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Background Research from the International Cancer Benchmarking Partnership (ICBP) demonstrates that international variation in lung cancer survival persists, particularly within early stage disease. There is a lack of international consensus on the critical contributing components to variation in lung cancer outcomes and the steps needed to optimise lung cancer services. These are needed to improve the quality of options for and equitable access to treatment, and ultimately improve survival. Methods Semi-structured interviews were conducted with 9 key informants from ICBP countries. An international clinical network representing 6 ICBP countries (Australia, Canada, Denmark, England, Ireland, New Zealand, Northern Ireland, Scotland & Wales) was established to share local clinical insights and examples of best practice. Using a modified Delphi consensus model, network members suggested and rated recommendations to optimise the management of lung cancer. Calls to Action were developed via Delphi voting as the most crucial recommendations, with Good Practice Points included to support their implementation. Results Five Calls to Action and thirteen Good Practice Points applicable to high income, comparable countries were developed and achieved 100% consensus. Calls to Action include (1) Implement cost-effective, clinically efficacious, and equitable lung cancer screening initiatives; (2) Ensure diagnosis of lung cancer within 30 days of referral; (3) Develop Thoracic Centres of Excellence; (4) Undertake an international audit of lung cancer care; and (5) Recognise improvements in lung cancer care and outcomes as a priority in cancer policy. Conclusion The recommendations presented are the voice of an expert international lung cancer clinical network, and signpost key considerations for policymakers in countries within the ICBP but also in other comparable high-income countries. These define a roadmap to help align and focus efforts in improving outcomes and management of lung cancer patients globally.

Sexuality is integral to a person's identity and is encompassed in holistic palliative care. Current directives emphasize psychosocial support that is sensitive to a variety of issues, including sexuality, and offer community nurses the mandate to facilitate expressing sexuality. Nurses fail to address sexuality for a variety of reasons. Appreciating patients' individuality and avoiding making assumptions are some of the requirements to enabling expression of sexuality. Nurses need wisdom and determination to discuss such issues, and it is important that they recognize opportunities and cues as they arise. This article provides an examination of the issues surrounding sexuality outlining an approach that captures `constant attention to detail'. This guides the `what', `how' and `why' sexuality in palliative care can be addressed. Ethics and safety aspects are briefly discussed and implications for practice suggested. Educating staff and focused education for the patient can positively influence sexuality and individuals' quality of life. [ABSTRACT FROM AUTHOR]

Many researchers begin their studies without clearly defined concepts. Moyra Ann Baldwin explains why researchers need to consider what it is they're researching using concept analysis before starting work. [ABSTRACT FROM AUTHOR]

Wheelchair locomotion is an important form of mobility for many individuals with spinal cord injury. However, manual wheelchair propulsion can lead to upper-limb pain and can be very inefficient. This has led investigators to apply biomechanics to the study of wheelchair use. The objectives of this study were (1) to determine the frequency content of the motion of both hands during two speeds of wheelchair propulsion, (2) to obtain the filter frequencies necessary to remove noise from wheelchair motion data, and (3) to provide signal-to-noise ratio data for wheelchair kinematics. The participants in this study were a random sample of manual wheelchair users with paraplegia caused by spinal cord injury. Subjects propelled their personal wheelchairs on a computer-controlled dynamometer at speeds of 0.9 m/s and 1.8 m/s. Motion data were collected at 60 Hz with the use of a commercial infrared marker-based system. The main outcome measures were arm motions and noise frequency spectra, filter cutoff frequencies, and signal-to-noise ratio. Our results indicate that there is no useful signal power above 6 Hz during manual wheelchair propulsion at the speeds that we analyzed. In many cases, there was no useful signal power above 4 Hz. This would indicate that the frequency content of manual wheelchair propulsion is similar to that of human gait. The mean signal-to-noise ratio varied from a high of 91 dB to a low of 21.8 dB. The signal-to-noise ratio was greatest in the x direction (along the line of progression) and lowest in the z direction (medial-lateral). Manual wheelchair propulsion kinematic data should be low-pass filtered at approximately 6 Hz for speeds at or below 1.8 m/s. The data presented in the archival literature appear to have been filtered at an appropriate frequency. [ABSTRACT FROM AUTHOR]

