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1.  Deep Transcriptional Sequencing of Mucosal Challenge Compartment from Rhesus Macaques Acutely Infected with Simian Immunodeficiency Virus Implicates Loss of Cell Adhesion Preceding Immune Activation 
Journal of Virology  2014;88(14):7962-7972.
ABSTRACT
Pathology resulting from human immunodeficiency virus (HIV) infection is driven by protracted inflammation; the primary loss of CD4+ T cells is caused by activation-driven apoptosis. Recent studies of nonhuman primates (NHPs) have suggested that during the acute phase of infection, antiviral mucosal immunity restricts viral replication in the primary infection compartment. These studies imply that HIV achieves systemic infection as a consequence of a failure in host antiviral immunity. Here, we used high-dose intrarectal inoculation of rhesus macaques with simian immunodeficiency virus (SIV) SIVmac251 to examine how the mucosal immune system is overcome by SIV during acute infection. The host response in rectal mucosa was characterized by deep mRNA sequencing (mRNA-seq) at 3 and 12 days postinoculation (dpi) in 4 animals for each time point. While we observed a strong host transcriptional response at 3 dpi, functions relating to antiviral immunity were absent. Instead, we observed a significant number of differentially expressed genes relating to cell adhesion and reorganization of the cytoskeleton. We also observed downregulation of genes encoding members of the claudin family of cell adhesion molecules, which are coexpressed with genes associated with pathology in the colorectal mucosa, and a large number of noncoding transcripts. In contrast, at 12 dpi the differentially expressed genes were enriched in those involved with immune system functions, in particular, functions relating to T cells, B cells, and NK cells. Our findings indicate that host responses that negatively affect mucosal integrity occur before inflammation. Consequently, when inflammation is activated at peak viremia, mucosal integrity is already compromised, potentially enabling rapid tissue damage, driving further inflammation.
IMPORTANCE The HIV pandemic is one of the major threats to human health, causing over a million deaths per year. Recent studies have suggested that mucosal antiviral immune responses play an important role in preventing systemic infection after exposure to the virus. Yet, despite their potential role in decreasing transmission rates between individuals, these antiviral mechanisms are poorly understood. Here, we carried out the first deep mRNA sequencing analysis of mucosal host responses in the primary infection compartment during acute SIV infection. We found that during acute infection, a significant host response was mounted in the mucosa before inflammation was triggered. Our analysis indicated that the response has a detrimental effect on tissue integrity, causing increased permeability, tissue damage, and recruitment of SIV target cells. These results emphasize the importance of mucosal host responses preceding immune activation in preventing systemic SIV infection.
doi:10.1128/JVI.00543-14
PMCID: PMC4097788  PMID: 24807713
2.  Impact of hepatitis C treatment initiation on adherence to concomitant medications 
Our study investigated whether initiating hepatitis C virus (HCV) treatment affected adherence to concomitant medications. Mixed effects linear regression was used to analyze data from 57 patients (29 co-infected with HIV) in a prospective study of HCV treatment-naïve patients initiating HCV treatment. Adherence was assessed using structured self-report at the time of treatment initiation, 12 weeks, and 24 weeks into treatment. There was no change in adherence to concomitant medications over the first 24 weeks of HCV treatment. There was a significant interaction effect such that the change in adherence to concomitant medications between baseline and 12 weeks differed between the HIV-infected and HIV-uninfected patients. Adherence to concomitant medications in the HIV-infected patients was found to decrease, whereas adherence in the HIV-uninfected patients was found to increase. HIV-infected patients may be more at risk for adherence problems in the first 12 weeks of HCV treatment as compared to HIV-uninfected patients.
doi:10.1016/j.jana.2013.07.004
PMCID: PMC3947339  PMID: 24070644
adherence; concomitant medications; HCV; HIV; treatment initiation
3.  Host genetic diversity enables Ebola hemorrhagic fever pathogenesis and resistance 
Science (New York, N.Y.)  2014;346(6212):987-991.
