Utilizing Nonequilibrium Isotope Enrichments to Dramatically Increase Turnover Measurement Ranges in Single Biopsy Samples from Humans.

The synthesis of new proteins and the degradation of old proteins in vivo can be quantified in serial samples using metabolic isotope labeling to measure turnover. Because serial biopsies in humans are impractical, we set out to develop a method to calculate the turnover rates of proteins from single human biopsies. This method involved a new metabolic labeling approach and adjustments to the calculations used in previous work to calculate protein turnover. We demonstrate that using a nonequilibrium isotope enrichment strategy avoids the time dependent bias caused by variable lag in label delivery to different tissues observed in traditional metabolic labeling methods. Turnover rates are consistent for the same subject in biopsies from different labeling periods, and turnover rates calculated in this study are consistent with previously reported values. We also demonstrate that by measuring protein turnover we can determine where proteins are synthesized. In human subjects a significant difference in turnover rates differentiated proteins synthesized in the salivary glands versus those imported from the serum. We also provide a data analysis tool, DeuteRater-H, to calculate protein turnover using this nonequilibrium metabolic 2H2O method.

Hypoxia Prevents Mitochondrial Dysfunction and Senescence in Human c-Kit+ Cardiac Progenitor Cells.

Senescence-associated dysfunction deleteriously affects biological activities of human c-Kit+ cardiac progenitor cells (hCPCs), particularly under conditions of in vitro culture. In comparison, preservation of self-renewal and decreases in mitochondrial reactive oxygen species (ROS) are characteristics of murine CPCs in vivo that reside within hypoxic niches. Recapitulating hypoxic niche oxygen tension conditions of ∼1% O2 in vitro for expansion of hCPCs rather than typical normoxic cell culture conditions (21% O2 ) could provide significant improvement of functional and biological activities of hCPCs. hCPCs were isolated and expanded under permanent hypoxic (hCPC-1%) or normoxic (hCPC-21%) conditions from left ventricular tissue explants collected during left ventricular assist device implantation. hCPC-1% exhibit increased self-renewal and suppression of senescence characteristics relative to hCPC-21%. Oxidative stress contributed to higher susceptibility to apoptosis, as well as decreased mitochondrial function in hCPC-21%. Hypoxia prevented accumulation of dysfunctional mitochondria, supporting higher oxygen consumption rates and mitochondrial membrane potential. Mitochondrial ROS was an upstream mediator of senescence since treatment of hCPC-1% with mitochondrial inhibitor antimycin A recapitulated mitochondrial dysfunction and senescence observed in hCPC-21%. NAD+ /NADH ratio and autophagic flux, which are key factors for mitochondrial function, were higher in hCPC-1%, but hCPC-21% were highly dependent on BNIP3/NIX-mediated mitophagy to maintain mitochondrial function. Overall, results demonstrate that supraphysiological oxygen tension during in vitro expansion initiates a downward spiral of oxidative stress, mitochondrial dysfunction, and cellular energy imbalance culminating in early proliferation arrest of hCPCs. Senescence is inhibited by preventing ROS through hypoxic culture of hCPCs. Stem Cells 2019;37:555-567.

Safety profiling of genetically engineered Pim-1 kinase overexpression for oncogenicity risk in human c-kit+ cardiac interstitial cells.

