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1.  Three-dimensional quantification of femoral head shape in controls and patients with cam-type femoroacetabular impingement 
Annals of biomedical engineering  2013;41(6):1162-1171.
An objective measurement technique to quantify 3D femoral head shape was developed and applied to normal subjects and patients with cam-type femoroacetabular impingement (FAI). 3D reconstructions were made from high-resolution CT images of 15 cam and 15 control femurs. Femoral heads were fit to ideal geometries consisting of rotational conchoids and spheres. Geometric similarity between native femoral heads and ideal shapes was quantified. The maximum distance native femoral heads protruded above ideal shapes and the protrusion area were measured. Conchoids provided a significantly better fit to native femoral head geometry than spheres for both groups. Cam-type FAI femurs had significantly greater maximum deviations (4.99±0.39 mm and 4.08±0.37 mm) than controls (2.41±0.31 mm and 1.75±0.30 mm) when fit to spheres or conchoids, respectively. The area of native femoral heads protruding above ideal shapes was significantly larger in controls when a lower threshold of 0.1 mm (for spheres) and 0.01 mm (for conchoids) was used to define a protrusion. The 3D measurement technique described herein could supplement measurements of radiographs in the diagnosis of cam-type FAI. Deviations up to 2.5 mm from ideal shapes can be expected in normal femurs while deviations of 4 to 5 mm are characteristic of cam-type FAI.
doi:10.1007/s10439-013-0762-1
PMCID: PMC3640621  PMID: 23413103
cam FAI; femur morphology; asphericity
2.  Pathogenic Influenza Viruses and Coronaviruses Utilize Similar and Contrasting Approaches To Control Interferon-Stimulated Gene Responses 
mBio  2014;5(3):e01174-14.
ABSTRACT
The broad range and diversity of interferon-stimulated genes (ISGs) function to induce an antiviral state within the host, impeding viral pathogenesis. While successful respiratory viruses overcome individual ISG effectors, analysis of the global ISG response and subsequent viral antagonism has yet to be examined. Employing models of the human airway, transcriptomics and proteomics datasets were used to compare ISG response patterns following highly pathogenic H5N1 avian influenza (HPAI) A virus, 2009 pandemic H1N1, severe acute respiratory syndrome coronavirus (SARS-CoV), and Middle East respiratory syndrome CoV (MERS-CoV) infection. The results illustrated distinct approaches utilized by each virus to antagonize the global ISG response. In addition, the data revealed that highly virulent HPAI virus and MERS-CoV induce repressive histone modifications, which downregulate expression of ISG subsets. Notably, influenza A virus NS1 appears to play a central role in this histone-mediated downregulation in highly pathogenic influenza strains. Together, the work demonstrates the existence of unique and common viral strategies for controlling the global ISG response and provides a novel avenue for viral antagonism via altered histone modifications.
IMPORTANCE
This work combines systems biology and experimental validation to identify and confirm strategies used by viruses to control the immune response. Using a novel screening approach, specific comparison between highly pathogenic influenza viruses and coronaviruses revealed similarities and differences in strategies to control the interferon and innate immune response. These findings were subsequently confirmed and explored, revealing both a common pathway of antagonism via type I interferon (IFN) delay as well as a novel avenue for control by altered histone modification. Together, the data highlight how comparative systems biology analysis can be combined with experimental validation to derive novel insights into viral pathogenesis.
doi:10.1128/mBio.01174-14
PMCID: PMC4030454  PMID: 24846384
3.  A New Discrete Element Analysis Method for Predicting Hip Joint Contact Stresses 
Journal of biomechanics  2013;46(6):1121-1127.
Quantifying cartilage contact stress is paramount to understanding hip osteoarthritis. Discrete element analysis (DEA) is a computationally efficient method to estimate cartilage contact stresses. Previous applications of DEA have underestimated cartilage stresses and yielded unrealistic contact patterns because they assumed constant cartilage thickness and/or concentric joint geometry. The study objectives were to: 1) develop a DEA model of the hip joint with subject-specific bone and cartilage geometry, 2) validate the DEA model by comparing DEA predictions to those of a validated finite element analysis (FEA) model, and 3) verify both the DEA and FEA models with a linear-elastic boundary value problem. Springs representing cartilage in the DEA model were given lengths equivalent to the sum of acetabular and femoral cartilage thickness and joint space in the FEA model. Material properties and boundary/loading conditions were equivalent. Walking, descending, and ascending stairs were simulated. Solution times for DEA and FEA models were ~7 seconds and ~65 minutes, respectively. Irregular, complex contact patterns predicted by DEA were in excellent agreement with FEA. DEA contact areas were 7.5%, 9.7% and 3.7% less than FEA for walking, descending stairs, and ascending stairs, respectively. DEA models predicted higher peak contact stresses (9.8–13.6 MPa) and average contact stresses (3.0–3.7 MPa) than FEA (6.2–9.8 and 2.0–2.5 MPa, respectively). DEA overestimated stresses due to the absence of the Poisson’s effect and a direct contact interface between cartilage layers. Nevertheless, DEA predicted realistic contact patterns when subject-specific bone geometry and cartilage thickness were used. This DEA method may have application as an alternative to FEA for pre-operative planning of joint-preserving surgery such as acetabular reorientation during peri-acetabular osteotomy.