Objective: To date, there is limited information about medical student duty hours, shelf scores, and overall clerkship performance in obstetrics and gynecology (OB/GYN). As a result, we were curious to know whether spending more time in the clinical environment translated to an improved learning experience or, in contrast, translated to decreased study time and worse overall clerkship performance., Study Design: A retrospective cohort analysis was performed at a single academic medical center of all medical students on the OB/GYN clerkship from August 2018 to June 2019. Recorded student duty hours were tabulated per day and per week, by student. National Board of Medical Examiners (NBME) Subject Exam (Shelf) equated percentile scores for the quarter of year were used., Results: Our statistical analysis showed that working long hours did not translate to higher or lower shelf score, or higher overall clerkship grade. However, working longer hours in the last 2 weeks of the clerkship was associated with high shelf score., Conclusion: Longer medical student duty hours did not correlate to higher shelf scores or overall clerkship grades. Future multicenter studies are necessary to evaluate the importance of medical student duty hours and continue optimizing the educational experience of the OB/GYN clerkship., Key Points: · Clinical hours were not associated with shelf examination scores.. · Clinical hours were not associated with overall clerkship grade.. · Longer clinical hours at the end of clerkship are correlated with higher examination scores.., Competing Interests: None declared., (Thieme. All rights reserved.)

Variation in body size has important implications for physical performance and fitness. For insects, adult size and morphology are determined by larval growth and metamorphosis. Female blue orchard bees, Osmia lignaria, (Say) provision a finite quantity of food to their offspring. In this study, we asked how provision-dependent variation in size changes adult morphology. We performed a diet manipulation in which some larvae were starved in the final instar and some were given unlimited food. We examined the consequences on adult morphology in two ways. First, allometric relationships between major body regions (head, thorax, abdomen) and total body mass were measured to determine relative growth of these structures. Second, morphometrics that are critical for flight (wing area, wing loading, and extra flight power index) were quantified. Head and thorax mass had hyperallometric relationships with body size, indicating these parts become disproportionately large in adults when larvae are given copious provisions. However, abdominal mass and wing area increased hypoallometrically with body size. Thus, large adults had disproportionately lighter abdomens and smaller wing areas than smaller adults. Though both males and females followed these general patterns, allometric patterns were affected by sex. For flight metrics, small adults had reduced wing loading and an increased extra flight power index. These results suggest that diet quantity alters development in ways that affect the morphometric trait relationships in adult O. lignaria and may lead to functional differences in performance., (© The Author(s) 2021. Published by Oxford University Press on behalf of Entomological Society of America.)

Interactive voice response and text message (IVR-T) technology may improve hypertension control in under-resourced settings. We conducted a randomized clinical trial to determine whether an IVR-T intervention would improve blood pressure (BP), medication adherence and visit keeping among adults with hypertension from multiple racial and ethnic groups in primary care at an Urban Indian Health Organization in Albuquerque, New Mexico. Two hundred and ninety-five participants were randomly assigned to IVR-T (N = 148) or to usual care (N = 147). The IVR-T arm received reminders for clinic visits, messages to reschedule missed clinic visits, monthly medication refill reminders, weekly motivational messages, and a blood pressure cuff. The usual care arm received no messages. The primary outcome was change in systolic BP (SBP) between baseline and 12 months. Secondary outcomes included change in SBP between baseline and 6 months, change in diastolic BP (DBP) at 6 and 12 months, self-reported adherence at 6 months, and the proportion of missed primary care clinic appointments. The intervention did not affect SBP or DBP at 6 or 12 months. The 12-month change in SBP/DBP was 1.66/1.10 mm Hg in usual care and 0.23/1.34 mm Hg in the intervention group (P values = .57 and .88, respectively). Self-reported medication adherence improved comparably in both groups, and there was no difference in percentage of kept visits. Several features of study design, clinic operations, and data transfer were barriers to demonstrating effectiveness., (© 2020 Wiley Periodicals LLC.)

