Otitis Media Middle Ear Effusion Identification and Characterization Using an Optical Coherence Tomography Otoscope.

OBJECTIVE: To determine the feasibility of detecting and differentiating middle ear effusions (MEEs) using an optical coherence tomography (OCT) otoscope. STUDY DESIGN: Cross-sectional study. SETTING: US tertiary care children's hospital. SUBJECTS AND METHODS: Seventy pediatric patients undergoing tympanostomy tube placement were preoperatively imaged using an OCT otoscope. A blinded reader quiz was conducted using 24 readers from 4 groups of tiered medical expertise. The primary outcome assessed was reader ability to detect presence/absence of MEE. A secondary outcome assessed was reader ability to differentiate serous vs nonserous MEE. RESULTS: OCT image data sets were analyzed from 45 of 70 total subjects. Blinded reader analysis of an OCT data subset for detection of MEE resulted in 90.6% accuracy, 90.9% sensitivity, 90.2% specificity, and intra/interreader agreement of 92.9% and 87.1%, respectively. Differentiating MEE type, reader identification of nonserous MEE had 70.8% accuracy, 53.6% sensitivity, 80.1% specificity, and intra/interreader agreement of 82.9% and 75.1%, respectively. Multivariate analysis revealed that age was the strongest predictor of OCT quality. The mean age of subjects with quality OCT was 5.01 years (n = 45), compared to 2.54 years (n = 25) in the remaining subjects imaged (P = .0028). The ability to capture quality images improved over time, from 50% to 69.4% over the study period. CONCLUSION: OCT otoscopy shows promise for facilitating accurate MEE detection. The imageability with the prototype device was affected by age, with older children being easier to image, similar to current ear diagnostic technologies.

Magnetomotive Displacement of the Tympanic Membrane Using Magnetic Nanoparticles: Toward Enhancement of Sound Perception.

OBJECTIVE: A novel hearing-aid scheme using magnetomotive nanoparticles (MNPs) as transducers in the tympanic membrane (TM) is proposed, aiming to noninvasively and directly induce a modulated vibration on the TM. METHODS: In this feasibility study, iron oxide (Fe3O4) nanoparticles were applied on ex vivo rat TM tissues and allowed to diffuse over ∼2 h. Subsequently, magnetic force was exerted on the MNP-laden TM via a programmable electromagnetic solenoid to induce the magnetomotion. Optical coherence tomography (OCT), along with its phase-sensitive measurement capabilities, was utilized to visualize and quantify the nanometer-scale vibrations generated on the TM tissues. RESULTS: The magnetomotive displacements induced on the TM were significantly greater than the baseline vibration of the TM without MNPs. In addition to a pure frequency tone, a chirped excitation and the corresponding spectroscopic response were also successfully generated and obtained. Finally, visualization of volumetric TM dynamics was achieved. CONCLUSION: This study demonstrates the effectiveness of magnetically inducing vibrations on TMs containing iron oxide nanoparticles, manipulating the amplitude and the frequency of the induced TM motions, and the capability of assessing the magnetomotive dynamics via OCT. SIGNIFICANCE: The results demonstrated here suggest the potential use of this noninvasive magnetomotive approach in future hearing aid applications. OCT can be utilized to investigate the magnetomotive dynamics of the TM, which may either enhance sound perception or magnetically induce the perception of sound without the need for acoustic speech signals.

Noninvasive in vivo optical coherence tomography tracking of chronic otitis media in pediatric subjects after surgical intervention.

In an institutional review board-approved study, 25 pediatric subjects diagnosed with chronic or recurrent otitis media were observed over a period of six months with optical coherence tomography (OCT). Subjects were followed throughout their treatment at the initial patient evaluation and preoperative consultation, surgery (intraoperative imaging), and postoperative follow-up, followed by an additional six months of records-based observation. At each time point, the tympanic membrane (at the light reflex region) and directly adjacent middle-ear cavity were observed in vivo with a handheld OCT probe and portable system. Imaging results were compared with clinical outcomes to correlate the clearance of symptoms in relation to changes in the image-based features of infection. OCT images of most all participants showed the presence of additional infection-related biofilm structures during their initial consultation visit and similarly for subjects imaged intraoperatively before myringotomy. Subjects with successful treatment (no recurrence of infectious symptoms) had no additional structures visible in OCT images during the postoperative visit. OCT image findings suggest surgical intervention consisting of myringotomy and tympanostomy tube placement provides a means to clear the middle ear of infection-related components, including middle-ear fluid and biofilms. Furthermore, OCT was demonstrated as a rapid diagnostic tool to prospectively monitor patients in both outpatient and surgical settings.