doi:10.1016/j.jbiomech.2013.01.012
PMCID: PMC3623562  PMID: 23453394
Hip; cartilage; cartilage mechanics; contact stress; discrete element analysis; finite element analysis; computational modeling
4.  Understanding and preventing wrong-patient electronic orders: a randomized controlled trial 
Objective
To evaluate systems for estimating and preventing wrong-patient electronic orders in computerized physician order entry systems with a two-phase study.
Materials and methods
In phase 1, from May to August 2010, the effectiveness of a ‘retract-and-reorder’ measurement tool was assessed that identified orders placed on a patient, promptly retracted, and then reordered by the same provider on a different patient as a marker for wrong-patient electronic orders. This tool was then used to estimate the frequency of wrong-patient electronic orders in four hospitals in 2009. In phase 2, from December 2010 to June 2011, a three-armed randomized controlled trial was conducted to evaluate the efficacy of two distinct interventions aimed at preventing these errors by reverifying patient identification: an ‘ID-verify alert’, and an ‘ID-reentry function’.
Results
The retract-and-reorder measurement tool effectively identified 170 of 223 events as wrong-patient electronic orders, resulting in a positive predictive value of 76.2% (95% CI 70.6% to 81.9%). Using this tool it was estimated that 5246 electronic orders were placed on wrong patients in 2009. In phase 2, 901 776 ordering sessions among 4028 providers were examined. Compared with control, the ID-verify alert reduced the odds of a retract-and-reorder event (OR 0.84, 95% CI 0.72 to 0.98), but the ID-reentry function reduced the odds by a larger magnitude (OR 0.60, 95% CI 0.50 to 0.71).
Discussion and conclusion
Wrong-patient electronic orders occur frequently with computerized provider order entry systems, and electronic interventions can reduce the risk of these errors occurring.
doi:10.1136/amiajnl-2012-001055
PMCID: PMC3638184  PMID: 22753810
CPOE; hospital medicine; informatics; medical errors; patient safety; quality; quality improvement
5.  Extracellular Matrix Density Regulates the Rate of Neovessel Growth and Branching in Sprouting Angiogenesis 
PLoS ONE  2014;9(1):e85178.
Angiogenesis is regulated by the local microenvironment, including the mechanical interactions between neovessel sprouts and the extracellular matrix (ECM). However, the mechanisms controlling the relationship of mechanical and biophysical properties of the ECM to neovessel growth during sprouting angiogenesis are just beginning to be understood. In this research, we characterized the relationship between matrix density and microvascular topology in an in vitro 3D organ culture model of sprouting angiogenesis. We used these results to design and calibrate a computational growth model to demonstrate how changes in individual neovessel behavior produce the changes in vascular topology that were observed experimentally. Vascularized gels with higher collagen densities produced neovasculatures with shorter vessel lengths, less branch points, and reduced network interconnectivity. The computational model was able to predict these experimental results by scaling the rates of neovessel growth and branching according to local matrix density. As a final demonstration of utility of the modeling framework, we used our growth model to predict several scenarios of practical interest that could not be investigated experimentally using the organ culture model. Increasing the density of the ECM significantly reduced angiogenesis and network formation within a 3D organ culture model of angiogenesis. Increasing the density of the matrix increases the stiffness of the ECM, changing how neovessels are able to deform and remodel their surroundings. The computational framework outlined in this study was capable of predicting this observed experimental behavior by adjusting neovessel growth rate and branching probability according to local ECM density, demonstrating that altering the stiffness of the ECM via increasing matrix density affects neovessel behavior, thereby regulated vascular topology during angiogenesis.
doi:10.1371/journal.pone.0085178
PMCID: PMC3898992  PMID: 24465500
6.  Desmopressin in the treatment of nocturia: clinical evidence and experience 
Therapeutic Advances in Urology  2013;5(6):310-317.
Nocturia is a common and bothersome condition experienced by both men and women. Studies have suggested that nocturia contributes a level of morbidity to those who suffer from the condition, both young and old. Desmopressin has historically been utilized to treat conditions such as central diabetes insipidus, certain bleeding disorders and primary nocturnal enuresis. Recently, interest has increased as to the use of desmopressin (a vasopressin analog) in the treatment of adult nocturia, for whom nocturnal polyuria is prevalent. While desmopressin has been traditionally administered in tablet and bioequivalent high dose melt formulations, newer low-dose orally disintegrating sublingual desmopressin has been recently studied to determine safe and efficacious dosing strategies. In this review, nocturia and its associated morbidities are discussed, followed by a contemporary literature review regarding the safety and efficacy of desmopressin for its treatment.
doi:10.1177/1756287213502116
PMCID: PMC3825109  PMID: 24294289
DDAVP; desmopressin; LUTS; nocturia; nocturnal polyuria
7.  Efficacy and Safety of Flexible Dose Fesoterodine in Men and Women with Overactive Bladder Symptoms Including Nocturnal Urinary Urgency 
The Journal of urology  2012;189(4):1396-1401.
