Predicting Leg Forces and Knee Moments Using Inertial Measurement Units: An In Vitro Study.

We compared the ability of seven machine learning algorithms to use wearable inertial measurement unit (IMU) data to identify the severe knee loading cycles known to induce microdamage associated with anterior cruciate ligament rupture. Sixteen cadaveric knee specimens, dissected free of skin and muscle, were mounted in a rig simulating standardized jump landings. One IMU was located above and the other below the knee, the applied three-dimensional action and reaction loads were measured via six-axis load cells, and the three-dimensional knee kinematics were also recorded by a laboratory motion capture system. Machine learning algorithms were used to predict the knee moments and the tibial and femur vertical forces; 13 knees were utilized for training each model, while three were used for testing its accuracy (i.e., normalized root-mean-square error) and reliability (Bland-Altman limits of agreement). The results showed the models predicted force and knee moment values with acceptable levels of error and, although several models exhibited some form of bias, acceptable reliability. Further research will be needed to determine whether these types of models can be modified to attenuate the inevitable in vivo soft tissue motion artifact associated with highly dynamic activities like jump landings.

Testing a Quaternion Conversion Method to Determine Human Three-Dimensional Tibiofemoral Angles During an In Vitro Simulated Jump Landing.

Lower limb joint kinematics have been measured in laboratory settings using fixed camera-based motion capture systems; however, recently inertial measurement units (IMUs) have been developed as an alternative. The purpose of this study was to test a quaternion conversion (QC) method for calculating the three orthogonal knee angles during the high velocities associated with a jump landing using commercially available IMUs. Nine cadaveric knee specimens were instrumented with APDM Opal IMUs to measure knee kinematics in one-legged 3-4× bodyweight simulated jump landings, four of which were used in establishing the parameters (training) for the new method and five for validation (testing). We compared the angles obtained from the QC method to those obtained from a commercially available sensor and algorithm (APDM Opal) with those calculated from an active marker motion capture system. Results showed a significant difference between both IMU methods and the motion capture data in the majority of orthogonal angles (p < 0.01), though the differences between the QC method and Certus system in the testing set for flexion and rotation angles were smaller than the APDM Opal algorithm, indicating an improvement. Additionally, in all three directions, both the limits of agreement and root-mean-square error between the QC method and the motion capture system were smaller than between the commercial algorithm and the motion capture.

A Comparison of Inertial Measurement Unit and Motion Capture Measurements of Tibiofemoral Kinematics during Simulated Pivot Landings.

Injuries are often associated with rapid body segment movements. We compared Certus motion capture and APDM inertial measurement unit (IMU) measurements of tibiofemoral angle and angular velocity changes during simulated pivot landings (i.e., ~70 ms peak) of nine cadaver knees dissected free of skin, subcutaneous fat, and muscle. Data from a total of 852 trials were compared using the Bland-Altman limits of agreement (LoAs): the Certus system was considered the gold standard measure for the angle change measurements, whereas the IMU was considered the gold standard for angular velocity changes. The results show that, although the mean peak IMU knee joint angle changes were slightly underestimated (2.1° for flexion, 0.2° for internal rotation, and 3.0° for valgus), the LoAs were large, ranging from 35.9% to 49.8%. In the case of the angular velocity changes, Certus had acceptable accuracy in the sagittal plane, with LoAs of ±54.9°/s and ±32.5°/s for the tibia and femur. For these rapid motions, we conclude that, even in the absence of soft tissues, the IMUs could not reliably measure these peak 3D knee angle changes; Certus measurements of peak tibiofemoral angular velocity changes depended on both the magnitude of the velocity and the plane of measurement.

Experimental test of error-disturbance uncertainty relations by weak measurement.

We experimentally test the error-disturbance uncertainty relation (EDR) in generalized, strength-variable measurement of a single photon polarization qubit, making use of weak measurement that keeps the initial signal state practically unchanged. We demonstrate that the Heisenberg EDR is violated, yet the Ozawa and Branciard EDRs are valid throughout the range of our measurement strength.

Relationship Between Lateral Tibial Posterior Slope and Tibiofemoral Kinematics During Simulated Jump Landings in Male Cadaveric Knees.