Advancement of stem cell-based treatment will involve next-generation approaches to enhance therapeutic efficacy which is often modest, particularly in the context of myocardial regenerative therapy. Our group has previously demonstrated the beneficial effect of genetic modification of cardiac stem cells with Pim-1 kinase overexpression to rejuvenate aged cells as well as potentiate myocardial repair. Despite these encouraging findings, concerns were raised regarding potential for oncogenic risk associated with Pim-1 kinase overexpression. Testing of Pim-1 engineered c-kit+ cardiac interstitial cells (cCIC) derived from heart failure patient samples for indices of oncogenic risk was undertaken using multiple assessments including soft agar colony formation, micronucleation, gamma-Histone 2AX foci, and transcriptome profiling. Collectively, findings demonstrate comparable phenotypic and biological properties of cCIC following Pim-1 overexpression compared with using baseline control cells with no evidence for oncogenic phenotype. Using a highly selective and continuous sensor for quantitative assessment of PIM1 kinase activity revealed a sevenfold increase in Pim-1 engineered vs. control cells. Kinase activity profiling using a panel of sensors for other kinases demonstrates elevation of IKKs), AKT/SGK, CDK1-3, p38, and ERK1/2 in addition to Pim-1 consistent with heightened kinase activity correlating with Pim-1 overexpression that may contribute to Pim-1-mediated effects. Enhancement of cellular survival, proliferation, and other beneficial properties to augment stem cell-mediated repair without oncogenic risk is a feasible, logical, and safe approach to improve efficacy and overcome current limitations inherent to cellular adoptive transfer therapeutic interventions.

Healthcare Resource Use and Cost Implications in the MOMENTUM 3 Long-Term Outcome Study.

BACKGROUND: The MOMENTUM 3 trial compares the centrifugal HeartMate 3 (HM3) with the axial HeartMate II (HMII) continuous-flow left ventricular assist system in patients with advanced heart failure, irrespective of the intended goal of therapy. The trial's 2-year clinical outcome (n=366) demonstrated superiority of the HM3 for the primary end point (survival free of a disabling stroke or reoperation to replace or remove a malfunctioning pump). This analysis evaluates health resource use and cost implications of the observed differences between the 2 devices while patients were enrolled in the trial. METHODS: We analyzed all hospitalizations and their associated costs occurring after discharge from the implant hospitalization until censoring (study withdrawal, heart transplantation, and pump exchange with a nonstudy device or death). Each adjudicated episode of hospital-based care was used to calculate costs (device-attributable and non-device-attributable event costs), estimated by using trial data and payer administrative claims databases. Cost savings stratified by subgroups (study outcome [transplant, death, or ongoing on device], intended goal of therapy, type of insurance, or sex) were also assessed. RESULTS: In 366 randomly assigned patients, 361 comprised the as-treated group (189 in the HM3 group and 172 in the HMII group), of whom 337 (177 in the HM3 group and 160 in the HMII group) were successfully discharged following implantation. The HM3 arm experienced fewer total hospitalizations per patient-year (HM3: 2.1±0.2 versus HMII: 2.7±0.2; P=0.015) and 8.3 fewer hospital days per patient-year on average (HM3: 17.1 days versus HMII: 25.5 days; P=0.003). These differences were driven by patients hospitalized for suspected pump thrombosis (HM3: 0.6% versus HMII: 12.5%; P<0.001) and stroke (HM3: 2.8% versus HMII: 11.3%; P=0.002). Controlled for time spent in the study (average cumulative cost per patient-year), postdischarge HM3 arm costs were 51% lower than with the HMII (HM3: $37 685±4251 versus HMII: $76 599±11 889, P<0.001) and similar in either bridge to transplant or destination therapy intent. CONCLUSIONS: In this 2-year outcome economic analysis of the MOMENTUM 3 trial, the HM3 demonstrated a reduction in rehospitalizations, hospital days spent during rehospitalizations, and a significant cost savings following discharge in comparison with the HMII left ventricular assist system, irrespective of the intended goal of therapy. CLINICAL TRIAL REGISTRATION: URL: https://www.clinicaltrials.gov . Unique identifier: NCT02224755.

Emergency Physician-Initiated Resuscitative Extracorporeal Membrane Oxygenation.