Purpose
Awakening from sleep to urinate is the hallmark of nocturia, a condition that impacts several facets of health related quality of life and for which current therapy is suboptimal. Given the paucity of prospective data on antimuscarinics for the management of nocturia, we investigated the efficacy and safety of flexible dose fesoterodine for the treatment of nocturnal urgency in subjects with nocturia and overactive bladder.
Materials and Methods
Subjects with 2 to 8 nocturnal urgency episodes per 24 hours began a 2-week, single-blind, placebo run-in followed by 1:1 randomization to 12 weeks of double-blind treatment with fesoterodine (4 mg daily for 4 weeks with an optional increase to 8 mg) or placebo using predefined criteria for nocturnal urgency episodes, nocturnal urine volume voided and total 24-hour urine volume voided. The primary end point was change from baseline to week 12 in the mean number of micturition related nocturnal urgency episodes per 24 hours.
Results
Overall 963 subjects were randomized from 2,990 screened, and 82% of subjects treated with fesoterodine and 84% of those treated with placebo completed the study. Significant improvements in the primary end point (−1.28 vs −1.07), in nocturnal micturitions per 24 hours (−1.02 vs −0.85) and in nocturnal frequency urgency sum (−4.01 vs −3.42) were observed with fesoterodine vs placebo (all p ≤0.01). Health related quality of life measures (overactive bladder questionnaire Symptom Bother −20.1 vs −16.5, sleep 22.3 vs 19.9 and other domains; all p <0.05) were improved with fesoterodine.
Conclusions
To our knowledge this is the first prospective study to assess antimuscarinic efficacy for reducing nocturnal urgency. Flexible dose fesoterodine significantly reduced nocturnal urgency episodes vs placebo in subjects with overactive bladder.
doi:10.1016/j.juro.2012.11.067
PMCID: PMC3679189  PMID: 23159276
muscarinic antagonists; urinary bladder; overactive; nocturia; lower urinary tract symptoms; treatment outcome
8.  Finite Element Modelling of the Glenohumeral Capsule Can Help Assess the Tested Region during a Clinical Exam 
The objective of this research was to examine the efficacy of evaluating the region of the glenohumeral capsule being tested by clinical exams for shoulder instability using finite element models of the glenohumeral joint. Specifically, the regions of high capsule strain produced by glenohumeral joint positions commonly used during a clinical exam were identified. Kinematics that simulated a simple translation test with an anterior load at three external rotation angles were applied to a validated, subject-specific finite element model of the glenohumeral joint at 60° of abduction. Maximum principal strains on the glenoid side of the IGHL were significantly higher than the maximum principal strains on the humeral side, for all three regions of the IGHL at 30° and 60° of external rotation. These regions of localized strain indicate that these joint positions might be used to test the glenoid side of the IGHL during this clinical exam, but are not useful for assessing the humeral side of the IGHL. The use of finite element models will facilitate the search for additional joint positions that isolate high strains to other IGHL regions, including the humeral side of the IGHL.
doi:10.1080/10255840903317378
PMCID: PMC3769951  PMID: 20013435
inferior glenohumeral ligament; soft tissue mechanics; strain; finite element
9.  Racial and socioeconomic disparities in the selection of prostate brachytherapy 
Purpose
To utilize the surveillance, epidemiology, and end results database to analyze whether there are racial or socioeconomic disparities associated with the selection of prostate brachytherapy.
Material and methods
We selected patients who were diagnosed with localized prostate cancer between 2004-2006 and who underwent treatment with radiation. Data regarding race and estimates of socioeconomic status were also obtained by analyzing the average reported cost of living adjusted income in the SEER county from which the patient was treated, and dividing these results into quartiles. Multivariate logistic regression analysis was used to determine whether there were any disparities associated with brachytherapy use.
Results
A total of 38 704 patients were included in the analysis. Most patients (57%) received EBRT alone, while the remaining 43% of patients had brachytherapy as a component of their treatment, either alone (30.2%) or in combination with EBRT (12.2%). On multivariate logistic regression, prostate brachytherapy use was less likely in African American patients with an odds ratio of 0.89 (95% CI: 0.84-0.95, p < 0.001), and was more likely to be used in those with higher socioeconomic status. Regarding socioeconomic status, the odds ratio for receiving brachytherapy was 1.65 (95% CI: 1.55-1.75) for the 25-50% quartile, 1.92 (95% CI: 1.81-2.04) for the 50-75% quartile, and 2.05 (95% CI: 1.93-2.18) for the 75-100% quartile, respectively (p < 0.001).