Quantitative Pneumatic Otoscopy Using a Light-Based Ranging Technique.

Otitis media is the leading cause of hearing loss in children. It is commonly associated with fluid in the ear, which can result in up to 45 dB of hearing loss for extended periods of time during a child's most important developmental years. Accurate assessment of middle ear effusions is an important part of understanding otitis media. Current technologies used to diagnose otitis media with effusion are pneumatic otoscopy, tympanometry, and acoustic reflectometry. While all of these techniques can reasonably diagnose the presence of an effusion, they provide limited information about the infection present behind the tympanic membrane.We have developed a technique based on low-coherence interferometry-a non-invasive optical ranging technique capable of sensing depth-resolved microscopic scattering features through the eardrum-to quantify eardrum thickness and integrity, as well as detect any effusion, purulence, or biofilm behind the tympanic membrane. In this manuscript, the technique is coupled with a pneumatic otoscope to measure minute deflections of the tympanic membrane from insufflation pressure stimuli. This results in quantitative measurements of tympanic membrane mobility, which may be used to gain a better understanding of the impact of infection on the membrane dynamics. A small pilot study of 15 subjects demonstrates the ability of pneumatic low-coherence interferometry to quantitatively differentiate normal ears from ears with effusions present. Analysis of the strengths and weaknesses of the technique, as well as focus areas of future research, is also discussed.

Ratiometric analysis of optical coherence tomography-measured in†vivo retinal layer thicknesses for the detection of early diabetic retinopathy.

Influence of diabetes mellitus (DM) and diabetic retinopathy (DR) on parafoveal retinal thicknesses and their ratios was evaluated. Six retinal layer boundaries were segmented from spectral-domain optical coherence tomography images using open-source software. Five study groups: (1) healthy control (HC) subjects, and subjects with (2) controlled DM, (3) uncontrolled DM, (4) controlled DR and (5) uncontrolled DR, were identified. The one-way analyses of variance (ANOVA) between adjacent study groups (i. e. 1 with 2, 2 with 3, etc) indicated differences in retinal thicknesses and ratios. Overall retinal thickness, ganglion cell layer (GCL) thickness, inner plexiform layer (IPL) thickness, and their combination (GCL+ IPL), appeared to be significantly less in the uncontrolled DM group when compared to controlled DM and controlled DR groups. Although the combination of nerve fiber layer (NFL) and GCL, and IPL thicknesses were not different, their ratio, (NFL+GCL)/IPL, was found to be significantly higher in the controlled DM group compared to the HC group. Comparisons of the controlled DR group with the controlled DM group, and with the uncontrolled DR group, do not show any differences in the layer thicknesses, though several significant ratios were obtained. Ratiometric analysis may provide more sensitive parameters for detecting changes in DR. Picture: A representative segmented OCT image of the human retina is shown.

Quantitative characterization of mechanically indented in vivo human skin in adults and infants using optical coherence tomography.

Influenced by both the intrinsic viscoelasticity of the tissue constituents and the time-evolved redistribution of fluid within the tissue, the biomechanical response of skin can reflect not only localized pathology but also systemic physiology of an individual. While clinical diagnosis of skin pathologies typically relies on visual inspection and manual palpation, a more objective and quantitative approach for tissue characterization is highly desirable. Optical coherence tomography (OCT) is an interferometry-based imaging modality that enables in vivo assessment of cross-sectional tissue morphology with micron-scale resolution, which surpasses those of most standard clinical imaging tools, such as ultrasound imaging and magnetic resonance imaging. This pilot study investigates the feasibility of characterizing the biomechanical response of in vivo human skin using OCT. OCT-based quantitative metrics were developed and demonstrated on the human subject data, where a significant difference between deformed and nondeformed skin was revealed. Additionally, the quantified postindentation recovery results revealed differences between aged (adult) and young (infant) skin. These suggest that OCT has the potential to quantitatively assess the mechanically perturbed skin as well as distinguish different physiological conditions of the skin, such as changes with age or disease.

