A scoping review of portable sensing for out-of-lab anterior cruciate ligament injury prevention and rehabilitation.

Anterior cruciate ligament (ACL) injury and ACL reconstruction (ACLR) surgery are common. Laboratory-based biomechanical assessment can evaluate ACL injury risk and rehabilitation progress after ACLR; however, lab-based measurements are expensive and inaccessible to most people. Portable sensors such as wearables and cameras can be deployed during sporting activities, in clinics, and in patient homes. Although many portable sensing approaches have demonstrated promising results during various assessments related to ACL injury, they have not yet been widely adopted as tools for out-of-lab assessment. The purpose of this review is to summarize research on out-of-lab portable sensing applied to ACL and ACLR and offer our perspectives on new opportunities for future research and development. We identified 49 original research articles on out-of-lab ACL-related assessment; the most common sensing modalities were inertial measurement units, depth cameras, and RGB cameras. The studies combined portable sensors with direct feature extraction, physics-based modeling, or machine learning to estimate a range of biomechanical parameters (e.g., knee kinematics and kinetics) during jump-landing tasks, cutting, squats, and gait. Many of the reviewed studies depict proof-of-concept methods for potential future clinical applications including ACL injury risk screening, injury prevention training, and rehabilitation assessment. By synthesizing these results, we describe important opportunities that exist for clinical validation of existing approaches, using sophisticated modeling techniques, standardization of data collection, and creation of large benchmark datasets. If successful, these advances will enable widespread use of portable-sensing approaches to identify ACL injury risk factors, mitigate high-risk movements prior to injury, and optimize rehabilitation paradigms.

Pre-operative gastrocnemius lengths in gait predict outcomes following gastrocnemius lengthening surgery in children with cerebral palsy.

Equinus deformity is one of the most common gait deformities in children with cerebral palsy. We examined whether estimates of gastrocnemius length in gait could identify limbs likely to have short-term and long-term improvements in ankle kinematics following gastrocnemius lengthening surgery to correct equinus. We retrospectively analyzed data of 891 limbs that underwent a single-event multi-level surgery (SEMLS), and categorized outcomes based on the normalcy of ankle kinematics. Limbs with short gastrocnemius lengths that received a gastrocnemius lengthening surgery as part of a SEMLS (case limbs) were 2.2 times more likely than overtreated limbs (i.e., limbs who did not have short lengths, but still received a lengthening surgery) to have a good surgical outcome at the follow-up gait visit (good outcome rate of 71% vs. 33%). Case limbs were 1.2 times more likely than control limbs (i.e., limbs that had short gastrocnemius lengths but no lengthening surgery) to have a good outcome (71% vs. 59%). Three-fourths of the case limbs with a good outcome at the follow-up gait visit maintained this outcome over time, compared to only one-half of the overtreated limbs. Our results caution against over-prescription of gastrocnemius lengthening surgery and suggest gastrocnemius lengths can be used to identify good surgical candidates.

Medical device surveillance with electronic health records.

Post-market medical device surveillance is a challenge facing manufacturers, regulatory agencies, and health care providers. Electronic health records are valuable sources of real-world evidence for assessing device safety and tracking device-related patient outcomes over time. However, distilling this evidence remains challenging, as information is fractured across clinical notes and structured records. Modern machine learning methods for machine reading promise to unlock increasingly complex information from text, but face barriers due to their reliance on large and expensive hand-labeled training sets. To address these challenges, we developed and validated state-of-the-art deep learning methods that identify patient outcomes from clinical notes without requiring hand-labeled training data. Using hip replacements-one of the most common implantable devices-as a test case, our methods accurately extracted implant details and reports of complications and pain from electronic health records with up to 96.3% precision, 98.5% recall, and 97.4% F1, improved classification performance by 12.8-53.9% over rule-based methods, and detected over six times as many complication events compared to using structured data alone. Using these additional events to assess complication-free survivorship of different implant systems, we found significant variation between implants, including for risk of revision surgery, which could not be detected using coded data alone. Patients with revision surgeries had more hip pain mentions in the post-hip replacement, pre-revision period compared to patients with no evidence of revision surgery (mean hip pain mentions 4.97 vs. 3.23; t = 5.14; p < 0.001). Some implant models were associated with higher or lower rates of hip pain mentions. Our methods complement existing surveillance mechanisms by requiring orders of magnitude less hand-labeled training data, offering a scalable solution for national medical device surveillance using electronic health records.