Conclusions
There do appear to be socioeconomic and racial disparities in the selection of prostate brachytherapy. These findings may have both significant equality of care as well as cost of care implications.
doi:10.5114/jcb.2013.37563
PMCID: PMC3797407  PMID: 24143148
brachytherapy; prostate cancer; racial disparities; radiation; socioeconomic disparities
10.  Quantitative Proteomic Analysis of HIV-1 Infected CD4+ T Cells Reveals an Early Host Response in Important Biological Pathways: Protein Synthesis, Cell Proliferation, and T-cell Activation 
Virology  2012;429(1):37-46.
Human immunodeficiency virus (HIV-1) depends upon host-encoded proteins to facilitate its replication while at the same time inhibiting critical components of innate and/or intrinsic immune response pathways. To characterize the host cell response on protein levels in CD4+ lymphoblastoid SUP-T1 cells after infection with HIV-1 strain LAI, we used mass spectrometry (MS)-based global quantitation with iTRAQ (isobaric tag for relative and absolute quantification). We found 266, 60 and 22 proteins differentially expressed (DE) (P-value ≤ 0.05) at 4, 8, and 20 hours post-infection (hpi), respectively, compared to time-matched mock-infected samples. The majority of changes in protein abundance occurred at an early stage of infection well before the de novo production of viral proteins. Functional analyses of these DE proteins showed enrichment in several biological pathways including protein synthesis, cell proliferation, and T-cell activation. Importantly, these early changes before the time of robust viral production have not been described before.
doi:10.1016/j.virol.2012.03.026
PMCID: PMC3358407  PMID: 22542004
Protein quantification; iTRAQ; HIV-1; T-cells; LC-MS/MS; Ribosomal proteins
11.  Finite Element Prediction of Cartilage Contact Stresses in Normal Human Hips 
Journal of Orthopaedic Research  2011;30(7):1133-1139.
Our objectives were to determine cartilage contact stress during walking, stair climbing and descending stairs in a well-defined group of normal volunteers and to assess variations in contact stress and area among subjects and across loading scenarios. Ten volunteers without history of hip pain or disease with normal lateral center-edge angle and acetabular index were selected. Computed tomography imaging with contrast was performed on one hip. Bone and cartilage surfaces were segmented from volumetric image data, and subject-specific finite element models were constructed and analyzed using a validated protocol. Acetabular contact stress and area were determined for seven activities. Peak stress ranged from 7.52±2.11 MPa for heel-strike during walking (233% BW) to 8.66±3.01 MPa for heel-strike during descending stairs (261% BW). Average contact area across all activities was 34% of the surface area of the acetabular cartilage. The distribution of contact stress was highly non-uniform, and more variability occurred among subjects for a given activity than among activities for a single subject. The magnitude and area of contact stress were consistent between activities, although inter-activity shifts in contact pattern were found as the direction of loading changed. Relatively small incongruencies between the femoral and acetabular cartilage had a large effect on the contact stresses. These effects tended to persist across all simulated activities. These results demonstrate the diversity and trends in cartilage contact stress in healthy hips during activities of daily living and provide a basis for future comparisons between normal and pathologic hips.
doi:10.1002/jor.22040
PMCID: PMC3348968  PMID: 22213112
Hip; Finite Element; Biomechanics; Cartilage Contact Stresses; Cartilage Pressure
12.  Sexual Victimization, Health Status, and VA Healthcare Utilization Among Lesbian and Bisexual OEF/OIF Veterans 
Journal of General Internal Medicine  2013;28(Suppl 2):604-608.
ABSTRACT
Background
Many lesbian and bisexual (LB) women veterans may have been targets of victimization in the military based on their gender and presumed sexual orientation, and yet little is known regarding the health or mental health of LB veterans, nor the degree to which they feel comfortable receiving care in the VA.
Objective
The purpose of this study was to examine the prevalence of mental health and gender-specific conditions, VA healthcare satisfaction and trauma exposure among LB veterans receiving VA care compared with heterosexually-identified women veterans receiving.
Design
Prospective cohort study of Operation Enduring Freedom/Operation Iraqi Freedom (OEF/OIF) women veterans at two large VA facilities.
Participants
Three hundred and sixty five women veterans that completed a baseline survey. Thirty-five veterans (9.6 %) identified as gay or lesbian (4.7 %), or bisexual (4.9 %).
Main Measures
Measures included sexual orientation, military sexual trauma, mental and gender-specific health diagnoses, and VA healthcare utilization and satisfaction.
Key Results
LB OEF/OIF veterans were significantly more likely to have experienced both military and childhood sexual trauma than heterosexual women (MST: 31 % vs. 13 %, p < .001; childhood sexual trauma: 60 % vs. 36 %, p = .01), to be hazardous drinkers (32 % vs. 16 %, p = .03) and rate their current mental health as worse than before deployment (35 % vs. 16 %, p < .001).