Low-cost hand-held probe for depth-resolved low-coherence interferometry.

We report on the development of a low-cost hand-held low-coherence interferometric imaging system based on the principle of linear optical coherence tomography (Linear OCT), a technique which was first proposed in the early 2000s as a simpler alternative to the conventional time-domain and Fourier-domain OCT. A bench-top implementation of the proposed technique is first presented and validated. The axial resolution, SNR, and sensitivity roll-of of the system was estimated to be 5.2 µm and 80 dB, and 3.7 dB over a depth of 0.15 mm, respectively. After validating the bench-top system, two hand-held probe implementations for contact-based imaging and in vivo human tympanic membrane imaging are presented. The performance of the proposed system was compared with a research-grade state-of-the-art Fourier-domain low coherence interferometry (LCI) system by imaging several biological and non-biological samples. The results of this study suggest that the proposed system might be a suitable choice for applications where imaging depth and SNR can be traded for lower cost and simpler optical design.

Non-invasive optical assessment of viscosity of middle ear effusions in otitis media.

Eustachian tube dysfunction can cause fluid to collect within the middle ear cavity and form a middle ear effusion (MEE). MEEs can persist for weeks or months and cause hearing loss as well as speech and learning delays in young children. The ability of a physician to accurately identify and characterize the middle ear for signs of fluid and/or infection is crucial to provide the most appropriate treatment for the patient. Currently, middle ear infections are assessed with otoscopy, which provides limited and only qualitative diagnostic information. In this study, we propose a method utilizing cross-sectional depth-resolved optical coherence tomography to noninvasively measure the diffusion coefficient and viscosity of colloid suspensions, such as a MEE. Experimental validation of the proposed technique on simulated MEE phantoms with varying viscosity and particulate characteristics is presented, along with some preliminary results from in vivo and ex vivo samples of human MEEs. In vivo Optical Coherence Tomography (OCT) image of a human tympanic membrane and Middle Ear Effusion (MEE) (top), with a CCD image of the tympanic membrane surface (inset). Below is the corresponding time-lapse M-mode OCT data acquired along the white dotted line over time, which can be analyzed to determine the Stokes-Einstein diffusion coefficient of the effusion.

Rapid diagnosis and differentiation of microbial pathogens in otitis media with a combined Raman spectroscopy and low-coherence interferometry probe: toward in vivo implementation.

We investigate and demonstrate the feasibility of using a combined Raman scattering (RS) spectroscopy and low-coherence interferometry (LCI) probe to differentiate microbial pathogens and improve our diagnostic ability of ear infections [otitis media (OM)]. While the RS probe provides noninvasive molecular information to identify and differentiate infectious microorganisms, the LCI probe helps to identify depth-resolved structural information as well as to guide and monitor positioning of the Raman spectroscopy beam for relatively longer signal acquisition times. A series of phantom studies, including the use of human middle ear effusion samples, were performed to mimic the conditions of in vivo investigations. These were also conducted to validate the feasibility of using this combined RS/LCI probe for point-of-care diagnosis of the infectious pathogen(s) in OM patients. This work establishes important parameters for future in vivo investigations of fast and accurate determination and diagnosis of infectious microorganisms in OM patients, potentially improving the efficacy and outcome of OM treatments, and importantly reducing the misuse of antibiotics in the presence of viral infections.

Ratiometric analysis of in vivo retinal layer thicknesses in multiple sclerosis.

We performed ratiometric analysis of retinal optical coherence tomography images for the first time in multiple sclerosis (MS) patients. The ratiometric analysis identified differences in several retinal layer thickness ratios in the cohort of MS subjects without a history of optic neuritis (ON) compared to healthy control (HC) subjects, and there was no difference in standard retinal nerve fiber layer thickness (RNFLT). The difference in such ratios between HC subjects and those with mild MS-disability, without a difference in RNFLT, further suggests the possibility of using layer ratiometric analysis for detecting early retinal changes in MS. Ratiometric analysis may be useful and potentially more sensitive for detecting disease changes in MS.

A Mosaicking Approach for In Vivo Thickness Mapping of the Human Tympanic Membrane Using Low Coherence Interferometry.