Introduction: We tested the impact of antiepileptic drug (AED) administration on post-cardiac arrest epileptiform electroencephalographic (EEG) activity., Methods: We studied an observational cohort of comatose subjects treated at a single academic medical center after cardiac arrest from September 2010 to January 2018. We aggregated the observed EEG patterns into 5 categories: suppressed; discontinuous background with superimposed epileptiform activity; discontinuous background without epileptiform features; continuous background with epileptiform activity; and continuous background without epileptiform activity. We calculated overall probabilities of transitions between EEG states in a multistate model, then used Aalen's additive regression to test if AEDs or hypothermia are associated with a change in these probabilities., Results: Overall, 828 subjects had EEG-monitoring for 42,840 h with a median of 40 [IQR 23-64] h per subject. Among patients with epileptiform findings on initial monitoring, 50% transitioned at least once to a non-epileptiform, non-suppressed state. By contrast, 19% with non-epileptiform initial activity transitioned to an epileptiform state at least once. Overall, 568 (78%) patients received at least one AED. Among patients with continuous EEG background activity, valproate, levetiracetam and lower body temperature were each associated with an increased probability of transition from epileptiform states to non-epileptiform states, where patients with discontinuous EEG background activity no agent linked to an increased probability of transitioning from epileptiform states., Conclusion: After cardiac arrest, the impact of AEDs may depend on the presence of continuous cortical background activity. These data serve to inform experimental work to better define the opportunities to improve neurologic care post-cardiac arrest., (Copyright © 2019. Published by Elsevier B.V.)

Background: Efficient and effective strategies for treating chronic health conditions such as hypertension are particularly needed for under-resourced clinics such as Urban Indian Health Organizations (UIHOs)., Objective: The objective of the Controlling Blood Pressure Trial is to assess the impact of an interactive voice response and text message (IVR-T) intervention compared with usual care among individuals with hypertension receiving care at a UIHO in Albuquerque, New Mexico. This manuscript presents the baseline characteristics of individuals enrolled in the trial and compares their characteristics with those in the hypertension registry who did not enroll in the trial., Methods: A hypertension registry developed from the clinic's electronic health record was used for recruitment. Potentially eligible participants were contacted by letter and then by phone. Those who expressed interest completed an in-person baseline visit that included a baseline survey and blood pressure measurement using standardized procedures. Individuals randomized to the intervention group could opt to receive either automated text messages or automated phone calls in either English or Spanish. The messages include reminders of upcoming appointments at First Nations Community HealthSource, requests to reschedule recently missed appointments, monthly reminders to refill medications, and weekly motivational messages to encourage self-care, appointment keeping, and medication taking for hypertension. Individuals in the IVR-T arm could opt to nominate a care partner to also receive notices of upcoming and missed appointments. Individuals in the IVR-T arm were also offered a home blood pressure monitor. Follow-up visits will be conducted at 6 months and 12 months., Results: Over a 9.5-month period from April 2017 to January 2018, 295 participants were enrolled from a recruitment list of 1497 individuals. The enrolled cohort had a mean age of 53 years, was 25.1% (74/295) American Indian or Alaska Native and 51.9% (153/295) Hispanic, and 39.0% (115/295) had a baseline blood pressure greater than or equal to 140/90 mmHg. Overall, the differences between those enrolled in the trial and patients with hypertension who were ineligible, those who could not be reached, or those who chose not to enroll were minimal. Enrolled individuals had a slightly lower blood pressure (129/77 mmHg vs 132/79 mmHg; P=.04 for systolic blood pressure and P=.01 for diastolic blood pressure), were more likely to self-pay for their care (26% vs 10%; P<.001), and had a more recent primary care visit (164 days vs 231 days; P<.001). The enrolled cohort reported a high prevalence of poor health, low socioeconomic status, and high levels of basic material needs., Conclusions: The Controlling Blood Pressure Trial has successfully enrolled a representative sample of individuals receiving health care at a UIHO. Trial follow-up will conclude in February 2019., Trial Registration: ClinicalTrials.gov NCT03135405; http://clinicaltrials.gov/ct2/show/NCT03135405 (Archived by WebCite http://www.webcitation.org/76H2B4SO6)., International Registered Report Identifier (irrid): DERR1-10.2196/11794., (©Emily B Schroeder, Kelly Moore, Spero M Manson, Megan A Baldwin, Glenn K Goodrich, Allen S Malone, Lisa E Pieper, Stanley Xu, Meredith M Fort, David Johnson, Linda Son-Stone, John F Steiner. Originally published in JMIR Research Protocols (http://www.researchprotocols.org), 02.04.2019.)