Conclusions
Many LB veterans have experienced sexual victimization, both within the military and as children, and struggle with substance abuse and poor mental health. Health care providers working with female Veterans should be aware of high rates of military sexual trauma and childhood abuse and refer women to appropriate VA treatment and support groups for sequelae of these experiences. Future research should focus on expanding this study to include a larger and more diverse sample of lesbian, gay, bisexual, and transgender veterans receiving care at VA facilities across the country.
doi:10.1007/s11606-013-2357-9
PMCID: PMC3695265  PMID: 23807072
lesbian; health services research; Veterans; women
13.  ENU Mutagenesis in Mice Identifies Candidate Genes For Hypogonadism 
Mammalian Genome  2012;23(5-6):346-355.
Genome-wide mutagenesis was performed in mice to identify candidate genes for male infertility, for which the predominant causes remain idiopathic. Mice were mutagenized using N-ethyl-N-nitrosourea (ENU), bred, and screened for phenotypes associated with the male urogenital system. Fifteen heritable lines were isolated and chromosomal loci were assigned using low density genome-wide SNP arrays. Ten of the fifteen lines were pursued further using higher resolution SNP analysis to narrow the candidate gene regions. Exon sequencing of candidate genes identified mutations in mice with cystic kidneys (Bicc1), cryptorchidism (Rxfp2), restricted germ cell deficiency (Plk4), and severe germ cell deficiency (Prdm9). In two other lines with severe hypogonadism candidate sequencing failed to identify mutations, suggesting defects in genes with previously undocumented roles in gonadal function. These genomic intervals were sequenced in their entirety and a candidate mutation was identified in SnrpE in one of the two lines. The line harboring the SnrpE variant retains substantial spermatogenesis despite small testis size, an unusual phenotype. In addition to the reproductive defects, heritable phenotypes were observed in mice with ataxia (Myo5a), tremors (Pmp22), growth retardation (unknown gene), and hydrocephalus (unknown gene). These results demonstrate that the ENU screen is an effective tool for identifying potential causes of male infertility.
doi:10.1007/s00335-011-9388-5
PMCID: PMC3358541  PMID: 22258617
14.  Solute Transport Across a Contact Interface in Deformable Porous Media 
Journal of Biomechanics  2012;45(6):1023-1027.
A finite element formulation of neutral solute transport across a contact interface between deformable porous media is implemented and validated against analytical solutions. By reducing the integral statements of external virtual work on the two contacting surfaces into a single contact integral, the algorithm automatically enforces continuity of solute molar flux across the contact interface, whereas continuity of the effective solute concentration (a measure of the solute mechano-chemical potential) is achieved using a penalty method. This novel formulation facilitates the analysis of problems in biomechanics where the transport of metabolites across contact interfaces of deformable tissues may be of interest. This contact algorithm is the first to address solute transport across deformable interfaces, and is made available in the public domain, open-source finite element code FEBio (http://mrl.sci.utah.edu/software).
doi:10.1016/j.jbiomech.2012.01.003
PMCID: PMC3351088  PMID: 22281406
Finite element modeling; contact mechanics; solute transport; porous media; biphasic theory
15.  The non-human primate reference transcriptome resource (NHPRTR) for comparative functional genomics 
Nucleic Acids Research  2012;41(D1):D906-D914.
RNA-based next-generation sequencing (RNA-Seq) provides a tremendous amount of new information regarding gene and transcript structure, expression and regulation. This is particularly true for non-coding RNAs where whole transcriptome analyses have revealed that the much of the genome is transcribed and that many non-coding transcripts have widespread functionality. However, uniform resources for raw, cleaned and processed RNA-Seq data are sparse for most organisms and this is especially true for non-human primates (NHPs). Here, we describe a large-scale RNA-Seq data and analysis infrastructure, the NHP reference transcriptome resource (http://nhprtr.org); it presently hosts data from12 species of primates, to be expanded to 15 species/subspecies spanning great apes, old world monkeys, new world monkeys and prosimians. Data are collected for each species using pools of RNA from comparable tissues. We provide data access in advance of its deposition at NCBI, as well as browsable tracks of alignments against the human genome using the UCSC genome browser. This resource will continue to host additional RNA-Seq data, alignments and assemblies as they are generated over the coming years and provide a key resource for the annotation of NHP genomes as well as informing primate studies on evolution, reproduction, infection, immunity and pharmacology.