Background: It is not known mechanistically whether a steeper lateral posterior tibial slope (LTS) leads to an increase in anterior tibial translation (ATT) as well as internal tibial rotation (ITR) during a given jump landing. Hypothesis: A steeper LTS will result in increased ATT and ITR during simulated jump landings when applying knee compression, flexion, and internal tibial torque of increasing severity. Study Design: Descriptive laboratory study. Methods: Seven pairs of cadaveric knees were harvested from young male adult donors (mean ± SD; age, 25.71 ± 5.53 years; weight, 71.51 ± 4.81 kg). The LTS of each knee was measured by a blinded observer from 3-T magnetic resonance images. Two sets of 25 impact trials of ∼700 N (1× body weight [BW] ±10%) followed by 2 sets of 25 trials of 1400 N (2× BW ±10%) were applied to a randomly selected knee of each pair. Similarly, on the contralateral knee, 2 sets of 25 impact trials of ∼1800 N (2.5× BW ±10%) followed by 2 sets of 25 trials of ∼2100 N (3× BW ±10%) were applied. Three-dimensional knee kinematics, including ATT and ITR, were measured at 400 Hz using optoelectronic motion capture. Two-factor linear mixed effect models were used to determine the relationship of LTS to ATT and ITR as impact loading increased. Results: As LTS increased, so did ATT and ITR during increasingly severe landings. LTS had an increasing effect on ATT (coefficient, 0.50; 95% CI, 0.29-0.71) relative to impact force (coefficient, 0.52; 95% CI, 0.50-0.53). ITR was proportional to LTS (coefficient, 1.36; 95% CI, 0.80-1.93) under increasing impact force (coefficient, 0.49; 95% CI, 0.47-0.52). For steeper LTS, the increase in ITR was proportionally greater than the increase in ATT. Conclusion: In male knee specimens, a steeper LTS significantly increased ATT and ITR during jump landings. Clinical Relevance: Increases in ITR and ATT during jump landings lead to increased strain on the anterior cruciate ligament and are therefore associated with greater risk of ligament failure.

Fatigue-driven compliance increase and collagen unravelling in mechanically tested anterior cruciate ligament.

Approximately 300,000 anterior cruciate ligament (ACL) tears occur annually in the United States, half of which lead to the onset of knee osteoarthritis within 10 years of injury. Repetitive loading is known to result in fatigue damage of both ligament and tendon in the form of collagen unravelling, which can lead to structural failure. However, the relationship between tissue's structural, compositional, and mechanical changes are poorly understood. Herein we show that repetitive submaximal loading of cadaver knees causes an increase in co-localised induction of collagen unravelling and tissue compliance, especially in regions of greater mineralisation at the ACL femoral enthesis. Upon 100 cycles of 4× bodyweight knee loading, the ACL exhibited greater unravelled collagen in highly mineralized regions across varying levels of stiffness domains as compared to unloaded controls. A decrease in the total area of the most rigid domain, and an increase in the total area of the most compliant domain was also found. The results highlight fatigue-driven changes in both protein structure and mechanics in the more mineralized regions of the ACL enthesis, a known site of clinical ACL failure. The results provide a starting point for designing studies to limit ligament overuse injury.

Anterior cruciate ligament microfatigue damage detected by collagen autofluorescence in situ.

PURPOSE: Certain types of repetitive sub-maximal knee loading cause microfatigue damage in the human anterior cruciate ligament (ACL) that can accumulate to produce macroscopic tissue failure. However, monitoring the progression of that ACL microfatigue damage as a function of loading cycles has not been reported. To explore the fatigue process, a confocal laser endomicroscope (CLEM) was employed to capture sub-micron resolution fluorescence images of the tissue in situ. The goal of this study was to quantify the in situ changes in ACL autofluorescence (AF) signal intensity and collagen microstructure as a function of the number of loading cycles. METHODS: Three paired and four single cadaveric knees were subjected to a repeated 4 times bodyweight landing maneuver known to strain the ACL. The paired knees were used to compare the development of ACL microfatigue damage on the loaded knee after 100 consecutive loading cycles, relative to the contralateral unloaded control knee, through second harmonic generation (SHG) and AF imaging using confocal microscopy (CM). The four single knees were used for monitoring progressive ACL microfatigue damage development by AF imaging using CLEM. RESULTS: The loaded knees from each pair exhibited a statistically significant increase in AF signal intensity and decrease in SHG signal intensity as compared to the contralateral control knees. Additionally, the anisotropy of the collagen fibers in the loaded knees increased as indicated by the reduced coherency coefficient. Two out of the four single knee ACLs failed during fatigue loading, and they exhibited an order of magnitude higher increase in autofluorescence intensity per loading cycle as compared to the intact knees. Of the three regions of the ACL - proximal, midsubstance and distal - the proximal region of ACL fibers exhibited the highest AF intensity change and anisotropy of fibers. CONCLUSIONS: CLEM can capture changes in ACL AF and collagen microstructures in situ during and after microfatigue damage development. Results suggest a large increase in AF may occur in the final few cycles immediately prior to or at failure, representing a greater plastic deformation of the tissue. This reinforces the argument that existing microfatigue damage can accumulate to induce bulk mechanical failure in ACL injuries. The variation in fiber organization changes in the ACL regions with application of load is consistent with the known differences in loading distribution at the ACL femoral enthesis.