The thickness of the human tympanic membrane (TM) is known to vary considerably across different regions of the TM. Quantitative determination of the thickness distribution and mapping of the TM is of significant importance in hearing research, particularly in mathematical modeling of middle-ear dynamics. Change in TM thickness is also associated with several middle-ear pathologies. Determination of the TM thickness distribution could therefore also enable a more comprehensive diagnosis of various otologic diseases. Despite its importance, very limited data on human TM thickness distribution, obtained almost exclusively from ex vivo samples, are available in the literature. In this study, the thickness distribution for the in vivo human TM is reported for the first time. A hand-held imaging system, which combines a low coherence interferometry (LCI) technique for single-point thickness measurement, with video-otoscopy for recording the image of the TM, was used to collect the data used in this study. Data were acquired by pointing the imaging probe over different regions of the TM, while simultaneously recording the LCI and concomitant TM surface video image data from an average of 500 locations on the TM. TM thickness distribution maps were obtained by mapping the LCI imaging sites onto an anatomically accurate wide-field image of the TM, which was generated by mosaicking the sequence of multiple small field-of-view video-otoscopy images. Descriptive statistics of the thickness measurements obtained from the different regions of the TM are presented, and the general thickness distribution trends are discussed.

Detection of retinal blood vessel changes in multiple sclerosis with optical coherence tomography.

Although retinal vasculitis is common in multiple sclerosis (MS), it is not known if MS is associated with quantitative abnormalities in retinal blood vessels (BVs). Optical coherence tomography (OCT) is suitable for examining the integrity of the anterior visual pathways in MS. In this paper we have compared the size and number of retinal blood vessels in patients with MS, with and without a history of optic neuritis (ON), and control subjects from the cross-sectional retinal images from OCT. Blood vessel diameter (BVD), blood vessel number (BVN), and retinal nerve fiber layer thickness (RNFLT) were extracted from OCT images collected from around the optic nerves of 129 eyes (24 control, 24 MS + ON, 81 MS-ON) of 71 subjects. Associations between blood vessel metrics, MS diagnosis, MS disability, ON, and RNFLT were evaluated using generalized estimating equation (GEE) models. MS eyes had a lower total BVD and BVN than control eyes. The effect was more pronounced with increased MS disability, and persisted in multivariate models adjusting for RNFLT and ON history. Twenty-nine percent (29%) of MS subjects had fewer retinal blood vessels than all control subjects. MS diagnosis, disability, and ON history were not associated with average blood vessel size. The relationship between MS and lower total BVD/BVN is not accounted for by RNFLT or ON. Further study is needed to determine the relationship between OCT blood vessel metrics and qualitative retinal blood vessel abnormalities in MS.

Intraoperative optical coherence tomography for assessing human lymph nodes for metastatic cancer.

BACKGROUND: Evaluation of lymph node (LN) status is an important factor for detecting metastasis and thereby staging breast cancer. Currently utilized clinical techniques involve the surgical disruption and resection of lymphatic structure, whether nodes or axillary contents, for histological examination. While reasonably effective at detection of macrometastasis, the majority of the resected lymph nodes are histologically negative. Improvements need to be made to better detect micrometastasis, minimize or eliminate lymphatic disruption complications, and provide immediate and accurate intraoperative feedback for in vivo cancer staging to better guide surgery. METHODS: We evaluated the use of optical coherence tomography (OCT), a high-resolution, real-time, label-free imaging modality for the intraoperative assessment of human LNs for metastatic disease in patients with breast cancer. We assessed the sensitivity and specificity of double-blinded trained readers who analyzed intraoperative OCT LN images for presence of metastatic disease, using co-registered post-operative histopathology as the gold standard. RESULTS: Our results suggest that intraoperative OCT examination of LNs is an appropriate real-time, label-free, non-destructive alternative to frozen-section analysis, potentially offering faster interpretation and results to empower superior intraoperative decision-making. CONCLUSIONS: Intraoperative OCT has strong potential to supplement current post-operative histopathology with real-time in situ assessment of LNs to preserve both non-cancerous nodes and their lymphatic vessels, and thus reduce the associated risks and complications from surgical disruption of lymphoid structures following biopsy.

Sensor-Based Technique for Manually Scanned Hand-Held Optical Coherence Tomography Imaging.