doi:10.1093/nar/gks1268
PMCID: PMC3531109  PMID: 23203872
16.  The Capsule’s Contribution to Total Hip Construct Stability – A Finite Element Analysis 
Instability is a significant concern in total hip arthroplasty, particularly when there is structural compromise of the capsule due to pre-existing pathology or due to necessities of surgical approach. An experimentally grounded fiber-direction-based finite element model of the hip capsule was developed, and was integrated with an established three-dimensional model of impingement/dislocation. Model validity was established by close similarity to results from a cadaveric experiment in a servohydraulic hip simulator. Parametric computational runs explored effects of graded levels of capsule thickness, of regional detachment from the capsule’s femoral or acetabular insertions, of surgical incisions of capsule substance, and of capsule defect repairs. Depending strongly upon the specific site, localized capsule defects caused varying degrees of construct stability compromise, with several specific situations involving over 60% decrement in dislocation resistance. Construct stability was returned substantially toward intact-capsule levels following well conceived repairs, although the suture sites involved were often at substantial risk of failure. These parametric model results underscore the importance of retaining or robustly repairing capsular structures in total hip arthroplasty, in order to maximize overall construct stability.
doi:10.1002/jor.21435
PMCID: PMC3160501  PMID: 21495065
Total hip arthroplasty; hip capsule; finite element analysis; suture failure
17.  FINITE ELEMENT IMPLEMENTATION OF MECHANO-CHEMICAL PHENOMENA IN NEUTRAL DEFORMABLE POROUS MEDIA UNDER FINITE DEFORMATION 
Biological soft tissues and cells may be subjected to mechanical as well as chemical (osmotic) loading under their natural physiological environment or various experimental conditions. The interaction of mechanical and chemical effects may be very significant under some of these conditions, yet the highly nonlinear nature of the set of governing equations describing these mechanisms poses a challenge for the modeling of such phenomena. This study formulated and implemented a finite element algorithm for analyzing mechano-chemical events in neutral deformable porous media under finite deformation. The algorithm employed the framework of mixture theory to model the porous permeable solid matrix and interstitial fluid, where the fluid consists of a mixture of solvent and solute. A special emphasis was placed on solute-solid matrix interactions, such as solute exclusion from a fraction of the matrix pore space (solubility) and frictional momentum exchange that produces solute hindrance and pumping under certain dynamic loading conditions. The finite element formulation implemented full coupling of mechanical and chemical effects, providing a framework where material properties and response functions may depend on solid matrix strain as well as solute concentration. The implementation was validated using selected canonical problems for which analytical or alternative numerical solutions exist. This finite element code includes a number of unique features that enhance the modeling of mechano-chemical phenomena in biological tissues. The code is available in the public domain, open source finite element program FEBio (http://mrl.sci.utah.edu/software).
doi:10.1115/1.4004810
PMCID: PMC3431289  PMID: 21950898
18.  Role of the Acetabular Labrum in Load Support Across the Hip Joint 
Journal of biomechanics  2011;44(12):2201-2206.
The relatively high incidence of labral tears among patients presenting with hip pain suggests that the acetabular labrum is often subjected to injurious loading in vivo. However, it is unclear whether the labrum participates in load transfer across the joint during activities of daily living. This study examined the role of the acetabular labrum in load transfer for hips with normal acetabular geometry and acetabular dysplasia using subject-specific finite element analysis. Models were generated from volumetric CT data and analyzed with and without the labrum during activities of daily living. The labrum in the dysplastic model supported 4-11% of the total load transferred across the joint, while the labrum in the normal model supported only 1-2% of the total load. Despite the increased load transferred to the acetabular cartilage in simulations without the labrum, there were minimal differences in cartilage contact stresses. This was because the load supported by the cartilage correlated to the cartilage contact area. A higher percentage of load was transferred to the labrum in the dysplastic model because the femoral head achieved equilibrium near the lateral edge of the acetabulum. The results of this study suggest that the labrum plays a larger role in load transfer and joint stability in hips with acetabular dysplasia than in hips with normal acetabular geometry.
doi:10.1016/j.jbiomech.2011.06.011
PMCID: PMC3225073  PMID: 21757198
acetabular labrum; hip; cartilage mechanics; finite element; dysplasia
19.  Effectiveness of a Cognitive Behavioral Weight Management Intervention in Obese Patients with Psychotic Disorders Compared to Patients with Non-Psychotic Disorders or No Psychiatric Disorders: Results from a 12-month, Real-World Study 
Objective
Studies of behavioral weight loss intervention in psychotic patients are sparse and its efficacy compared to other obese patients is unknown. Therefore, we compared the effect of a cognitive-behavioral weight loss intervention in obese subjects with psychotic disorders, other psychiatric diagnoses and without psychiatric disorders.
Methods
12-month, naturalistic study of weekly group or individual cognitive-behavioral weight management in 222 consecutively enrolled obese patients (body mass index (BMI):43.7±9.6) with psychotic-spectrum disorders (PSD, n=47), other psychiatric disorders (OPD, n=49) and no psychiatric disorder (NPD, n=126).