BACKGROUND: Extracorporeal membrane oxygenation (ECMO) has several applications as a resuscitative intervention, including extracorporeal cardiopulmonary resuscitation (ECPR). ECPR is rarely initiated in the emergency department (ED) by emergency physicians outside regional academic institutions. OBJECTIVES: To evaluate whether ECPR improves clinical outcomes after cardiac arrest when initiated by emergency physicians (EPs) in a nonacademic hospital. METHODS AND MATERIALS: We performed a retrospective analysis of prospectively identified consecutive EP-initiated ECMO subjects from a single community hospital over a 7-year period. Logistic regression and propensity models tested the association between ECPR and survival to hospital discharge compared with concurrent ECPR-eligible control subjects. RESULTS: Over 7 years (2010-2017), EPs initiated ECMO on 58 subjects; 44 (76%) were venoarterial cases (43 ECPR) initiated in the ED. Of those, 11 (25%) survived to discharge (n = 9 with cerebral performance category score 1) and most were still alive after 5 years (66%). Adjusting for known covariates, ECPR subjects were more likely than concurrent controls to survive to discharge (odds ratio 8.4; 95% confidence interval 1.2-60.4). Propensity analysis revealed a favorable trend toward survival to discharge after ECPR (odds ratio 2.0; 95% confidence interval 0.51-7.8). CONCLUSIONS: Emergency physicians initiated ECMO with promising clinical outcomes. Prospective trials are needed to define the efficacy, safety, and cost-effectiveness of EP-initiated ECMO.

Female Human Spines with Simulated Osteolytic Defects: CT-based Structural Analysis of Vertebral Body Strength.

Purpose To evaluate a CT structural analysis protocol (SAP) for estimating the strength of human female cadaveric spines with lytic lesions. Materials and Methods Osteolytic foci was created in the middle vertebra of 44 thoracic and lumbar three-level segments from 11 female cadavers (age range, 50-70 years). The segments underwent CT by using standard clinical protocol and their failure strength was assessed at CT SAP. The spines were mechanically tested to failure in pure axial compression or in compression with torsion. The relationships of defect size, bone mineral density, and predicted failure load (at CT SAP) with measured vertebral strength were assessed with linear regression. Analysis of variance and Tukey test were used to evaluate the effect of region and mechanical test on spine strength. Results With axial compression, CT SAP predictions of vertebral strength correlated with the thoracic (r = 0.84; P < .001) and lumbar (r = 0.85; P < .001) segment-measured strength. Bone mineral density correlated with the lumbar (r = 0.64; P = .003) and thoracic (r, 0.51; P = .050) strength. At compression with torsion, CT SAP predictions of strength were moderately correlated with vertebral strength (r = 0.66; P = .018). At compression with torsion, bone mineral density was not correlated with spinal strength (thoracic and lumbar: r = 0.31 and r = 0.26, respectively; P = .539 and .610, respectively). The lytic focus size (range, 28%-41%) was not associated with vertebral strength. Conclusion CT SAP assessment of strength in vertebrae with lytic lesions correlated with the measured strength of female vertebral bodies. © RSNA, 2018 Online supplemental material is available for this article.

Thermoacoustic Lensing in Ultrasound Imaging of Nonechogenic Tissue During High-intensity Focused Ultrasound Exposure.

We develop a ray-tracing theory to describe the effects of thermoacoustic lensing during high-intensity focused ultrasound (HIFU) on ultrasound images of reflectors lying distal to the HIFU focal region and discuss the application of thermal lensing effects to dose monitoring in HIFU therapy. By analyzing the effects of thermal and geometric delays of acoustic rays passing through a region of tissue undergoing localized heating, we show how the shape of a reflector distal to the heated region can be predicted and present experimental measurements in good agreement with the model. We also apply the model in reverse to estimate the thermal profile of a heated region based on a measured change in the shape of a distal reflector during HIFU delivery. As an example, we apply this technique to the measurements of thermal diffusion in porcine fat. An interesting aspect of the technique is that it can be applied to measure temperature in nonechogenic tissues as long as there is an observable reflector in the ultrasound images that is located distal to the region of localized heating.

In vivo measurement of basilar membrane vibration in the unopened chinchilla cochlea using high frequency ultrasound.