Objectives  Despite the morbidity associated with late preterm and early-term births, there is limited data on pregnant women's perception of neonatal risk based on gestational age (GA). Therefore, our objective was to determine pregnant women's perception of neonatal risks at varying GAs. Method  Through an anonymous 24-question survey, pregnant women were asked to designate the GA at delivery that is desirable, safe, and defined as full term. Responses were compared based on race, history of preterm birth, and medical comorbidities. Results  Among the 233 survey respondents, the majority (62.9%) desired delivery at 36 to 39 weeks' gestation. Black women were more likely to desire delivery at 28 to 35 weeks compared with other racial/ethnic groups ( p  = 0.005). Women with a history of preterm birth or medical complications were less likely to desire delivery at 40 weeks. More than 40% of respondents thought delivery at 8 months of pregnancy was safe and 40.3% responded that 37 weeks' gestation is considered term. Conclusion  Misconceptions surrounding the definition of a term pregnancy are pervasive and vary by race, obstetric history, and medical comorbidities. Our findings highlight the need for patient education about appropriate gestational length, especially in minority and high-risk populations.

Validated computational knee simulations are valuable tools for design phase development of knee replacement devices. Recently, a dynamic finite element (FE) model of the Kansas knee simulator was kinematically validated during gait and deep flexion cycles. In order to operate the computational simulator in the same manner as the experiment, a proportional-integral-derivative (PID) controller was interfaced with the FE model to control the quadriceps actuator excursion and produce a target flexion profile regardless of implant geometry or alignment conditions. The controller was also expanded to operate multiple actuators simultaneously in order to produce in vivo loading conditions at the joint during dynamic activities. Subsequently, the fidelity of the computational model was improved through additional muscle representation and inclusion of relative hip-ankle anterior-posterior (A-P) motion. The PID-controlled model was able to successfully recreate in vivo loading conditions (flexion angle, compressive joint load, medial-lateral load distribution or varus-valgus torque, internal-external torque, A-P force) for deep knee bend, chair rise, stance-phase gait and step-down activities.

Painful patellar crepitus is a potential complication in up to 14% of patients following posterior-stabilized (PS) total knee arthroplasty (TKA). A recent clinical study identified influential patient and surgical variables by comparing a group of crepitus patients with controls matched for age, sex, and body mass index. The purpose of our study was to evaluate effects of variables identified as significant in the clinical study, including patellar ligament length, femoral component flexion, patellar button size, and position of the joint line, on contact between the quadriceps tendon and the PS femoral component. A previously verified finite element model was utilized to estimate tendo-femoral contact during deep flexion activity. Using discrete perturbations, the computational model confirmed the clinical findings in that an increased patellar ligament length, flexed femoral component, lowered joint line, and larger patellar component all reduced potentially deleterious contact near the intercondylar notch. With the selected level of anatomic and component alignment perturbations, the most influential factor affecting tendo-femoral contact was patellar ligament length. Three crepitus patients with matched controls were subsequently modeled, and contact with the anterior border of the notch was present in each crepitus patient, but none of the controls. Alternative surgical alignments for these patients were evaluated to improve the potential long-term outcomes. By characterizing conditions that may lead to painful crepitus, the modeling approach supports clinicians by identifying pre-surgical indicators and important alignment parameters to control intraoperatively., (Copyright © 2012 Orthopaedic Research Society.)

Phosphorylation of estrogen receptor-α (ERα) is critical for its transcription factor activity and may determine its predictive and therapeutic value as a biomarker for ERα-positive breast cancers. Recent attention has turned to the poorly understood ERα hinge domain, as phosphorylation at serine 305 (Ser305) associates with poor clinical outcome and endocrine resistance. We show that phosphorylation of a neighboring hinge domain site, Ser294, analyzed by multiple reaction monitoring mass spectrometry of ERα immunoprecipitates from human breast cancer cells is robustly phosphorylated exclusively by ligand (estradiol and tamoxifen) activation of ERα and not by growth factor stimulation (EGF, insulin, heregulin-β). In a reciprocal fashion, Ser305 phosphorylation is induced by growth factors but not ligand activation of ERα. Phosphorylation at Ser294 and Ser305 is suppressed upon co-stimulation by EGF and ligand, respectively, unlike the N-terminal (AF-1) domain Ser118 and Ser167 sites of ERα where phosphorylation is enhanced by ligand and growth factor co-stimulation. Inhibition of cyclin-dependent kinases (CDK) by roscovitine or SNS-032 suppresses ligand-activated Ser294 phosphorylation without affecting Ser118 or Ser104/Ser106 phosphorylation. Likewise, cell-free studies using recombinant ERα and specific cyclin-CDK complexes suggest that Ser294 phosphorylation is primarily induced by the transcription-regulating and cell-cycle-independent kinase CDK7. Thus, CDK-dependent phosphorylation at Ser294 differentiates ligand-dependent from ligand-independent activation of Ser305 phosphorylation, showing that hinge domain phosphorylation patterns uniquely inform on the various ERα activation mechanisms thought to underlie the biologic and clinical diversity of hormone-dependent breast cancers.

