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.

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.

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.

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.

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.

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.).

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.

Optical coherence tomography: current and future clinical applications in otology.

PURPOSE OF REVIEW: This article reviews literature on the use of optical coherence tomography (OCT) in otology and provides the reader with a timely update on its current clinical and research applications. The discussion focuses on the principles of OCT, the use of the technology for the diagnosis of middle ear disease and for the delineation of in-vivo cochlear microarchitecture and function. RECENT FINDINGS: Recent advances in OCT include the measurement of structural and vibratory properties of the tympanic membrane, ossicles and inner ear in healthy and diseased states. Accurate, noninvasive diagnosis of middle ear disease, such as otosclerosis and acute otitis media using OCT, has been validated in clinical studies, whereas inner ear OCT imaging remains at the preclinical stage. The development of recent microscopic, otoscopic and endoscopic systems to address clinical and research problems is reviewed. SUMMARY: OCT is a real-time, noninvasive, nonionizing, point-of-care imaging modality capable of imaging ear structures in vivo. Although current clinical systems are mainly focused on middle ear imaging, OCT has also been shown to have the ability to identify inner ear disease, an exciting possibility that will become increasingly relevant with the advent of targeted inner ear therapies.

Ultrafast Phased-Array Imaging Using Sparse Orthogonal Diverging Waves.

We present a new transmit pulse encoding scheme for ultrafast phased-array imaging called sparse orthogonal diverging wave imaging (SODWI). In SODWI, Hadamard encoding is used to selectively invert transmit pulse phases beamformed with a diverging wave delay profile. This approach has the advantage of delivering energy to a much wider field of view than conventional Hadamard-encoded multielement synthetic transmit aperture (HMSTA), making it more suitable for phased-array applications. With SODWI, we use a synthetic transmit element delay insertion (STEDI) approach which produces significant improvements in resolution, grating lobe level, and signal-to-noise ratio (SNR) over HMSTA. We also show how in SODWI a subset of the Hadamard codes can be sparsely selected to increase the imaging frame rate at the expense of image quality. SODWI is then compared with a variety of beamforming schemes for phased-array applications, including HMSTA, STEDI-HMSTA, diverging wave imaging (DWI), synthetic aperture (SA), and focused imaging. We present the results by implementing this technique on a 64-channel custom beamforming platform with a 40-MHz phased array. When a full set of codes is used, SODWI outperforms focused imaging contrast and SNR by 2.7 and 1.8 dB in addition to an 8× increase in frame rate, respectively.

Cardiac interstitial tetraploid cells can escape replicative senescence in rodents but not large mammals.

Cardiomyocyte ploidy has been described but remains obscure in cardiac interstitial cells. Ploidy of c-kit+ cardiac interstitial cells was assessed using confocal, karyotypic, and flow cytometric technique. Notable differences were found between rodent (rat, mouse) c-kit+ cardiac interstitial cells possessing mononuclear tetraploid (4n) content, compared to large mammals (human, swine) with mononuclear diploid (2n) content. In-situ analysis, confirmed with fresh isolates, revealed diploid content in human c-kit+ cardiac interstitial cells and a mixture of diploid and tetraploid content in mouse. Downregulation of the p53 signaling pathway provides evidence why rodent, but not human, c-kit+ cardiac interstitial cells escape replicative senescence. Single cell transcriptional profiling reveals distinctions between diploid versus tetraploid populations in mouse c-kit+ cardiac interstitial cells, alluding to functional divergences. Collectively, these data reveal notable species-specific biological differences in c-kit+ cardiac interstitial cells, which could account for challenges in extrapolation of myocardial from preclinical studies to clinical trials.

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.

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.

Optical Coherence Tomography Doppler Vibrometry Measurement of Stapes Vibration in Patients With Stapes Fixation and Normal Controls.