The basilar membrane and organ of Corti in the cochlea are essential for sound detection and frequency discrimination in normal hearing. There are currently no methods used for real-time high resolution clinical imaging or vibrometry of these structures. The ability to perform such imaging could aid in the diagnosis of some pathologies and advance understanding of the causes. It is demonstrated that high frequency ultrasound can be used to measure basilar membrane vibrations through the round window of chinchilla cochleas in vivo. The basic vibration characteristics of the basilar membrane agree with previous studies that used other methods, although as expected, the sensitivity of ultrasound was not as high as optical methods. At the best frequency for the recording location, the average vibration velocity amplitude was about 4 mm/s/Pa with stimulus intensity of 50 dB sound pressure level. The displacement noise floor was about 0.4 nm with 256 trial averages (5.12 ms per trial). Although vibration signals were observed, which likely originated from the organ of Corti, the spatial resolution was not adequate to resolve any of the sub-structures. Improvements to the ultrasound probe design may improve resolution and allow the responses of these different structures to be better discriminated.

Principles of HeartMate II implantation to avoid pump malposition and migration.

Proper left ventricular assist device (LVAD) insertion will help maximize LVAD flow and may reduce adverse events such as right heart failure and pump thrombosis. Although no standardized insertion technique has been universally accepted, the goals are: unobstructed inflow cannula, unobstructed outflow graft with avoidance of right ventricular compression, and prevention of pump migration. To achieve these objectives for the HeartMate II LVAD, we delineate four principles: proper pump pocket creation, optimized positioning of inflow cannula and outflow graft, proper pump position in the body, and fixation. These basic principles are easy to implement and have been beneficial in our patients, assuring long-term unobstructed LVAD flow.

Factors Related to Pump Thrombosis With the Heartmate II Left Ventricular Assist Device.

BACKGROUND: Recent reports suggested that HeartMate II (HMII) thrombosis rates may be higher in implants after 2011. We characterize events at HMII centers (>100 HMII implants) whose device thrombosis rates are equivalent or lower than reported by INTERMACS. METHODS: Seven centers pooled implants from 2011 through June 2013 to examine pump thrombus and identify characteristics and clinical strategies that potentially mitigate the risk. A total of 666 patients (age 59 ± 13 years; 81% male) were studied (support duration: 13.7 ± 8.3 months, cumulative: 759 patient years). Median target INR was 2.25 (range 2.0 to 2.5), and median pump speed was 9200 rpm (range 8600 to 9600). Pump thrombus was suspected with clinical evidence (e.g., hemolysis, positive ramp test) requiring intervention (e.g., anticoagulation therapy, pump exchange) or patient death. RESULTS: Suspected pump thrombus occurred in 24/666 (3.6%) patients within three months of implant. At six months, 38/666 (5.7%) had suspected pump thrombus including 24 (3.6%) resulting in pump exchange or death. Stroke (hemorrhagic: 0.049, and ischemic: 0.048 events/patient year) and survival (six months: 88 ± 1%; 1 year: 81 ± 2%) were consistent with national averages. Suspected pump thrombus patients were younger (55 ± 13 vs. 59 ± 13, p = 0.046) and had more females (31.6% vs. 18.3%, p = 0.054). There was no difference in indication, etiology of heart failure, or body size. CONCLUSIONS: This analysis demonstrates low HMII thrombus events. Minimization of risk factors by uniform implant techniques and consistent post-op management may reduce device thrombosis. A larger scale multicenter evaluation may better elucidate the difference in thrombus events between centers.

Accountable care organizations: impact on pharmacy.

The Patient Protection and Affordable Care Act (PPACA) has considerably transformed the approaches being used to deliver health care in the United States. It was enacted to expand health insurance access, improve funding for health professions education, and reform patient care delivery. The traditional fee-for-service payment system has been criticized for overspending and providing substandard quality of care. The Accountable Care Organization (ACO) was developed as a payment reform mechanism to slow rising health care costs and improve quality. Under this concept, networks of clinicians and hospitals share responsibility for a population of patients and are held accountable for the financial and clinical outcomes. Due to high rates of medication misuse, nonadherence to therapeutic medication regimens, and preventable adverse drug events, pharmacists are in an ideal position to manage drug therapy and reduce health care expenditures; as such, they may be valuable assets to the ACO team. This article discusses the role of the pharmacist in the era of ACOs specifically and health care reform globally. It outlines pharmacy-related quality of care measures, medication therapy management (MTM) programs (which may provide the foundation for pharmacist involvement in ACOs), and pharmacist functions in patient-centered medical homes (through which ACO services may be organized). The article concludes with a description of successful ACO models that have incorporated pharmacists into their programs.