Complications of the patellofemoral (PF) joint remain a common cause for revision of total knee replacements. PF complications, such as patellar maltracking, subluxation, and implant failure, have been linked to femoral and patellar component alignment. In this study, a dynamic finite element model of an implanted PF joint was applied in conjunction with a probabilistic simulation to establish relationships between alignment parameters and PF kinematics, contact mechanics, and internal stresses. Both traditional sensitivity analysis and a coupled probabilistic and principal component analysis approach were applied to characterize relationships between implant alignment and resulting joint mechanics. Critical alignment parameters, and combinations of parameters, affecting PF mechanics were identified for three patellar designs (dome, modified dome, and anatomic). Femoral internal-external (I-E) alignment was identified as a critical alignment factor for all component designs, influencing medial-lateral contact force and anterior-posterior translation. The anatomic design was sensitive to patellar flexion-extension (F-E) alignment, while the dome, as expected, was less influenced by rotational alignment, and more by translational position. The modified dome was sensitive to a combination of superior-inferior, F-E, and I-E alignments. Understanding the relationships and design-specific dependencies between alignment parameters can aid preoperative planning, and help focus instrumentation design on those alignment parameters of primary concern., (Copyright © 2012 Orthopaedic Research Society.)

In vitro pre-clinical testing of total knee replacement (TKR) devices is a necessary step in the evaluation of new implant designs. Whole joint knee simulators, like the Kansas knee simulator (KKS), provide a controlled and repeatable loading environment for comparative evaluation of component designs or surgical alignment under dynamic conditions. Experimental testing, however, is time and cost prohibitive for design-phase evaluation of tens or hundreds of design variations. Experimentally-verified computational models provide an efficient platform for analysis of multiple components, sizes, and alignment conditions. The purpose of the current study was to develop and verify a computational model of a dynamic, whole joint knee simulator. Experimental internal-external and valgus-varus laxity tests, followed by dynamic deep knee bend and gait simulations in the KKS were performed on three cadaveric specimens. Specimen-specific finite element (FE) models of posterior-stabilized TKR were created from magnetic resonance images and CAD geometry. The laxity data was used to optimize mechanical properties of tibiofemoral soft-tissue structures on a specimen-specific basis. Each specimen was subsequently analyzed in a computational model of the experimental KKS, simulating both dynamic activities. The computational model represented all joints and actuators in the experimental setup, including a proportional-integral-derivative (PID) controller to drive quadriceps actuation. The computational model was verified against six degree-of-freedom patellofemoral (PF) and tibiofemoral (TF) kinematics and actuator loading during both deep knee bend and gait activities, with good agreement in trends and magnitudes between model predictions and experimental kinematics; differences were less than 1.8 mm and 2.2° for PF and TF translations and rotations. The whole joint FE simulator described in this study can be applied to investigate a wide range of clinical and research questions., (Copyright © 2011 Elsevier Ltd. All rights reserved.)

Patellofemoral (PF)-related pathologies, including joint laxity, patellar maltracking, cartilage degradation and anterior knee pain, affect nearly 25% of the population. Researchers have investigated the influence of articular geometry on kinematics and contact mechanics in order to gain insight into the etiology of these conditions. The purpose of the current study was to create a three-dimensional statistical shape model of the PF joint and to characterize relationships between PF shape and function (kinematics and contact mechanics). A statistical shape model of the patellar and femoral articular surfaces and their relative alignment was developed from magnetic resonance images. Using 15 shape parameters, the model characterized 97% of the variation in the training set. The first three shape modes primarily described variation in size, patella alta-baja and depth of the sulcus groove. A previously verified finite element model was used to predict kinematics and contact mechanics for each subject. Combining the shape and joint mechanics data, a statistical shape-function model was developed that established quantitative relations of how changes in the shape of the PF joint influence mechanics. The predictive capability of the shape-function model was evaluated by comparing statistical model and finite element predictions, resulting in kinematic root mean square errors of less than 3° and 2.5 mm. The key results of the study are dually in the implementation of a novel approach linking statistical shape and finite element models and the relationships elucidated between PF articular geometry and mechanics., (Copyright © 2011 Elsevier Ltd. All rights reserved.)