Existing mouse models of lethal Ebola virus infection do not reproduce hallmark symptoms of Ebola hemorrhagic fever, neither delayed blood coagulation and disseminated intravascular coagulation, nor death from shock, thus restricting pathogenesis studies to non-human primates. Here we show that mice from the Collaborative Cross exhibit distinct disease phenotypes following mouse-adapted Ebola virus infection. Phenotypes range from complete resistance to lethal disease to severe hemorrhagic fever characterized by prolonged coagulation times and 100% mortality. Inflammatory signaling was associated with vascular permeability and endothelial activation, and resistance to lethal infection arose by induction of lymphocyte differentiation and cellular adhesion, likely mediated by the susceptibility allele Tek. These data indicate that genetic background determines susceptibility to Ebola hemorrhagic fever.
doi:10.1126/science.1259595
PMCID: PMC4241145  PMID: 25359852
4.  Formation of Microvascular Networks: Role of Stromal Interactions Directing Angiogenic Growth 
In the adult, angiogenesis leads to an expanded microvascular network as new vessel segments are added to an existing microcirculation. Necessarily, growing neovessels must navigate through tissue stroma as they locate and grow toward other vessel elements. We have a growing body of evidence demonstrating that angiogenic neovessels reciprocally interact with the interstitial matrix of the stroma resulting in directed neovascular growth during angiogenesis. Given the compliance and the viscoelastic properties of collagen, neovessel guidance by the stroma is likely due to compressive strain transverse to the direction of primary tensile forces present during active tissue deformation. Similar stromal strains control the final network topology of the new microcirculation, including the distribution of arterioles, capillaries, and venules. In this case, stromal-derived stimuli must be present during the post-angiogenesis remodeling and maturation phases of neovascularization to have this effect. Interestingly, the preexisting organization of vessels prior to the start of angiogenesis has no lasting influence on the final, new network architecture. Combined, the evidence describes interplay between angiogenic neovessels and stroma that is important in directed neovessel growth and invasion. This dynamic is also likely a mechanism by which global tissue forces influence vascular form and function.
doi:10.1111/micc.12115
PMCID: PMC4032604  PMID: 24447042
angiogenesis; stroma; matrix; neovessel; remodeling
5.  Micromechanical Model of a Surrogate for Collagenous Soft Tissues: Development, Validation and Analysis of Mesoscale Size Effects 
Aligned, collagenous tissues such as tendons and ligaments are composed primarily of water and type I collagen, organized hierarchically into nanoscale fibrils, microscale fibers and mesoscale fascicles. Force transfer across scales is complex and poorly understood. Since innervation, the vasculature, damage mechanisms and mechanotransduction occur at the microscale and mesoscale, understanding multiscale interactions is of high importance. This study used a physical model in combination with a computational model to isolate and examine the mechanisms of force transfer between scales. A collagen-based surrogate served as the physical model. The surrogate consisted of extruded collagen fibers embedded within a collagen gel matrix. A micromechanical finite element model of the surrogate was validated using tensile test data that was recorded using a custom tensile testing device mounted on a confocal microscope. Results demonstrated that the experimentally measured macroscale strain was not representative of the microscale strain, which was highly inhomogeneous. The micromechanical model, in combination with a macroscopic continuum model, revealed that the microscale inhomogeneity resulted from size effects in the presence of a constrained boundary. A sensitivity study indicated that significant scale effects would be present over a range of physiologically relevant inter-fiber spacing values and matrix material properties. The results indicate that the traditional continuum assumption is not valid for describing the macroscale behavior of the surrogate, and that boundary-induced size effects are present.