Learning one's genetic risk changes physiology independent of actual genetic risk.

Millions of people now access personal genetic risk estimates for diseases such as Alzheimer's, cancer and obesity1. While this information can be informative2-4, research on placebo and nocebo effects5-8 suggests that learning of one's genetic risk may evoke physiological changes consistent with the expected risk profile. Here we tested whether merely learning of one's genetic risk for disease alters one's actual risk by making people more likely to exhibit the expected changes in gene-related physiology, behaviour and subjective experience. Individuals were genotyped for actual genetic risk and then randomly assigned to receive either a 'high-risk' or 'protected' genetic test result for obesity via cardiorespiratory exercise capacity (experiment 1, N = 116) or physiological satiety (experiment 2, N = 107) before engaging in a task in which genetic risk was salient. Merely receiving genetic risk information changed individuals' cardiorespiratory physiology, perceived exertion and running endurance during exercise, and changed satiety physiology and perceived fullness after food consumption in a self-fulfilling manner. Effects of perceived genetic risk on outcomes were sometimes greater than the effects associated with actual genetic risk. If simply conveying genetic risk information can alter actual risk, clinicians and ethicists should wrestle with appropriate thresholds for when revealing genetic risk is warranted.

Estimating the effect size of surgery to improve walking in children with cerebral palsy from retrospective observational clinical data.

Single-event multilevel surgery (SEMLS) is a standard treatment approach aimed at improving gait for patients with cerebral palsy, but the effect of this approach compared to natural progression without surgical intervention is unclear. In this study, we used retrospective patient history, physical exam, and three-dimensional gait analysis data from 2,333 limbs to build regression models estimating the effect of SEMLS on gait, while controlling for expected natural progression. Post-hoc classifications using the regression model results identified which limbs would exhibit gait within two standard deviations of typical gait at the follow-up visit with or without a SEMLS with 73% and 77% accuracy, respectively. Using these models, we found that, while surgery was expected to have a positive effect on 93% of limbs compared to natural progression, in only 37% of limbs was this expected effect a clinically meaningful improvement. We identified 26% of the non-surgically treated limbs that may have shown a clinically meaningful improvement in gait had they received surgery. Our models suggest that pre-operative physical therapy focused on improving biomechanical characteristics, such as walking speed and strength, may improve likelihood of positive surgical outcomes. These models are shared with the community to use as an evaluation tool when considering whether or not a patient should undergo a SEMLS.

OpenSim: Simulating musculoskeletal dynamics and neuromuscular control to study human and animal movement.

Movement is fundamental to human and animal life, emerging through interaction of complex neural, muscular, and skeletal systems. Study of movement draws from and contributes to diverse fields, including biology, neuroscience, mechanics, and robotics. OpenSim unites methods from these fields to create fast and accurate simulations of movement, enabling two fundamental tasks. First, the software can calculate variables that are difficult to measure experimentally, such as the forces generated by muscles and the stretch and recoil of tendons during movement. Second, OpenSim can predict novel movements from models of motor control, such as kinematic adaptations of human gait during loaded or inclined walking. Changes in musculoskeletal dynamics following surgery or due to human-device interaction can also be simulated; these simulations have played a vital role in several applications, including the design of implantable mechanical devices to improve human grasping in individuals with paralysis. OpenSim is an extensible and user-friendly software package built on decades of knowledge about computational modeling and simulation of biomechanical systems. OpenSim's design enables computational scientists to create new state-of-the-art software tools and empowers others to use these tools in research and clinical applications. OpenSim supports a large and growing community of biomechanics and rehabilitation researchers, facilitating exchange of models and simulations for reproducing and extending discoveries. Examples, tutorials, documentation, and an active user forum support this community. The OpenSim software is covered by the Apache License 2.0, which permits its use for any purpose including both nonprofit and commercial applications. The source code is freely and anonymously accessible on GitHub, where the community is welcomed to make contributions. Platform-specific installers of OpenSim include a GUI and are available on simtk.org.

Prostaglandin E2 is essential for efficacious skeletal muscle stem-cell function, augmenting regeneration and strength.