Hand-held optical coherence tomography (OCT) imaging probes offer flexibility to image sites that are otherwise challenging to access. While the majority of hand-held imaging probes utilize galvanometer- or MEMS-scanning mirrors to transversely scan the imaging beam, these probes are commonly limited to lateral fields-of-view (FOV) of only a few millimeters. The use of a freehand manually scanned probe can significantly increase the lateral FOV. However, using the traditional fixed-rate triggering scheme for data acquisition in a manually scanned probe results in imaging artifacts due to variations in the scan velocity of the imaging probe. These artifacts result in a structurally inaccurate image of the sample. In this paper, we present a sensor-based manual scanning technique for OCT imaging, where real-time feedback from an optical motion sensor is used to trigger data acquisition. This technique is able to circumvent the problem of motion artifacts during manual scanning by adaptively altering the trigger rate based on the instantaneous scan velocity, enabling OCT imaging over a large lateral FOV. The feasibility of the proposed technique is demonstrated by imaging several biological and nonbiological samples.

Real-time automated thickness measurement of the in vivo human tympanic membrane using optical coherence tomography.

BACKGROUND: Otitis media (OM), an infection in the middle ear, is extremely common in the pediatric population. Current gold-standard methods for diagnosis include otoscopy for visualizing the surface features of the tympanic membrane (TM) and making qualitative assessments to determine middle ear content. OM typically presents as an acute infection, but can progress to chronic OM, and after numerous infections and antibiotic treatments over the course of many months, this disease is often treated by surgically inserting small tubes in the TM to relieve pressure, enable drainage, and provide aeration to the middle ear. Diagnosis and monitoring of OM is critical for successful management, but remains largely qualitative. METHODS: We have developed an optical coherence tomography (OCT) system for high-resolution, depth-resolved, cross-sectional imaging of the TM and middle ear content, and for the quantitative assessment of in vivo TM thickness including the presence or absence of a middle ear biofilm. A novel algorithm was developed and demonstrated for automatic, real-time, and accurate measurement of TM thickness to aid in the diagnosis and monitoring of OM and other middle ear conditions. The segmentation algorithm applies a Hough transform to the OCT image data to determine the boundaries of the TM to calculate thickness. RESULTS: The use of OCT and this segmentation algorithm is demonstrated first on layered phantoms and then during real-time acquisition of in vivo OCT from humans. For the layered phantoms, measured thicknesses varied by approximately 5 µm over time in the presence of large axial and rotational motion. In vivo data also demonstrated differences in thicknesses both spatially on a single TM, and across normal, acute, and chronic OM cases. CONCLUSIONS: Real-time segmentation and thickness measurements of image data from both healthy subjects and those with acute and chronic OM demonstrate the use of OCT and this algorithm as a robust, quantitative, and accurate method for use during real-time in vivo human imaging.

Noninvasive depth-resolved optical measurements of the tympanic membrane and middle ear for differentiating otitis media.

OBJECTIVE/HYPOTHESIS: In this study, optical coherence tomography (OCT) is used to noninvasively and quantitatively determine tympanic membrane (TM) thickness and the presence and thickness of any middle-ear biofilm located behind the TM. These new metrics offer the potential to differentiate normal, acute, and chronic otitis media (OM) infections in pediatric subjects. STUDY DESIGN: Case series with comparison group. METHODS: The TM thickness of 34 pediatric subjects was acquired using a custom-built, handheld OCT system following a traditional otoscopic ear exam. RESULTS: Overall thickness (TM and any associated biofilm) was shown to be statistically different for normal, acute, and chronic infection groups (normal-acute and normal-chronic: P value < 0.001; acute-chronic: P value = 0.0016). Almost all observed scans from the chronic group had an accompanying biofilm structure. When the thickness of the TM and biofilm were considered separately in chronic OM, the chronic TM thickness correlated with the normal group (P value = 0.68) yet was still distinct from the acute OM group (P value < 0.001), indicating that the TM in chronic OM returns to relatively normal thickness levels. CONCLUSION: Identifying these physical changes in vivo provides new metrics for noninvasively and quantitatively differentiating normal, acute, and chronic OM. This new diagnostic information has the potential to assist physicians to more effectively and efficiently screen, manage, and refer patients based on quantitative data. LEVEL OF EVIDENCE: 4.

In vivo pump-probe optical coherence tomography imaging in Xenopus laevis.