doi:10.1007/s10237-013-0475-2
PMCID: PMC3676693  PMID: 23400805
Collagen; soft tissue; ligament; tendon; composites; biomechanics; finite element method
6.  Neoadjuvant Concurrent Chemoradiation for Curative Treatment of Penile Squamous Cell Carcinoma 
Introduction. Penile cancer is a rare malignancy often treated with neoadjuvant chemotherapy followed by surgery. However, the utility of neoadjuvant chemoradiation, particularly when the tumor is resistant to chemotherapy alone, has not been established. In this study, we report a case of pT3cN3M0 penile squamous cell carcinoma with progression of nodal disease on chemotherapy, which was cured with use of neoadjuvant concurrent chemoradiation. Case Report. A 65-year-old male presented with a fixed left inguinal lymph node with associated firmness of the penile glans. Biopsies of both sites revealed evidence of squamous cell carcinoma. The patient underwent partial penectomy for the primary lesion and began neoadjuvant chemotherapy to reduce the size of the unresectable left inguinal node. However, he displayed disease progression in the left inguinal node. As such, we attempted concurrent chemoradiation therapy with regression of his nodal disease. The patient was able to undergo left inguinal node dissection and has no evidence of disease 18 months since his initial surgery. Conclusion. The use of neoadjuvant chemoradiation for bulky cN2-3 disease seems appropriate in the setting of progressive disease. Further studies are necessary to assess the utility of concurrent chemoradiation both in the neoadjuvant and salvage setting.
doi:10.1155/2014/479376
PMCID: PMC4220572  PMID: 25400960
7.  Effects of Decorin Proteoglycan on Fibrillogenesis, Ultrastructure, and Mechanics of Type I Collagen Gels 
The proteoglycan decorin is known to affect both the fibrillogenesis and the resulting ultrastructure of in vitro polymerized collagen gels. However, little is known about its effects on mechanical properties. In this study, 3D collagen gels were polymerized into tensile test specimens in the presence of decorin proteoglycan, decorin core protein, or dermatan sulfate (DS). Collagen fibrillogenesis, ultrastructure, and mechanical properties were then quantified using a turbidity assay, 2 forms of microscopy (SEM and confocal), and tensile testing. The presence of decorin proteoglycan or core protein decreased the rate and ultimate turbidity during fibrillogenesis and decreased the number of fibril aggregates (fibers) compared to control gels. The addition of decorin and core protein increased the linear modulus by a factor of 2 compared to controls, while the addition of DS reduced the linear modulus by a factor of 3. Adding decorin after fibrillogenesis had no effect, suggesting that decorin must be present during fibrillogenesis to increase the mechanical properties of the resulting gels. These results show that the inclusion of decorin proteoglycan during fibrillogenesis of Type I collagen increases the modulus and tensile strength of resulting collagen gels. The increase in mechanical properties when polymerization occurs in the presence of the decorin proteoglycan is due to a reduction in the aggregation of fibrils into larger order structures such as fibers and fiber bundles.
doi:10.1016/j.matbio.2013.04.004
PMCID: PMC3795835  PMID: 23608680
decorin; collagen; fibrillogenesis; mechanics; ultrastructure
8.  Evaluation of a Post-Processing Approach for Multiscale Analysis of Biphasic Mechanics of Chondrocytes 
Understanding the mechanical behavior of chondrocytes as a result of cartilage tissue mechanics has significant implications for both evaluation of mechanobiological function and to elaborate on damage mechanisms. A common procedure for prediction of chondrocyte mechanics (and of cell mechanics in general) relies on a computational post-processing approach where tissue level deformations drive cell level models. Potential loss of information in this numerical coupling approach may cause erroneous cellular scale results, particularly during multiphysics analysis of cartilage. The goal of this study was to evaluate the capacity of 1st and 2nd order data passing to predict chondrocyte mechanics by analyzing cartilage deformations obtained for varying complexity of loading scenarios. A tissue scale model with a sub-region incorporating representation of chondron size and distribution served as control. The postprocessing approach first required solution of a homogeneous tissue level model, results of which were used to drive a separate cell level model (same characteristics as the subregion of control model). The 1st data passing appeared to be adequate for simplified loading of the cartilage and for a subset of cell deformation metrics, e.g., change in aspect ratio. The 2nd order data passing scheme was more accurate, particularly when asymmetric permeability of the tissue boundaries were considered. Yet, the method exhibited limitations for predictions of instantaneous metrics related to the fluid phase, e.g., mass exchange rate. Nonetheless, employing higher-order data exchange schemes may be necessary to understand the biphasic mechanics of cells under lifelike tissue loading states for the whole time history of the simulation.