Results
PSD patients had greater treatment persistence (48.9%) and longer treatment duration (8.7±4.4 months) than OPD (22.4%, 5.4±4.3 months) and NPD (22.2%, 4.9±4.7 months) patients (p’s<.01, number-needed-to-treat (NNT)=3). In last-observation-carried-forward analyses, PSD patients had greater percent baseline weight loss at 12 months (5.1±9.3%) than OPD and NPD patients (2.7±5.5% and 2.4±6.3%); greater percent BMI loss at 9 and 12 months than both groups (p’s<.05), and greater BMI loss at 9 months (2.1±3.5) and 12 months (2.3±4.1) than NPD patients (1.1±2.3 and 1.2±2.4). Furthermore, weight loss ≥5%, occurred in 42.6% of PSD patients vs. 18.4% and 23.0% in OPD and NPD patients (p’s<.01, NNT=5 and 6). The strongest weight loss predictor was treatment duration (β=.51–.54, p<.001). Attrition was predicted by NPD (p=.001) and OPD group status (p=.036), lower proportion of group sessions (p=.002), higher depression (p=.028), and lower baseline BMI (p=0.030).
Conclusions
Psychosis-spectrum disorder patients had greater weight loss than other obese patients. Non-adherence and depression should be targeted to enhance weight loss success.
doi:10.1097/JCP.0b013e31825cccd2
PMCID: PMC3389573  PMID: 22722502
Obesity; Weight Management Program; Weight Loss; Attrition; Psychosis
20.  An Algorithmic Approach to Surgical Decision-making in Acetabular Retroversion 
Orthopedics  2011;34(1):10.
We prospectively collected clinical data during the period 2001–2006 on 60 hips with symptomatic femoroacetabular impingement that had radiographic evidence of acetabular retroversion defined as a crossover sign on an adequate anteroposterior radiograph or retroversion on magnetic resonance imaging or computed tomography. Our treatment algorithm for acetabular retroversion used measurements of acetabular coverage (lateral center edge angle and the posterior wall sign) and condition of acetabular cartilage to direct treatment of acetabular retroversion. The algorithm directed the surgeon to perform a periacetabular-osteotomy (PAO) in 30 hips and in 30 hips a surgical-dislocation and osteochondroplasty (SDO) of the femoral head-neck junction and acetabular rim. HHS and Tönnis radiographic grading were collected preoperatively and at latest followup. The HHS improved from 52 to 90 in the hips treated with SDO and 72 to 91 in the hips treated with PAO, with an overall survivorship of 96% at four years. Patient follow-up averaged 46 months (range 24–75). Elimination of the crossover sign and correction of the posterior wall sign occurred in over 90% of all patients when present. The results indicate that hips with acetabular retroversion, deficient posterior and/or lateral acetabular coverage and intact hyaline cartilage can be effectively treated with acetabular reorientation while retroverted hips with anterior over-coverage but sufficient posterior coverage are effectively treated with osteochondroplasty of the acetabulum and proximal femur.
doi:10.3928/01477447-20101123-07
PMCID: PMC3399593  PMID: 21210626
21.  Correlation between radiographic measures of acetabular morphology with 3D femoral head coverage in patients with acetabular retroversion 
Acta Orthopaedica  2012;83(3):233-239.
Background and purpose
Acetabular retroversion may result in anterior acetabular over-coverage and posterior deficiency. It is unclear how standard radiographic measures of retroversion relate to measurements from 3D models, generated from volumetric CT data. We sought to: (1) compare 2D radiographic measurements between patients with acetabular retroversion and normal control subjects, (2) compare 3D measurements of total and regional femoral head coverage between patients and controls, and (3) quantify relationships between radiographic measurements of acetabular retroversion to total and regional coverage of the femoral head.
Patients and methods
For 16 patients and 18 controls we measured the extrusion index, crossover ratio, acetabular angle, acetabular index, lateral center edge angle, and a new measurement termed the “posterior wall distance”. 3D femoral coverage was determined from volumetric CT data using objectively defined acetabular rim projections, head-neck junctions, and 4 anatomic regions. For radiographic measurements, intra-observer and inter-observer reliabilities were evaluated and associations between 2D radiographic and 3D model-based measures were determined.
Results
Compared to control subjects, patients with acetabular retroversion had a negative posterior wall distance, increased extrusion index, and smaller lateral center edge angle. Differences in the acetabular index between groups approached statistical significance. The acetabular angle was similar between groups. Acetabular retroversion was associated with a slight but statistically significant increase in anterior acetabular coverage, especially in the anterolateral region. Retroverted hips had substantially less posterior coverage, especially in the posterolateral region.