Direct measurement of the wavelength of sound waves in the human skull.

The results of a study of the three-dimensional vibration of two dry human skulls in response to harmonic excitation are presented. The vibratory response exhibits three distinct types of motion across the range of audible frequencies. At low frequencies below 1000 Hz, whole-head quasi-rigid motion is seen. At the middle frequencies between 1000 and 6000 Hz, the motion exhibits a series of increasingly complex modal patterns. Above 6000 Hz, the response is wavelike and clear wavefronts can be distinguished in the vibration data. In this regime the relationship between wavelength and frequency is calculated and compared to a number of theories of skull vibration that have been proposed.

Fabrication and performance of a single-crystal lead magnesium niobate-lead titanate cylindrical hydrophone.

The development of a piezoelectric hydrophone based on lead magnesium niobate-lead titanate [PbMg1/3Nb2/3O3-PbTiO3 (PMN-PT)] single-crystal piezoelectric as the hydrophone substrate is reported. Although PMN-PT can possess much higher piezoelectric sensitivity than traditional lead zirconate titanate (PZT) piezoelectrics, it is highly anisotropic and therefore there is a large gain in sensitivity only when the crystal structure is oriented in a specific direction. Because of this, simply replacing the PZT substrate with a PMN-PT cylinder is not an optimal solution because the crystal orientation does not uniformly align with the circumferential axis of the hydrophone. Therefore, a composite hydrophone that maintains the optimal crystal axis around the hydrophone circumference has been developed. An 11.3 mm diameter composite hydrophone cylinder was fabricated from a single <110> cut PMN-PT rectangular plate. Solid end caps were applied to the cylinder and the sensitivity was directly compared with a solid PZT-5A cylindrical hydrophone of equal dimensions in a hydrophone test tank. The charge sensitivity showed a 9.1 dB improvement over the PZT hydrophone and the voltage sensitivity showed a 3.5 dB improvement. This was in good agreement with the expected theoretical improvements of 10.1 and 4.5 dB, respectively.

Finite-Element Modelling Based on Optical Coherence Tomography and Corresponding X-ray MicroCT Data for Three Human Middle Ears.

PURPOSE: Optical coherence tomography (OCT) is an emerging imaging modality which is non-invasive, can be employed in vivo, and can record both anatomy and vibrations. The purpose here is to explore the application of finite-element (FE) modelling to OCT data. METHODS: We recorded vibrations for three human cadaver middle ears using OCT. We also have X-ray microCT images from the same ears. Three FE models were built based on geometries obtained from the microCT images. The material properties and boundary conditions of the models were obtained from previously reported studies. RESULTS: Tympanic-membrane (TM) vibration patterns were computed for the three models and compared with the patterns measured using OCT. Frequency responses were also computed for all three models for several locations in the middle ear and compared with the OCT displacements and with the literature. The three models were compared with each other in terms of geometry and function. Parameter sensitivity analyses were done and the results were compared among the models and with the literature. The simulated TM displacement patterns are qualitatively similar to the OCT results. The simulated displacements are closer to the OCT results for 500 Hz and 1 kHz but the differences are greater at 2 kHz. CONCLUSION: This study provides an initial look at the combined use of OCT measurements and FE modelling based on subject-specific anatomy. The geometries and parameters of the existing FE models could be modified for individual patients in the future to help identify abnormalities in the middle ear.

Geometrically accurate real-time volumetric visualization of the middle ear using optical coherence tomography.