HYPOTHESIS: Ears with otosclerotic stapes fixation will exhibit lower-than-normal levels of ossicular mobility as measured by Optical Coherence Tomography Doppler Vibrometry (OCT-DV). BACKGROUND: OCT-DV measures the vibration of middle ear structures in response to sound non-invasively through the intact tympanic membrane. This allows, in particular, direct measurement of the vibration at the lenticular process of the incus which is expected to be lower in patients with otosclerotic stapes fixation. METHODS: OCT-DV was performed on ears presumptively diagnosed with otosclerosis (n = 13) and a group of normal control ears (n = 42). Displacement was measured at the umbo and the lenticular process of the incus in response to 500 and 1000 Hz stimulus tones at 100 dBSPL. MAIN OUTCOME MEASURE: The ability to discriminate between groups was assessed using receiver operator characteristic analysis, with the main outcome measures being the area-under-curve (AUC) and the sensitivity and specificity. RESULTS: For the best condition tested (500 Hz at the incus), the AUC was 0.998 and discriminated the otosclerotic from normal ears with a sensitivity/specificity of 1.00/0.98. One anomalous patient with surgically confirmed stapes fixation exhibited hypermobility at the umbo, possibly due to a partial ossicular discontinuity. Despite the high umbo mobility, this patient's stapes fixation was correctly discriminated based on the measured incus vibration levels. CONCLUSIONS: OCT-DV is a promising tool for preoperatively assessing ossicular mobility non-invasively in the clinic. Our results suggest OCT-DV may also be useful in discriminating other ossicular pathologies that result in conductive hearing loss.

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.

Pump Position Impacts HeartMate II Left Ventricular Assist Device Thrombosis.

The PREVENtion of HeartMate II pump Thrombosis through clinical management (PREVENT) study was a multicenter, prospective investigation to evaluate the rate of pump thrombosis (PT) with adoption of a uniform set of surgical and medical practices for left ventricular assist device implantation. We sought to quantify pump position at baseline and retrospectively define a pump position associated with poor clinical outcomes. Chest x-rays at baseline were prospectively obtained per protocol. Pump pocket depth, inflow cannula (IC) angle relative to the pump, and IC angle relative to the vertical were measured. Pumps falling in the tail-ends of the IC angle and pump pocket depth distributions were categorized as having an extreme pump position within the PREVENT study. Patients with extreme pump position had a significantly higher risk of confirmed and suspected PT, hemolysis, and elevated lactate dehydrogenase. In a multivariable analysis of survival free of confirmed PT, extreme pump position was an independent risk factor (hazard ratio = 3.6; 95% confidence interval = 1.5-8.9; p = 0.006) when adjusting for differences in pump speed and anticoagulation level. Our analysis shows that HeartMate II pump position at implant can significantly impact event-free survival and the incidence of adverse events at 6 months.

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.

New Imaging Modalities in Otology.

Despite steady improvements in cross-sectional imaging of the ear, current technologies still have limitations in terms of resolution, diagnosis, functional assessment and safety. In this chapter, state-of-the-art imaging techniques in current clinical practice are presented including cone-beam computerized tomography, non-echo planar imaging magnetic resonance imaging, imaging for labyrinthine hydrops and imaging of the central auditory pathways. Potential future imaging modalities are also presented, including optical coherence tomography (OCT) and high-frequency ultrasound (HFUS) of the ear. These experimental modalities offer new opportunities for the assessment of ear structure and function. For example, middle ear structures can be visualized through the tympanic membrane, basilar membrane vibrations can be assessed through the round window and the passage of cochlear implants can be assessed in decalcified cochlear. Functional assessment of the middle ear using Doppler techniques are also discussed, including measurement of tympanic membrane and middle ear vibration amplitudes, visualization of dynamic changes, such as tensor tympani movements and movement of the tympanic membrane with breathing. These new modalities currently have limitations that preclude mainstream clinical use. For example, OCT is limited by the optical scattering of the thickened tympanic membrane and HFUS needs a coupling medium such as gel or fluid from the transducer to the imaged structure although it can visualize through thicker tissues. Nevertheless, further development of these novel techniques may provide an enhanced ability to assess the ear in conjunction with current technologies.