Skeletal muscles harbor quiescent muscle-specific stem cells (MuSCs) capable of tissue regeneration throughout life. Muscle injury precipitates a complex inflammatory response in which a multiplicity of cell types, cytokines, and growth factors participate. Here we show that Prostaglandin E2 (PGE2) is an inflammatory cytokine that directly targets MuSCs via the EP4 receptor, leading to MuSC expansion. An acute treatment with PGE2 suffices to robustly augment muscle regeneration by either endogenous or transplanted MuSCs. Loss of PGE2 signaling by specific genetic ablation of the EP4 receptor in MuSCs impairs regeneration, leading to decreased muscle force. Inhibition of PGE2 production through nonsteroidal anti-inflammatory drug (NSAID) administration just after injury similarly hinders regeneration and compromises muscle strength. Mechanistically, the PGE2 EP4 interaction causes MuSC expansion by triggering a cAMP/phosphoCREB pathway that activates the proliferation-inducing transcription factor, Nurr1 Our findings reveal that loss of PGE2 signaling to MuSCs during recovery from injury impedes muscle repair and strength. Through such gain- or loss-of-function experiments, we found that PGE2 signaling acts as a rheostat for muscle stem-cell function. Decreased PGE2 signaling due to NSAIDs or increased PGE2 due to exogenous delivery dictates MuSC function, which determines the outcome of regeneration. The markedly enhanced and accelerated repair of damaged muscles following intramuscular delivery of PGE2 suggests a previously unrecognized indication for this therapeutic agent.

Sanativo Wound Healing Product Does Not Accelerate Reepithelialization in a Mouse Cutaneous Wound Healing Model.

BACKGROUND: Sanativo is an over-the-counter Brazilian product derived from Amazon rainforest plant extract that is purported to improve the healing of skin wounds. Two experimental studies have shown accelerated closure of nonsplinted excisional wounds in rat models. However, these models allow for significant contraction of the wound and do not approximate healing in the tight skin of humans. METHODS: Full-thickness excisional wounds were created on the dorsal skin of mice and were splinted with silicone rings, a model that forces the wound to heal by granulation and reepithelialization. Sanativo or a control solution was applied either daily or every other day to the wounds. Photographs were taken every other day, and the degree of reepithelialization of the wounds was determined. RESULTS: With both daily and every-other-day applications, Sanativo delayed reepithelialization of the wounds. Average time to complete healing was faster with control solution versus Sanativo in the daily application group (9.4 versus 15.2 days; p < 0.0001) and the every-other-day application group (11 versus 13 days; p = 0.017). The size of visible scar at the last time point of the study was not significantly different between the groups, and no differences were found on histologic examination. CONCLUSIONS: Sanativo wound healing compound delayed wound reepithelialization in a mouse splinted excisional wound model that approximates human wound healing. The size of visible scar after complete healing was not improved with the application of Sanativo. These results should cast doubt on claims that this product can improve wound healing in humans.

In Vivo Interrogation of Spinal Mechanosensory Circuits.

Spinal dorsal horn circuits receive, process, and transmit somatosensory information. To understand how specific components of these circuits contribute to behavior, it is critical to be able to directly modulate their activity in unanesthetized in vivo conditions. Here, we develop experimental tools that enable optogenetic control of spinal circuitry in freely moving mice using commonly available materials. We use these tools to examine mechanosensory processing in the spinal cord and observe that optogenetic activation of somatostatin-positive interneurons facilitates both mechanosensory and itch-related behavior, while reversible chemogenetic inhibition of these neurons suppresses mechanosensation. These results extend recent findings regarding the processing of mechanosensory information in the spinal cord and indicate the potential for activity-induced release of the somatostatin neuropeptide to affect processing of itch. The spinal implant approach we describe here is likely to enable a wide range of studies to elucidate spinal circuits underlying pain, touch, itch, and movement.

Optogenetic and chemogenetic strategies for sustained inhibition of pain.

Spatially targeted, genetically-specific strategies for sustained inhibition of nociceptors may help transform pain science and clinical management. Previous optogenetic strategies to inhibit pain have required constant illumination, and chemogenetic approaches in the periphery have not been shown to inhibit pain. Here, we show that the step-function inhibitory channelrhodopsin, SwiChR, can be used to persistently inhibit pain for long periods of time through infrequent transdermally delivered light pulses, reducing required light exposure by >98% and resolving a long-standing limitation in optogenetic inhibition. We demonstrate that the viral expression of the hM4D receptor in small-diameter primary afferent nociceptor enables chemogenetic inhibition of mechanical and thermal nociception thresholds. Finally, we develop optoPAIN, an optogenetic platform to non-invasively assess changes in pain sensitivity, and use this technique to examine pharmacological and chemogenetic inhibition of pain.