Interpretation
We found that a number of 2D radiographic measures of acetabular morphology were correlated with 3D model-based measures of total and regional femoral head coverage. These correlations may be used to assist in the diagnosis of retroversion and for preoperative planning.
doi:10.3109/17453674.2012.684138
PMCID: PMC3369147  PMID: 22553905
22.  Verification, Validation and Sensitivity Studies in Computational Biomechanics 
Computational techniques and software for the analysis of problems in mechanics have naturally moved from their origins in the traditional engineering disciplines to the study of cell, tissue and organ biomechanics. Increasingly complex models have been developed to describe and predict the mechanical behavior of such biological systems. While the availability of advanced computational tools has led to exciting research advances in the field, the utility of these models is often the subject of criticism due to inadequate model verification and validation. The objective of this review is to present the concepts of verification, validation and sensitivity studies with regard to the construction, analysis and interpretation of models in computational biomechanics. Specific examples from the field are discussed. It is hoped that this review will serve as a guide to the use of verification and validation principles in the field of computational biomechanics, thereby improving the peer acceptance of studies that use computational modeling techniques.
doi:10.1080/10255840601160484
PMCID: PMC3361760  PMID: 17558646
Verification; Validation; Sensitivity Studies; Computational Modeling; Biomechanics; Review
23.  EQUIVALENCE BETWEEN SHORT-TIME BIPHASIC AND INCOMPRESSIBLE ELASTIC MATERIAL RESPONSES 
Porous-permeable tissues have often been modeled using porous media theories such as the biphasic theory. This study examines the equivalence of the short-time biphasic and incompressible elastic responses for arbitrary deformations and constitutive relations from first principles. This equivalence is illustrated in problems of unconfined compression of a disk, and of articular contact under finite deformation, using two different constitutive relations for the solid matrix of cartilage, one of which accounts for the large disparity observed between the tensile and compressive moduli in this tissue. Demonstrating this equivalence under general conditions provides a rationale for using available finite element codes for incompressible elastic materials as a practical substitute for biphasic analyses, so long as only the short-time biphasic response is sought. In practice, an incompressible elastic analysis is representative of a biphasic analysis over the short-term response δt≪Δ2/‖C4‖||K||, where Δ is a characteristic dimension, C4 is the elasticity tensor and K is the hydraulic permeability tensor of the solid matrix. Certain notes of caution are provided with regard to implementation issues, particularly when finite element formulations of incompressible elasticity employ an uncoupled strain energy function consisting of additive deviatoric and volumetric components.
doi:10.1115/1.2720918
PMCID: PMC3312381  PMID: 17536908
24.  Finding Consistent Strain Distributions in the Glenohumeral Capsule Between Two Subjects: Implications for Development of Physical Examinations 
Journal of biomechanics  2010;44(4):607-613.
The anterior-inferior glenohumeral capsule is the primary passive stabilizer to the glenohumeral joint during anterior dislocation. Physical examinations following dislocation are crucial for proper diagnosis of capsule pathology; however, they are not standardized for joint position which may lead to misdiagnoses and poor outcomes. To suggest joint positions for physical examinations where the stability provided by the capsule may be consistent among patients, the objective of this study was to evaluate the distribution of maximum principal strain on the anterior-inferior capsule using two validated subject-specific finite element models of the glenohumeral joint at clinically relevant joint positions. The joint positions with 25 N anterior load applied at 60° of glenohumeral abduction and 10°, 20°, 30° and 40° of external rotation resulted in distributions of strain that were similar between shoulders (r2 ≥ 0.7). Furthermore, those positions with 20° to 40° of external rotation resulted in capsule strains on the glenoid side of the anterior band of the inferior glenohumeral ligament that were significantly greater than in all other capsule regions. These findings suggest that anterior stability provided by the anterior-inferior capsule may be consistent among subjects at joint positions with 60° of glenohumeral abduction and a mid-range (20° to 40°) of external rotation, and that the glenoid side has the greatest contribution to stability at these joint positions. Therefore, it may be possible to establish standard joint positions for physical examinations that clinicians can use to effectively diagnose pathology in the anterior-inferior capsule following dislocation and lead to improved outcomes.
doi:10.1016/j.jbiomech.2010.11.018
PMCID: PMC3042532  PMID: 21144519
shoulder; glenohumeral joint; finite element models; ligament; strain
25.  Finite Element Algorithm for Frictionless Contact of Porous Permeable Media Under Finite Deformation and Sliding 
Background
This study formulates and implements a finite element contact algorithm for solid-fluid (biphasic) mixtures, accommodating both finite deformation and sliding. The finite element source code is made available to the general public.
Methods
The algorithm uses a penalty method regularized with an augmented Lagrangian method to enforce the continuity of contact traction and normal component of fluid flux across the contact interface. The formulation addresses the need to automatically enforce free-draining conditions outside of the contact interface. The formulation addresses the need to automatically enforce free-draining conditions outside of the contact interface.
Results
The accuracy of the implementation is verified using contact problems for which exact solutions are obtained by alternative analyses. Illustrations are also provided that demonstrate large deformations and sliding under configurations relevant to biomechanical applications such as articular contact.
Conclusions
This study addresses an important computational need in the biomechanics of porous-permeable soft tissues. Placing the source code in the public domain provides a useful resource to the biomechanics community.
doi:10.1115/1.4001034
PMCID: PMC2953263  PMID: 20887031

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