Nonlocal dispersion cancellation using entangled photons.

A pair of optical pulses traveling through two dispersive media will become broadened and, as a result, the degree of coincidence between the optical pulses will be reduced. For a pair of entangled photons, however, nonlocal dispersion cancellation in which the dispersion experienced by one photon cancels the dispersion experienced by the other photon is possible. In this paper, we report an experimental demonstration of nonlocal dispersion cancellation using entangled photons. The degree of two-photon coincidence is shown to increase beyond the limit attainable without entanglement. Our results have important applications in fiber-based quantum communication and quantum metrology.

An Anterior Cruciate Ligament Failure Mechanism.

BACKGROUND: Nearly three-quarters of anterior cruciate ligament (ACL) injuries occur as "noncontact" failures from routine athletic maneuvers. Recent in vitro studies revealed that repetitive strenuous submaximal knee loading known to especially strain the ACL can lead to its fatigue failure, often at the ACL femoral enthesis. HYPOTHESIS: ACL failure can be caused by accumulated tissue fatigue damage: specifically, chemical and structural evidence of this fatigue process will be found at the femoral enthesis of ACLs from tested cadaveric knees, as well as in ACL explants removed from patients undergoing ACL reconstruction. STUDY DESIGN: Controlled laboratory study. METHODS: One knee from each of 7 pairs of adult cadaveric knees were repetitively loaded under 4 times-body weight simulated pivot landings known to strain the ACL submaximally while the contralateral, unloaded knee was used as a comparison. The chemical and structural changes associated with this repetitive loading were characterized at the ACL femoral enthesis at multiple hierarchical collagen levels by employing atomic force microscopy (AFM), AFM-infrared spectroscopy, molecular targeting with a fluorescently labeled collagen hybridizing peptide, and second harmonic imaging microscopy. Explants from ACL femoral entheses from the injured knee of 5 patients with noncontact ACL failure were also characterized via similar methods. RESULTS: AFM-infrared spectroscopy and collagen hybridizing peptide binding indicate that the characteristic molecular damage was an unraveling of the collagen molecular triple helix. AFM detected disruption of collagen fibrils in the forms of reduced topographical surface thickness and the induction of ~30- to 100-nm voids in the collagen fibril matrix for mechanically tested samples. Second harmonic imaging microscopy detected the induction of ~10- to 100-µm regions where the noncentrosymmetric structure of collagen had been disrupted. These mechanically induced changes, ranging from molecular to microscale disruption of normal collagen structure, represent a previously unreported aspect of tissue fatigue damage in noncontact ACL failure. Confirmatory evidence came from the explants of 5 patients undergoing ACL reconstruction, which exhibited the same pattern of molecular, nanoscale, and microscale structural damage detected in the mechanically tested cadaveric samples. CONCLUSION: The authors found evidence of accumulated damage to collagen fibrils and fibers at the ACL femoral enthesis at the time of surgery for noncontact ACL failure. This tissue damage was similar to that found in donor knees subjected in vitro to repetitive 4 times-body weight impulsive 3-dimensional loading known to cause a fatigue failure of the ACL. CLINICAL RELEVANCE: These findings suggest that some ACL injuries may be due to an exacerbation of preexisting hierarchical tissue damage from activities known to place larger-than-normal loads on the ACL. Too rapid an increase in these activities could cause ACL tissue damage to accumulate across length scales, thereby affecting ACL structural integrity before it has time to repair. Prevention necessitates an understanding of how ACL loading magnitude and frequency are anabolic, neutral, or catabolic to the ligament.

Experimental violation and reformulation of the Heisenberg's error-disturbance uncertainty relation.

The uncertainty principle formulated by Heisenberg in 1927 describes a trade-off between the error of a measurement of one observable and the disturbance caused on another complementary observable such that their product should be no less than the limit set by Planck's constant. However, Ozawa in 1988 showed a model of position measurement that breaks Heisenberg's relation and in 2003 revealed an alternative relation for error and disturbance to be proven universally valid. Here, we report an experimental test of Ozawa's relation for a single-photon polarization qubit, exploiting a more general class of quantum measurements than the class of projective measurements. The test is carried out by linear optical devices and realizes an indirect measurement model that breaks Heisenberg's relation throughout the range of our experimental parameter and yet validates Ozawa's relation.

Systemic immune modulation induced by alcoholic beverage intake in obese-diabetes (db/db) mice.