Instances of anterior knee pain and patellar fracture are significant complications following total knee replacement (TKR). Bone strain measured in the patella can provide an indication of patellar fracture risk and may also be related to anterior knee pain. The objective of this study was to develop subject-specific finite element models of the patellofemoral (PF) joint including density-mapped material properties to gain insight into the patellar bone strain distribution in the natural and implanted knee. In eight subjects, the volume of bone experiencing strains >0.5% in the implanted condition was ∼200% larger, on average, than the natural condition. An inverse relationship with a correlation of -0.74 was established between postoperative bone volume and strain in the implanted specimens, suggesting that patellar geometry may be a useful indicator of postoperative strain. Comparing strains between regions (superior, inferior, medial, and lateral), it was found that although highly strained bone was evenly distributed between medial and lateral regions in the natural case, the implanted specimens demonstrated significantly larger volumes of highly strained bone medially as a result of substantially lower modulus bone in the medial compartment. Understanding distributions of PF strain may aid in preoperative identification of those patients at risk for patellar fracture or anterior knee pain, guidance regarding altered component placement for at-risk patients, and design of components considering the implications of PF load transfer and patellar strain distribution., (Copyright © 2010 Orthopaedic Research Society.)

Many aspects of biomechanics are variable in nature, including patient geometry, joint mechanics, implant alignment and clinical outcomes. Probabilistic methods have been applied in computational models to predict distributions of performance given uncertain or variable parameters. Sensitivity analysis is commonly used in conjunction with probabilistic methods to identify the parameters that most significantly affect the performance outcome; however, it does not consider coupled relationships for multiple output measures. Principal component analysis (PCA) has been applied to characterize common modes of variation in shape and kinematics. In this study, a novel, combined probabilistic and PCA approach was developed to characterize relationships between multiple input parameters and output measures. To demonstrate the benefits of the approach, it was applied to implanted patellofemoral (PF) mechanics to characterize relationships between femoral and patellar component alignment and loading and the resulting joint mechanics. Prior studies assessing PF sensitivity have performed individual perturbation of alignment parameters. However, the probabilistic and PCA approach enabled a more holistic evaluation of sensitivity, including identification of combinations of alignment parameters that most significantly contributed to kinematic and contact mechanics outcomes throughout the flexion cycle, and the predictive capability to estimate joint mechanics based on alignment conditions without requiring additional analysis. The approach showed comparable results for Monte Carlo sampling with 500 trials and the more efficient Latin Hypercube sampling with 50 trials. The probabilistic and PCA approach has broad applicability to biomechanical analysis and can provide insight into the interdependencies between implant design, alignment and the resulting mechanics., (Copyright © 2010 Elsevier Ltd. All rights reserved.)

Finite element methods have been applied to evaluate in vivo joint behavior, new devices, and surgical techniques but have typically been applied to a small or single subject cohort. Anatomic variability necessitates the use of many subject-specific models or probabilistic methods in order to adequately evaluate a device or procedure for a population. However, a fully deformable finite element model can be computationally expensive, prohibiting large multisubject or probabilistic analyses. The aim of this study was to develop a group of subject-specific models of the patellofemoral joint and evaluate trade-offs in analysis time and accuracy with fully deformable and rigid body articular cartilage representations. Finite element models of eight subjects were used to tune a pressure-overclosure relationship during a simulated deep flexion cycle. Patellofemoral kinematics and contact mechanics were evaluated and compared between a fully deformable and a rigid body analysis. Additional eight subjects were used to determine the validity of the rigid body pressure-overclosure relationship as a subject-independent parameter. There was good agreement in predicted kinematics and contact mechanics between deformable and rigid analyses for both the tuned and test groups. Root mean square differences in kinematics were less than 0.5 deg and 0.2 mm for both groups throughout flexion. Differences in contact area and peak and average contact pressures averaged 5.4%, 9.6%, and 3.8%, respectively, for the tuned group and 6.9%, 13.1%, and 6.4%, respectively, for the test group, with no significant differences between the two groups. There was a 95% reduction in computational time with the rigid body analysis as compared with the deformable analysis. The tuned pressure-overclosure relationship derived from the patellofemoral analysis was also applied to tibiofemoral (TF) articular cartilage in a group of eight subjects. Differences in contact area and peak and average contact pressures averaged 8.3%, 11.2%, and 5.7% between rigid and deformable analyses in the tibiofemoral joint. As statistical, probabilistic, and optimization techniques can require hundreds to thousands of analyses, a viable platform is crucial to component evaluation or clinical applications. The computationally efficient rigid body platform described in this study may be integrated with statistical and probabilistic methods and has potential clinical application in understanding in vivo joint mechanics on a subject-specific or population basis.