Structural foundations of optogenetics: Determinants of channelrhodopsin ion selectivity.

The structure-guided design of chloride-conducting channelrhodopsins has illuminated mechanisms underlying ion selectivity of this remarkable family of light-activated ion channels. The first generation of chloride-conducting channelrhodopsins, guided in part by development of a structure-informed electrostatic model for pore selectivity, included both the introduction of amino acids with positively charged side chains into the ion conduction pathway and the removal of residues hypothesized to support negatively charged binding sites for cations. Engineered channels indeed became chloride selective, reversing near -65 mV and enabling a new kind of optogenetic inhibition; however, these first-generation chloride-conducting channels displayed small photocurrents and were not tested for optogenetic inhibition of behavior. Here we report the validation and further development of the channelrhodopsin pore model via crystal structure-guided engineering of next-generation light-activated chloride channels (iC++) and a bistable variant (SwiChR++) with net photocurrents increased more than 15-fold under physiological conditions, reversal potential further decreased by another ∼ 15 mV, inhibition of spiking faithfully tracking chloride gradients and intrinsic cell properties, strong expression in vivo, and the initial microbial opsin channel-inhibitor-based control of freely moving behavior. We further show that inhibition by light-gated chloride channels is mediated mainly by shunting effects, which exert optogenetic control much more efficiently than the hyperpolarization induced by light-activated chloride pumps. The design and functional features of these next-generation chloride-conducting channelrhodopsins provide both chronic and acute timescale tools for reversible optogenetic inhibition, confirm fundamental predictions of the ion selectivity model, and further elucidate electrostatic and steric structure-function relationships of the light-gated pore.

Rejuvenation of the muscle stem cell population restores strength to injured aged muscles.

The elderly often suffer from progressive muscle weakness and regenerative failure. We demonstrate that muscle regeneration is impaired with aging owing in part to a cell-autonomous functional decline in skeletal muscle stem cells (MuSCs). Two-thirds of MuSCs from aged mice are intrinsically defective relative to MuSCs from young mice, with reduced capacity to repair myofibers and repopulate the stem cell reservoir in vivo following transplantation. This deficiency is correlated with a higher incidence of cells that express senescence markers and is due to elevated activity of the p38α and p38ß mitogen-activated kinase pathway. We show that these limitations cannot be overcome by transplantation into the microenvironment of young recipient muscles. In contrast, subjecting the MuSC population from aged mice to transient inhibition of p38α and p38ß in conjunction with culture on soft hydrogel substrates rapidly expands the residual functional MuSC population from aged mice, rejuvenating its potential for regeneration and serial transplantation as well as strengthening of damaged muscles of aged mice. These findings reveal a synergy between biophysical and biochemical cues that provides a paradigm for a localized autologous muscle stem cell therapy for the elderly.

Virally mediated optogenetic excitation and inhibition of pain in freely moving nontransgenic mice.

Primary nociceptors are the first neurons involved in the complex processing system that regulates normal and pathological pain. Because of constraints on pharmacological and electrical stimulation, noninvasive excitation and inhibition of these neurons in freely moving nontransgenic animals has not been possible. Here we use an optogenetic strategy to bidirectionally control nociceptors of nontransgenic mice. Intrasciatic nerve injection of adeno-associated viruses encoding an excitatory opsin enabled light-inducible stimulation of acute pain, place aversion and optogenetically mediated reductions in withdrawal thresholds to mechanical and thermal stimuli. In contrast, viral delivery of an inhibitory opsin enabled light-inducible inhibition of acute pain perception, and reversed mechanical allodynia and thermal hyperalgesia in a model of neuropathic pain. Light was delivered transdermally, allowing these behaviors to be induced in freely moving animals. This approach may have utility in basic and translational pain research, and enable rapid drug screening and testing of newly engineered opsins.

Optogenetic control of targeted peripheral axons in freely moving animals.