We introduce a novel system for geometrically accurate, continuous, live, volumetric middle ear optical coherence tomography imaging over a 10.9mm×30∘×30∘ field of view (FOV) from a handheld imaging probe. The system employs a discretized spiral scanning (DC-SC) pattern to rapidly collect volumetric data and applies real-time scan conversion and lateral angular distortion correction to reduce geometric inaccuracies to below the system's lateral resolution over 92% of the FOV. We validate the geometric accuracy of the resulting images through comparison with co-registered micro-computed tomography (micro-CT) volumes of a phantom target and a cadaveric middle ear. The system's real-time volumetric imaging capabilities are assessed by imaging the ear of a healthy subject while performing dynamic pressurization of the middle ear in a Valsalva maneuver.

Transtympanic Visualization of Cochlear Implant Placement With Optical Coherence Tomography: A Pilot Study.

OBJECTIVE: This study aimed to evaluate the ability of transtympanic middle ear optical coherence tomography (ME-OCT) to assess placement of cochlear implants (CIs) in situ. PATIENT: A 72-year-old man with bilateral progressive heredodegenerative sensorineural hearing loss due to work-related noise exposure received a CI with a slim modiolar electrode for his right ear 3 months before his scheduled checkup. INTERVENTION: A custom-built swept source ME-OCT system (λo = 1550 nm, ∆λ = 40 nm) designed for transtympanic middle ear imaging was used to capture a series of two- and three-dimensional images of the patient's CI in situ. Separately, transtympanic OCT two-dimensional video imaging and three-dimensional imaging were used to visualize insertion and removal of a CI with a slim modiolar electrode in a human cadaveric temporal bone through a posterior tympanotomy. MAIN OUTCOME MEASURE: Images and video were analyzed qualitatively to determine the visibility of implant features under ME-OCT imaging and quantitatively to determine insertion depth of the CI. RESULTS: After implantation, the CI electrode could be readily visualized in the round window niche under transtympanic ME-OCT in both the patient and the temporal bone. In both cases, characteristic design features of the slim modiolar electrode allowed us to quantify the insertion depth from our images. CONCLUSIONS: ME-OCT could potentially be used in a clinic as a noninvasive, nonionizing means to confirm implant placement. This study shows that features of the CI electrode visible under ME-OCT can be used to quantify insertion depth in the postoperative ear.

Optical Clearing Agents for Optical Imaging Through Cartilage Tympanoplasties: A Preclinical Feasibility Study.

HYPOTHESIS: Optical clearing agents (OCAs) can render cartilage tympanoplasty grafts sufficiently transparent to permit visualization of middle ear structures in an operated ear using optical coherence tomography (OCT) imaging. METHODS: Pieces of human tragal cartilage were treated with glycerol, a commonly used OCA. A reference reflector was imaged with OCT through the tympanoplasty as it cleared and the optical attenuation of the graft was measured. The reversibility of clearing and the dimensional changes associated with glycerol absorption were also measured. In a separate experiment, a human cadaveric temporal bone was prepared to simulate an ossiculoplasty surgery with cartilage replacement of the tympanic membrane. A partial ossicular replacement prosthesis (PORP) inserted in the ear was imaged with OCT through a 0.4mm cartilage graft optically cleared with glycerol. MAIN OUTCOME MEASURE: The optical attenuation of 0.4mm cartilage grafts decreased at 2.3+/-1.1 dB/min following treatment with glycerol, reaching a total decrease in attenuation of 13.6+/-5.9 dB after 7 minutes. The optical and dimensional effects of glycerol absorption were reversable following saline washout. In the temporal bone preparation, treatment of a cartilage graft with glycerol resulted in a 13 dB increase in signal-to-noise ratio and a 13 dB increase in contrast for visualizing the PORP through the graft with OCT. CONCLUSIONS: Optical clearing agents offer a potential pathway towards optical coherence tomography imaging of the middle ear in post-surgical ears with cartilage grafts.

Transaxillary Stenting of LVAD Outflow Graft Obstruction.

An 82-year-old man with a HeartMate II left ventricular assist device presented with low-flow alarms and cardiogenic shock secondary to left ventricular assist device outflow graft obstruction. Given high risk for redo sternotomy, the heart team decided on percutaneous intervention with peripheral stents, a procedure that is currently limited to case reports. (Level of Difficulty: Advanced.).