Subject-specific finite element models developed from imaging data provide functional representation of anatomical structures and have been used to evaluate healthy and pathologic knee mechanics. The creation of subject-specific models is a time-consuming process when considering manual segmentation and hexahedral (hex) meshing of the articular surfaces to ensure accurate contact assessment. Previous studies have emphasized automated mesh mapping to bone geometry from computed tomography (CT) scans, but have not considered cartilage and soft tissue structures. Statistical shape modeling has been proposed as an alternative approach to develop a population of subject models, but still requires manual segmentation and registration of a training set. Accordingly, the aim of the current study was to develop an efficient, integrated mesh-morphing-based segmentation approach to create hex meshes of subject-specific geometries from scan data, to apply the approach to natural femoral, tibial, and patellar cartilage from magnetic resonance (MR) images, and to demonstrate the creation of a statistical shape model of the knee characterizing the modes of variation using principal component analysis. The platform was demonstrated on MR scans from 10 knees and enabled hex mesh generation of the knee articular structures in approximately 1.5h per subject. In a subset of geometries, average root mean square geometric differences were 0.54 mm for all structures and in quasi-static analyses over a range of flexion angles, differences in predicted peak contact pressures were less than 5.3% between the semi-automated and manually generated models. The integrated segmentation, mesh-morphing approach was employed in the efficient development of subject-specific models and a statistical shape model, where populations of subject-specific models have application to implant design evaluation or surgical planning., (Copyright 2009 Elsevier Ireland Ltd. All rights reserved.)

An approach to the generation of gas phase ions by field extraction from liquid solutions has been investigated. The method uses a polymer membrane with nano-size channels as an interface between the liquid and the atmospheric pressure gas. Ions are produced by dissociation in the polar solvent and secondary ion-molecular reactions in the solution, which fills the channels of the membrane. Field extraction of the ions from the channels is stimulated by pulses of the electric discharge between the membrane and an adjacent electrode in the gas. The gas-phase ions are removed from the extraction zone by air flow and are detected by mass spectrometry. Possibilities of the membrane interface for generation of gas phase ions have been demonstrated from mass spectral investigation curried out for angiotensin II, gramicidin S and cytochrome C solutions. The current kinetics of the membrane ion source has been investigated to elucidate the mechanism of the ion extraction.

Verified and efficient representations of knee ligamentous constraints are essential to forward-dynamic models for prediction of knee mechanics. The objectives of this study were to develop an efficient probabilistic representation of knee ligamentous constraint using the advanced mean value (AMV) probabilistic approach, and to compare the AMV representation with the gold standard Monte Carlo (MC) approach. Specifically, the effects of inherent uncertainty in ligament stiffness, reference strain and attachment site locations on joint constraint were assessed. An explicit finite element model of the knee was evaluated under a series of anterior-posterior (AP) and internal-external (IE) loading at full extension and 90 degrees flexion. Distributions of AP and IE laxity were predicted using experimentally-based levels of ligament parameter variability. Importance factors identified the critical properties affecting the predicted bounds, and agreed with reported ligament recruitment. The AMV method agreed closely with MC results with a four-fold reduction in computation time.

Verified computational models represent an efficient method for studying the relationship between articular geometry, soft-tissue constraint, and patellofemoral (PF) mechanics. The current study was performed to evaluate an explicit finite element (FE) modeling approach for predicting PF kinematics in the natural and implanted knee. Experimental three-dimensional kinematic data were collected on four healthy cadaver specimens in their natural state and after total knee replacement in the Kansas knee simulator during a simulated deep knee bend activity. Specimen-specific FE models were created from medical images and CAD implant geometry, and included soft-tissue structures representing medial-lateral PF ligaments and the quadriceps tendon. Measured quadriceps loads and prescribed tibiofemoral kinematics were used to predict dynamic kinematics of an isolated PF joint between 10 degrees and 110 degrees femoral flexion. Model sensitivity analyses were performed to determine the effect of rigid or deformable patellar representations and perturbed PF ligament mechanical properties (pre-tension and stiffness) on model predictions and computational efficiency. Predicted PF kinematics from the deformable analyses showed average root mean square (RMS) differences for the natural and implanted states of less than 3.1 degrees and 1.7 mm for all rotations and translations. Kinematic predictions with rigid bodies increased average RMS values slightly to 3.7 degrees and 1.9 mm with a five-fold decrease in computational time. Two-fold increases and decreases in PF ligament initial strain and linear stiffness were found to most adversely affect kinematic predictions for flexion, internal-external tilt and inferior-superior translation in both natural and implanted states. The verified models could be used to further investigate the effects of component alignment or soft-tissue variability on natural and implant PF mechanics.