Optogenetic control of the peripheral nervous system (PNS) would enable novel studies of motor control, somatosensory transduction, and pain processing. Such control requires the development of methods to deliver opsins and light to targeted sub-populations of neurons within peripheral nerves. We report here methods to deliver opsins and light to targeted peripheral neurons and robust optogenetic modulation of motor neuron activity in freely moving, non-transgenic mammals. We show that intramuscular injection of adeno-associated virus serotype 6 enables expression of channelrhodopsin (ChR2) in motor neurons innervating the injected muscle. Illumination of nerves containing mixed populations of axons from these targeted neurons and from neurons innervating other muscles produces ChR2-mediated optogenetic activation restricted to the injected muscle. We demonstrate that an implanted optical nerve cuff is well-tolerated, delivers light to the sciatic nerve, and optically stimulates muscle in freely moving rats. These methods can be broadly applied to study PNS disorders and lay the groundwork for future therapeutic application of optogenetics.

Can biomechanical variables predict improvement in crouch gait?

Many patients respond positively to treatments for crouch gait, yet surgical outcomes are inconsistent and unpredictable. In this study, we developed a multivariable regression model to determine if biomechanical variables and other subject characteristics measured during a physical exam and gait analysis can predict which subjects with crouch gait will demonstrate improved knee kinematics on a follow-up gait analysis. We formulated the model and tested its performance by retrospectively analyzing 353 limbs of subjects who walked with crouch gait. The regression model was able to predict which subjects would demonstrate 'Improved' and 'Unimproved' knee kinematics with over 70% accuracy, and was able to explain approximately 49% of the variance in subjects' change in knee flexion between gait analyses. We found that improvement in stance phase knee flexion was positively associated with three variables that were drawn from knowledge about the biomechanical contributors to crouch gait: (i) adequate hamstrings lengths and velocities, possibly achieved via hamstrings lengthening surgery, (ii) normal tibial torsion, possibly achieved via tibial derotation osteotomy, and (iii) sufficient muscle strength.

New MR imaging methods for metallic implants in the knee: artifact correction and clinical impact.

PURPOSE: To evaluate two magnetic resonance imaging (MRI) techniques, slice encoding for metal artifact correction (SEMAC) and multiacquisition variable-resonance image combination (MAVRIC), for their ability to correct for artifacts in postoperative knees with metal. MATERIALS AND METHODS: A total of 25 knees were imaged in this study. Fourteen total knee replacements (TKRs) in volunteers were scanned with SEMAC, MAVRIC, and 2D fast spin-echo (FSE) to measure artifact extent and implant rotation. The ability of the sequences to measure implant rotation and dimensions was compared in a TKR knee model. Eleven patients with a variety of metallic hardware were imaged with SEMAC and FSE to compare artifact extent and subsequent patient management was recorded. RESULTS: SEMAC and MAVRIC significantly reduced artifact extent compared to FSE (P < 0.0001) and were similar to each other (P = 0.58), allowing accurate measurement of implant dimensions and rotation. The TKRs were properly aligned in the volunteers. Clinical imaging with SEMAC in symptomatic knees significantly reduced artifact (P < 0.05) and showed findings that were on the majority confirmed by subsequent noninvasive or invasive patient studies. CONCLUSION: SEMAC and MAVRIC correct for metal artifact, noninvasively providing high-resolution images with superb bone and soft tissue contrast.

Short telomeres and stem cell exhaustion model Duchenne muscular dystrophy in mdx/mTR mice.

In Duchenne muscular dystrophy (DMD), dystrophin mutation leads to progressive lethal skeletal muscle degeneration. For unknown reasons, dystrophin deficiency does not recapitulate DMD in mice (mdx), which have mild skeletal muscle defects and potent regenerative capacity. We postulated that human DMD progression is a consequence of loss of functional muscle stem cells (MuSC), and the mild mouse mdx phenotype results from greater MuSC reserve fueled by longer telomeres. We report that mdx mice lacking the RNA component of telomerase (mdx/mTR) have shortened telomeres in muscle cells and severe muscular dystrophy that progressively worsens with age. Muscle wasting severity parallels a decline in MuSC regenerative capacity and is ameliorated histologically by transplantation of wild-type MuSC. These data show that DMD progression results, in part, from a cell-autonomous failure of MuSC to maintain the damage-repair cycle initiated by dystrophin deficiency. The essential role of MuSC function has therapeutic implications for DMD.