High Resolution and Labeling Free Studying the 3D Microstructure of the Pars Tensa-Annulus Unit of Mice.

Hearing loss is a serious illness affecting people's normal life enormously. The acoustic properties of a tympanic membrane play an important role in hearing, and highly depend on its geometry, composition, microstructure and connection to the surrounding annulus. While the conical geometry of the tympanic membrane is critical to the sound propagation in the auditory system, it presents significant challenges to the study of the 3D microstructure of the tympanic membrane using traditional 2D imaging techniques. To date, most of our knowledge about the 3D microstructure and composition of tympanic membranes is built from 2D microscopic studies, which precludes an accurate understanding of the 3D microstructure, acoustic behaviors and biology of the tissue. Although the tympanic membrane has been reported to contain elastic fibers, the morphological characteristic of the elastic fibers and the spatial arrangement of the elastic fibers with the predominant collagen fibers have not been shown in images. We have developed a 3D imaging technique for the three-dimensional examination of the microstructure of the full thickness of the tympanic membranes in mice without requiring tissue dehydration and stain. We have also used this imaging technique to study the 3D arrangement of the collagen and elastic fibrillar network with the capillaries and cells in the pars tensa-annulus unit at a status close to the native. The most striking findings in the study are the discovery of the 3D form of the elastic and collagen network, and the close spatial relationships between the elastic fibers and the elongated fibroblasts in the tympanic membranes. The 3D imaging technique has enabled to show the 3D waveform contour of the collagen and elastic scaffold in the conical tympanic membrane. Given the close relationship among the acoustic properties, composition, 3D microstructure and geometry of tympanic membranes, the findings may advance the understanding of the structure-acoustic functionality of the tympanic membrane. The knowledge will also be very helpful in the development of advanced cellular therapeutic technologies and 3D printing techniques to restore damaged tympanic membranes to a status close to the native.

Large Lytic Defects Produce Kinematic Instability and Loss of Compressive Strength in Human Spines: An in Vitro Study.

BACKGROUND: In patients with spinal metastases, kinematic instability is postulated to be a predictor of pathologic vertebral fractures. However, the relationship between this kinematic instability and the loss of spinal strength remains unknown. METHODS: Twenty-four 3-level thoracic and lumbar segments from 8 cadaver spines from female donors aged 47 to 69 years were kinematically assessed in axial compression (180 N) and axial compression with a flexion or extension moment (7.5 Nm). Two patterns of lytic defects were mechanically simulated: (1) a vertebral body defect, corresponding to Taneichi model C (n = 13); and (2) the model-C defect plus destruction of the ipsilateral pedicle and facet joint, corresponding to Taneichi model E (n = 11). The kinematic response was retested, and compression strength was measured. Two-way repeated-measures analysis of variance was used to test the effect of each model on the kinematic response of the segment. Multivariable linear regression was used to test the association between the kinematic parameters and compressive strength of the segment. RESULTS: Under a flexion moment, and for both models C and E, the lesioned spines exhibited greater flexion range of motion (ROM) and axial translation than the control spines. Both models C and E caused lower extension ROM and greater axial, sagittal, and transverse translation under an extension moment compared with the control spines. Two-way repeated-measures analysis revealed that model E, compared with model C, caused significantly greater changes in extension and torsional ROM under an extension moment, and greater sagittal translation under a flexion moment. For both models C and E, greater differences in flexion ROM and sagittal translation under a flexion moment, and greater differences in extension ROM and in axial and transverse translation under an extension moment, were associated with lower compressive strength of the lesioned spines. CONCLUSIONS: Critical spinal lytic defects result in kinematic abnormalities and lower the compressive strength of the spine. CLINICAL RELEVANCE: This experimental study demonstrates that lytic foci degrade the kinematic stability and compressive strength of the spine. Understanding the mechanisms for this degradation will help to guide treatment decisions that address inferred instability and fracture risk in patients with metastatic spinal disease.