doi:10.1080/10255842.2013.809711
PMCID: PMC4157590  PMID: 23809004
multiscale; computational modeling; finite element; cartilage; chondrocyte; poroelastic; biphasic; tissue mechanics; cell mechanics; homogenization
9.  Finite element predictions of cartilage contact mechanics in hips with retroverted acetabula 
BACKGROUND
A contributory factor to hip osteoarthritis (OA) is abnormal cartilage mechanics. Acetabular retroversion, a version deformity of the acetabulum, has been postulated to cause OA via decreased posterior contact area and increased posterior contact stress. Although cartilage mechanics cannot be measured directly in-vivo to evaluate the causes of OA, they can be predicted using finite element (FE) modeling.
OBJECTIVE
The objective of this study was to compare cartilage contact mechanics between hips with normal and retroverted acetabula using subject-specific FE modeling. METHODS: Twenty subjects were recruited and imaged: ten with normal acetabula and ten with retroverted acetabula. FE models were constructed using a validated protocol. Walking, stair ascent, stair descent and rising from a chair were simulated. Acetabular cartilage contact stress and contact area were compared between groups.
RESULTS
Retroverted acetabula had superomedial cartilage contact patterns, while normal acetabula had widely distributed cartilage contact patterns. In the posterolateral acetabulum, average contact stress and contact area during walking and stair descent were 2.6 to 7.6 times larger in normal than retroverted acetabula (p ≤ 0.017). Conversely, in the superomedial acetabulum, peak contact stress during walking was 1.2 to 1.6 times larger in retroverted than normal acetabula (p ≤ 0.044). Further differences varied by region and activity.
CONCLUSIONS
This study demonstrated superomedial contact patterns in retroverted acetabula versus widely distributed contact patterns in normal acetabula. Smaller posterolateral contact stress in retroverted acetabula than in normal acetabula suggests that increased posterior contact stress may not be the link between retroversion and OA.
doi:10.1016/j.joca.2013.06.008
PMCID: PMC3779536  PMID: 23792188
hip; cartilage mechanics; finite element; acetabular retroversion; osteoarthritis
10.  Long-term tolerance and outcomes for dose escalation in early salvage post-prostatectomy radiation therapy 
Radiation Oncology Journal  2014;32(3):179-186.
Purpose
To study the long-term outcomes and tolerance in our patients who received dose escalated radiotherapy in the early salvage post-prostatectomy setting.
Materials and Methods
The medical records of 54 consecutive patients who underwent radical prostatectomy subsequently followed by salvage radiation therapy (SRT) to the prostate bed between 2003-2010 were analyzed. Patients included were required to have a pre-radiation prostate specific antigen level (PSA) of 2 ng/mL or less. The median SRT dose was 70.2 Gy. Biochemical failure after salvage radiation was defined as a PSA level >0.2 ng/mL. Biochemical control and survival endpoints were analyzed using the Kaplan-Meier method. Univariate and multivariate Cox regression analysis were used to identify the potential impact of confounding factors on outcomes.
Results
The median pre-SRT PSA was 0.45 ng/mL and the median follow-up time was 71 months. The 4- and 7-year actuarial biochemical control rates were 75.7% and 63.2%, respectively. The actuarial 4- and 7-year distant metastasis-free survival was 93.7% and 87.0%, respectively, and the actuarial 7-year prostate cancer specific survival was 94.9%. Grade 3 late genitourinary toxicity developed in 14 patients (25.9%), while grade 4 late genitourinary toxicity developed in 2 patients (3.7%). Grade 3 late gastrointestinal toxicity developed in 1 patient (1.9%), and grade 4 late gastrointestinal toxicity developed in 1 patient (1.9%).
