4%, and 11% in flexion, extension, lateral bending, and axial rotation, respectively. The FE results illustrated lower von Mises stress on the rods and higher forces at the PSO site at higher degeneration grades and while using the interbody spacers. CONCLUSIONS: Larger and less degenerated discs adjacent to the PSO site may warrant consideration for interbody cage instrumentation to decrease the risk of rod fracture and PSO site non-union.

Does number of rods matter? 4-, 5-, and 6-rods across a lumbar pedicle subtraction osteotomy: a finite element analysis.

PURPOSE: To assess biomechanics of a lumbar PSO stabilized with different multi-rod constructs (4-, 5-, 6-rods) using satellite and accessory rods. METHODS: A validated spinopelvic finite element model with a L3 PSO was used to evaluate the following constructs: 2 primary rods T10-pelvis ("Control"), two satellite rods (4-rod), two satellite rods + one accessory rod (5-rod), or two satellite rods + two accessory rods (6-rod). Data recorded included: ROM T10-S1 and L2-L4, von Mises stresses on primary, satellite, and accessory rods, factor of safety yield stress, and force across the PSO surfaces. Percent differences relative to Control were calculated. RESULTS: Compared to Control, 4-rods increased PSO flexion and extension. Lower PSO ROMs were observed for 5- and 6-rods compared to 4-rods. However, 4-rod (348.6 N) and 5-rod (343.2 N) showed higher PSO forces than 2-rods (336 N) and 6-rods had lower PSO forces (324.2 N). 5- and 6-rods led to the lowest rod von Mises stresses across the PSO. 6-rod had the maximum factor of safety on the primary rods. CONCLUSIONS: In this finite element analysis, 4-rods reduced stresses on primary rods across a lumbar PSO. Although increased rigidity afforded by 5- and 6-rods decreased rod stresses, it resulted in less load transfer to the anterior vertebral column (particularly for 6-rod), which may not be favorable for the healing of the anterior column. A balance between the construct's rigidity and anterior load sharing is essential.