This paper introduces the concept of the dissertation as an experiential method of learning about research. Undertaking a dissertation can be seen as proof of graduateness and the gold standard of undergraduate and postgraduate assessment. The skills demanded in research and concept analysis are compared. The requirements of demonstrating rigour and scholarship in dissertations, usually associated with traditional research methods, are shown to be present in concept analysis. There is a justification for concept analysis as a dissertation research method on the basis that the purpose of research is to expand a body of knowledge through a process of systematic and scientific enquiry. Institutions in which dissertation modules are studied have a responsibility to cultivate a research culture that encourages creativity. The dissertation is an opportunity for students to move away from the security associated with traditional methods of research: to engage with novel and sophisticated methods.

A systematic study of posttranslational modifications of the estrogen receptor isolated from the MCF-7 human breast cancer cell line is reported. Proteolysis with multiple enzymes, mass spectrometry, and tandem mass spectrometry achieved very high sequence coverage for the full-length 66-kDa endogenous protein from estradiol-treated cell cultures. Nine phosphorylated serine residues were identified, three of which were previously unreported and none of which were previously observed by mass spectrometry by any other laboratory. Two additional modified serine residues were identified in recombinant protein, one previously reported but not observed here in endogenous protein and the other previously unknown. Although major emphasis was placed on identifying new phosphorylation sites, N-terminal loss of methionine accompanied by amino acetylation and a lysine side chain acetylation (or possibly trimethylation) were also detected. The use of both HPLC-ESI and MALDI interfaced to different mass analyzers gave higher sequence coverage and identified more sites than could be achieved by either method alone. The estrogen receptor is critical in the development and progression of breast cancer. One previously unreported phosphorylation site identified here was shown to be strongly dependent on estradiol, confirming its potential significance to breast cancer. Greater knowledge of this array of posttranslational modifications of estrogen receptor, particularly phosphorylation, will increase our understanding of the processes that lead to estradiol-induced activation of this protein and may aid the development of therapeutic strategies for management of hormone-dependent breast cancer.

Activated estrogen receptor (ERalpha) plays a critical role in breast cancer development and is a major target for drug treatment. Serine phosphorylation within the N-terminal domain (NTD) contributes to ERalpha activation and may also cause drug resistance. Previous biochemical identification of phosphorylated ERalpha residues was limited to protein artificially overexpressed in transfected cell lines. We report mass spectrometric methods that have allowed the identification of a new site within the NTD of ERalpha isolated from cultured human breast cancer cells. Immunoprecipitation, trypsin digestion, and analysis by nano-LC-ESI-MS/MS (Q-STAR, MDS Sciex) and vMALDI-MS(n) (Finnigan LTQ, Thermo-Electron) identified peptides containing 8 of 14 serine residues within the NTD, one being partially phosphorylated Ser-167, known but not previously reported by MS. Chymotrypsin digestion revealed other known sites at Ser-102/104/106 and 118. Tandem methods developed for the peptide containing Ser-118 and the use of hypothesis-driven experiments--i.e., the assumption that an intact phosphopeptide showing no molecular ion might yield fragment ions including loss of phosphoric acid in vMALDI-MS/MS--allowed the identification of a novel site at Ser-154. Quantitation by selected reaction monitoring demonstrated 6-fold and 2.5-fold increases in Ser-154 phosphorylation in estradiol- and EGF-treated cells, respectively, compared to controls, confirmed by immunoblotting with a novel rabbit polyclonal antibody. Thus, the protein isolation and MS strategies described here can facilitate discovery of novel phosphorylation sites within low abundance, clinically important cancer targets like ERalpha, and may thereby contribute to our understanding of the role of phosphorylation in the development of breast cancer.