Conclusion
In this series with long-term follow-up, early SRT provided outcomes and toxicity profiles similar to those reported from the three major randomized trials studying adjuvant radiation therapy.
doi:10.3857/roj.2014.32.3.179
PMCID: PMC4194301  PMID: 25324990
Dose escalation; Prostate cancer; Radiation therapy; Salvage
11.  Effect of Elastin Digestion on the Quasi-static Tensile Response of Medial Collateral Ligament 
Elastin is a structural protein that provides resilience to biological tissues. We examined the contributions of elastin to the quasi-static tensile response of porcine medial collateral ligament through targeted disruption of the elastin network with pancreatic elastase. Elastase concentration and treatment time were varied to determine a dose response. Whereas elastin content decreased with increasing elastase concentration and treatment time, the change in peak stress after cyclic loading reached a plateau above 1 U/ml elastase and 6 hr treatment. For specimens treated with 2 U/ml elastase for 6 hr, elastin content decreased approximately 35%. Mean peak tissue strain after cyclic loading (4.8%, p≥0.300), modulus (275 MPa, p≥0.114) and hysteresis (20%, p≥0.553) were unaffected by elastase digestion, but stress decreased significantly after treatment (up to 2 MPa, p≤0.049). Elastin degradation had no effect on failure properties, but tissue lengthened under the same pre-stress. Stiffness in the linear region was unaffected by elastase digestion, suggesting that enzyme treatment did not disrupt collagen. These results demonstrate that elastin primarily functions in the toe region of the stress-strain curve, yet contributes load support in the linear region. The increase in length after elastase digestion suggests that elastin may pre-stress and stabilize collagen crimp in ligaments.
doi:10.1002/jor.22352
PMCID: PMC4112956  PMID: 23553827
ligament; elastin; elastase; tensile; quasi-static
12.  Manipulating the Microvasculature and Its Microenvironment 
The microvasculature is a dynamic cellular system necessary for tissue health and function. Therapeutic strategies that target the microvasculature are expanding and evolving, including those promoting angiogenesis and microvascular expansion. When considering how to manipulate angiogenesis, either as part of a tissue construction approach or a therapy to improve tissue blood flow, it is important to know the microenvironmental factors that regulate and direct neovessel sprouting and growth. Much is known concerning both diffusible and matrix-bound angiogenic factors, which stimulate and guide angiogenic activity. How the other aspects of the extravascular microenvironment, including tissue biomechanics and structure, influence new vessel formation is less well known. Recent research, however, is providing new insights into these mechanisms and demonstrating that the extent and character of angiogenesis (and the resulting new microcirculation) is significantly affected. These observations and the resulting implications with respect to tissue construction and microvascular therapy are addressed.
PMCID: PMC4096003  PMID: 24580565
angiogenesis; microvessels; microvascular orientation; microvascular remodeling; microvessel guidance; three-dimensional (3D) vascular constructs; matrix mechanics
13.  A Computational Model of In Vitro Angiogenesis based on Extracellular Matrix Fiber Orientation 
Recent interest in the process of vascularization within the biomedical community has motivated numerous new research efforts focusing on the process of angiogenesis. Although the role of chemical factors during angiogenesis has been well documented, the role of mechanical factors, such as the interaction between angiogenic vessels and the extracellular matrix, remain poorly understood. In vitro methods for studying angiogenesis exist, however measurements available using such techniques often suffer from limited spatial and temporal resolution. For this reason, computational models have been extensively employed to investigate various aspects of angiogenesis. This manuscript outlines the formulation and validation of a simple and robust computational model developed to accurately simulate angiogenesis based on length, branching, and orientation morphometrics collected from vascularized tissue constructs. Excellent agreement was observed between computational and experimental morphometric data over time. Computational predictions of microvessel orientation within an anisotropic matrix correlated well with experimental data. The accuracy of this modeling approach makes it a valuable platform for investigating the role of mechanical interactions during angiogenesis.
doi:10.1080/10255842.2012.662678
PMCID: PMC3459304  PMID: 22515707
Angiogenesis; computational model; tissue engineering; extracellular matrix; fiber orientation; matrix anisotropy
14.  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
15.  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
16.  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
17.  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
18.  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
19.  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
20.  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
21.  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
22.  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
23.  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
24.  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
25.  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

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