Currently, optical coherence tomography (OCT), is not capable of obtaining molecular information often crucial for identification of disease. To enable molecular imaging with OCT, we have further developed a technique that harnesses transient changes in light absorption in the sample to garner molecular information. A Fourier-domain Pump-Probe OCT (PPOCT) system utilizing a 532 nm pump and 830 nm probe has been developed for imaging hemoglobin. Methylene blue, a biological dye with well-know photophysics, was used to characterize the system before investigating the origin of the hemoglobin PPOCT signal. The first in vivo PPOCT images were recorded of the vasculature in Xenopus laevis. The technique was shown to work equally well in flowing and nonflowing vessels. Furthermore, PPOCT was compared with other OCT extensions which require flow, such as Doppler OCT and phase-variance OCT. PPOCT was shown to better delineate tortuous vessels, where nodes often restrict Doppler and phase-variance reconstruction.

Molecular specificity in photoacoustic microscopy by time-resolved transient absorption.

We have recently harnessed transient absorption, a resonant two-photon process, for ultrahigh resolution photoacoustic microscopy, achieving nearly an order of magnitude improvement in axial resolution. The axial resolution is optically constrained due to the two-photon process unlike traditional photoacoustic microscopy where the axial resolution is inversely proportional to the frequency bandwidth of the detector. As a resonant process, the arrival time of the two photons need not be instantaneous. Systematically recording the signal as a function of the delay between two pulses will result in the measurement of an exponential decay whose time constant is related to the molecular dynamics. This time constant, analogous to the fluorescence lifetime, but encompassing nonradiative decay as well, can be used to differentiate between molecular systems with overlapping absorption spectra. This is frequently the situation for closely related yet distinct molecules such as redox pairs. In order to enable the measure of the exponential decay, we have reconfigured our transient absorption ultrasonic microscopy (TAUM) system to incorporate two laser sources with precisely controlled pulse trains. The system was tested by measuring Rhodamine 6G, an efficient laser dye where the molecular dynamics are dominated by the fluorescence pathway. As expected, the measured exponential time constant or ground state recovery time, 3.3±0.7 ns, was similar to the well-known fluorescence lifetime, 4.11±0.05 ns. Oxy- and deoxy-hemoglobin are the quintessential pair whose relative concentration is related to the local blood oxygen saturation. We have measured the ground state recovery times of these two species in fully oxygenated and deoxygenated bovine whole blood to be 3.7±0.8 ns and 7.9±1.0 ns, respectively. Hence, even very closely related pairs of molecules may be differentiated with this technique.

Volumetric imaging of erythrocytes using label-free multiphoton photoacoustic microscopy.

Photoacoustic microscopy (PAM) is an imaging modality well suited to mapping vasculature and other strong absorbers in tissue. However, one of the primary drawbacks to PAM when used for high-resolution imaging is the relatively poor axial resolution due to the inverse dependence on the transducer bandwidth. While submicron lateral resolution PAM can be achieved by tightly focusing the excitation light, the axial resolution is fundamentally limited to 10s of microns for typical transducer frequencies. Here we present a multiphoton PAM technique called transient absorption ultrasonic microscopy (TAUM), which results in a completely optically resolved voxel with an experimentally measured axial resolution of 1.5 microns. This technique is demonstrated by imaging individual red blood cells in three dimensions in blood smear and ex vivo tissues. To the best of our knowledge, this is the first demonstration of fully resolved, volumetric photoacoustic imaging of erythrocytes.

Optical coherence tomography for advanced screening in the primary care office.

Optical coherence tomography (OCT) has long been used as a diagnostic tool in the field of ophthalmology. The ability to observe microstructural changes in the tissues of the eye has proved very effective in diagnosing ocular disease. However, this technology has yet to be introduced into the primary care office, where indications of disease are first encountered. We have developed a portable, handheld imaging probe for use in the primary care setting and evaluated its tissue site accessibility, ability to observe diseased tissue, and screening capabilities in in vivo human patients, particularly for pathologies related to the eye, ear and skin. Various stages of diabetic retinopathy were investigated using the handheld probe and early-stage diabetic retinopathy was flagged as abnormal from the OCT images. At such early stages of disease, it is difficult to observe abnormalities with the limited tools that are currently available to primary care physicians. These results indicate that OCT shows promise to transform from being a diagnostic technology in the medical and surgical specialities to a screening technology in the primary care office and at the front-line of healthcare.