Predicting outcomes of rectus femoris transfer surgery.

Rectus femoris transfer surgery is a common treatment for stiff knee gait in children with cerebral palsy. Unfortunately, the improvement in knee motion after surgery is inconsistent. There is great interest in understanding the causes of stiff knee gait and determining predictors of improved knee motion after surgery. This study demonstrates that it is possible to predict whether or not a patient's knee motion will improve following rectus femoris transfer surgery with greater than 80% accuracy. A predictive model was developed that requires only a few preoperative gait analysis measurements, already collected as a routine part of treatment planning. Our examination of 62 patients before and after rectus femoris transfer revealed that a combination of hip power, knee power, and knee flexion velocity at toe-off correctly predicted postoperative outcome for 80% of cases. With the addition of two more preoperative measurements, hip flexion and internal rotation, prediction accuracy increased to nearly 88%. Other combinations of preoperative gait analysis measurements also predicted outcomes with high accuracy. These results provide insight into factors related to positive outcomes and suggest that predictive models provide a valuable tool for determining indications for rectus femoris transfer.

Mechanisms of improved knee flexion after rectus femoris transfer surgery.

Rectus femoris transfer is frequently performed to treat stiff-knee gait in subjects with cerebral palsy. In this surgery, the distal tendon is released from the patella and re-attached to one of several sites, such as the sartorius or the iliotibial band. Surgical outcomes vary, and the mechanisms by which the surgery improves knee motion are unclear. The purpose of this study was to clarify the mechanism by which the transferred muscle improves knee flexion by examining three types of transfers. Muscle-actuated dynamic simulations were created of ten children diagnosed with cerebral palsy and stiff-knee gait. These simulations were altered to represent surgical transfers of the rectus femoris to the sartorius and the iliotibial band. Rectus femoris transfers in which the muscle remained attached to the underlying vasti through scar tissue were also simulated by reducing but not eliminating the muscle's knee extension moment. Simulated transfer to the sartorius, which converted the rectus femoris' knee extension moment to a flexion moment, produced 32+/-8 degrees improvement in peak knee flexion on average. Simulated transfer to the iliotibial band, which completely eliminated the muscle's knee extension moment, predicted only slightly less improvement in peak knee flexion (28+/-8 degrees ). Scarred transfer simulations, which reduced the muscle's knee extension moment, predicted significantly less (p<0.001) improvement in peak knee flexion (14+/-5 degrees ). Simulations revealed that improved knee flexion following rectus femoris transfer is achieved primarily by reduction of the muscle's knee extension moment. Reduction of scarring of the rectus femoris to underlying muscles has the potential to enhance knee flexion.

Averaging different alignment axes improves femoral rotational alignment in computer-navigated total knee arthroplasty.

BACKGROUND: Computer navigation systems generally establish the rotational alignment axis of the femoral component on the basis of user-defined anatomic landmarks. However, navigation systems can also record knee kinematics and average alignment axes established with multiple techniques. We hypothesized that establishing femoral rotational alignment with the use of kinematic techniques is more accurate and precise (repeatable) than the use of anatomic techniques and that establishing femoral rotational alignment by averaging the results of different alignment techniques is more accurate and precise than the use of a single technique. METHODS: Twelve orthopaedic surgeons used three anatomic and two kinematic alignment techniques to establish femoral rotational alignment axes in a series of nine cadaver knees. The axes derived with the individual anatomic and kinematic techniques as well as the axes derived with six combination techniques--i.e., those involving averaging of the alignments established with two of the individual techniques--were compared against a reference axis established with computed tomography images of each femur. RESULTS: The kinematic methods were not more accurate (did not have smaller mean errors) or more precise (repeatable) than the anatomic techniques. The combination techniques were accurate (five of the six had a mean error of <5 degrees ) and significantly more precise than all but one of the single methods. The percentage of measurements with <5 degrees of error as compared with the reference epicondylar axis was 37% for the individual anatomic techniques, 30% for the individual kinematic techniques, and 58% for the combination techniques. CONCLUSIONS: Averaging the results of kinematic and anatomic techniques, which is possible with computer navigation systems, appears to improve the accuracy of rotational alignment of the femoral component. The number of rotational alignment outliers was reduced when combination techniques were used; however, they are still a problem and continued improvement in methods to accurately establish rotation of the femoral component in total knee arthroplasty is needed.