Alcohol over-consumption is generally immunosuppressive. In this study, the effects of single or repetitive alcohol administration on the systemic immunity of db/db mice were observed to clarify the possible mechanisms for the increased susceptibility of obese individuals to alcohol-related immunological health problems. Alcohol (as a form of commercially available 20% distilled-alcoholic beverage) was orally administered one-time or seven times over 2 weeks to db/db mice and normal C57BL/6J mice. Immunologic alterations were analyzed by observation of body weight and animal activity, along with proportional changes of splenocytes for natural killer cells, macrophages, and T and B lymphocytes. Modulation of plasma cytokine level and immune-related genes were also ascertained by micro-bead assay and a microarray method, respectively. The immune micro-environment of db/db mice was an inflammatory state and adaptive cellular immunity was significantly suppressed. Low-dose alcohol administration reversed the immune response, decreasing inflammatory responses and the increment of adaptive immunity mainly related to CD4(+) T cells, but not CD8(+) T cells, to normal background levels. Systemic immune modulation due to alcohol administration in the obese-diabetic mouse model may be useful in the understanding of the induction mechanism, which will aid the development of therapeutics for related secondary diseases.

Chemotherapeutic candidate inducing immunological death of human tumor cell lines.

The immunological death induction by EY-6 on the human tumor cell lines was screened. Human colon carcinoma (HCT15, HCT116), gastric carcinoma (MKN74, SNU668), and myeloma (KMS20, KMS26, KMS34) cells were died by EY-6 treatment with dose-dependent manner. CRT expression, a typical marker for the immunological death, was increased on the EY-6-treated colorectal and gastric cancer cells. Interestingly, the effects on the myeloma cell lines were complicated showing cell line dependent differential modulation. Cytokine secretion from the EY-6 treated tumor cells were dose and cell-dependent. IFN-γ and IL-12 secretion was increased in the treated cells (200% to over 1000% of non-treated control), except HCT116, SNU668 and KMS26 cells which their secretion was declined by EY-6. Data suggest the potential of EY-6 as a new type of immuno-chemotherapeutics inducing tumor-specific cell death. Further studies are planned to confirm the efficacy of EY-6 including in vivo study.

Cellular Mechanism of Newly Synthesized Indoledione Derivative-induced Immunological Death of Tumor Cell.

BACKGROUND: EY-6 is one of the newly synthesized indoledione derivatives to induce tumor cell-specific cell death. In this study, we investigated the mechanism of immunological death induced by EY-6 at mouse colon cancer cell as well as at the normal immune cell represented by dendritic cell. METHODS: C57BL/6 mouse syngeneic colon cancer cell MC38 was treated with EY-6, and analyzed by MTT for viability test, flow cytometry for confirming surface expressing molecules and ELISA for detection of cytokine secretion. Normal myeloid-dendritic cell (DC) was ex vivo cultured from bone marrow hematopoietic stem cells of C57BL/6 mice with GM-CSF and IL-4 to analyze the DC uptake of dead tumor cells and to observe the effect of EY-6 on the normal DC. RESULTS: EY-6 killed the MC38 tumor cells in a dose dependent manner (25, 50 and 100 µM) with carleticulin induction. And EY-6 induced the secretion of IFN-γ but not of TNF-α from the MC38 tumor cells. EY-6 did not kill the ex-vivo cultured DCs at the dose killing tumor cells and did slightly but not significantly induced the DC maturation. The OVA-specific cross-presentation ability of DC was not induced by chemical treatment (both MHC II and MHC I-restricted antigen presentation). CONCLUSION: Data indicate that the EY-6 induced tumor cell specific and immunological cell death by modulation of tumor cell phenotype and cytokine secretion favoring induction of specific immunity eliminating tumor cells.

Phase I/II study of immunotherapy using autologous tumor lysate-pulsed dendritic cells in patients with metastatic renal cell carcinoma.

This phase I/II study was conducted to evaluate the feasibility, safety and efficacy of immunotherapy using tumor lysate (TL)-pulsed dendritic cells (DC) in patients with metastatic renal cell carcinoma (RCC). DC were generated by culturing peripheral blood mononuclear cells in the presence of GM-CSF and IL-4 and were pulsed with autologous TL and keyhole limpet hemocyanin (KLH). Maturation of DC was induced by a combined treatment of CD40 ligand, IFN and monocyte-conditioned medium. The patients were administered two cycles of TL-pulsed DCs vaccination, each of which comprised of four doses injected subcutaneously at biweekly intervals. Nine patients were included. The immunotherapy was well tolerated without severe side effects. One patient achieved an objective partial response (PR). Five patients showed stable disease (SD), and the remaining three had progressive disease (PD). With a median follow-up of 17.5 months, the median time to progression was 5.2 months and the median overall survival was 29 months. In the antigen-specific lymphocyte proliferation assay, eight patients showed a proliferative response, which tended to be stronger in patients with SD or PR than in patients with PD. The ELISPOT assay was performed in two patients and indicated that one patient with PR showed a much stronger response than another with PD. Our results suggest that TL-pulsed DC immunotherapy in combination with nephrectomy affect the natural course of RCC and are associated with clinical benefits for patients with metastatic diseases.