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. Author manuscript; available in PMC: 2022 Sep 8.
Published in final edited form as: Curr Ophthalmol Rep. 2021 May 18;9(2):39–47. doi: 10.1007/s40135-021-00265-1

Update on imaging modalities for ocular surface pathologies

Osmel P Alvarez 1, Anat Galor 2, Ghada AlBayyat 3, Carol L Karp 4
PMCID: PMC9455836  NIHMSID: NIHMS1787847  PMID: 36093383

Abstract

Purpose of review:

To discuss recent studies of imaging modalities for ocular surface pathologies.

Recent findings:

Novel micro-ocular coherence tomography technology can produce high-resolution images of corneal cellular and nervous structures. Ocular coherence tomography angiography can aid in detecting early stage limbal stem cell deficiency. Several studies used in vivo confocal microscopy to evaluate corneal nerve metrics and morphology.

Summary:

The applications of anterior segment optical coherence tomography, anterior segment optical coherence tomography angiography, ultrasound biomicroscopy, and in vivo confocal microscopy are useful technologies for imaging the ocular surface. Several studies have used artificial intelligence in combination with imaging technologies to create reliable and effective systems to detect and visualize ocular surface pathologies. AS OCT continues to be a key imaging tool and future development of μOCT technology may further enhance its utility.

Keywords: Ocular surface imaging, ocular surface pathologies, anterior segment optical coherence tomography, anterior segment optical coherence tomography angiography, ultrasound biomicroscopy, confocal microscopy

Introduction

Imaging technology is an essential asset for any ocular surface clinician. From the 1980s through today, various imaging modalities have emerged and evolved into powerful tools that greatly facilitate the diagnosis, management, visualization, and study of many ocular surface pathologies. Some of the most widely used imaging modalities include optical coherence tomography, optical coherence tomography angiography, ultrasound biomicroscopy, and in vivo confocal microscopy. In this review, we will discuss some of the most recent studies involving these technologies and how they are relevant to ocular surface practitioners.

Anterior segment optical coherence tomography

Background

Optical coherence tomography (OCT) was first used to image biological tissue in 1991 by Huang et al and the first use of OCT for the anterior segment of the eye was by Izatt et al in 1994 (1, 2). OCT uses low-coherence interferometry to produce two-dimensional images of optical scattering that are suitable for noninvasive imaging of biological tissues (1). Since its creation, OCT has evolved from time-domain (TD-OCT) to spectral-domain (TD-OCT) to current swept-source technology, greatly increasing its resolution capabilities (3). Currently available high resolution anterior segment OCT (HR AS OCT) devices have resolutions ranging from approximately five to ten microns or less, and scan depths of about two to seven millimeters (4). Newer ultra-high resolution (UHR AS OCT) devices have resolution of less than 5 microns (5). AS OCT is particularly useful in imaging ocular surface pathologies, including ocular surface squamous neoplasia, pterygia, pinguecula, lymphoma, melanoma, nevi, Fuchs’ endothelial corneal dystrophy, dry eye disease, keratoconus, and more (6-11) [Figure 1, Figure 2].

Figure 1.

Figure 1.

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Fifty-seven-year-old white female with corneal lesion. A. Slit lamp image of the left eye with corneal lesion (arrow). Dotted line demonstrates the orientation of the AS OCT raster. B. High-resolution AS OCT showing normal hypo-reflective epithelium with localized hyperreflective subepithelial nodular lesion (arrow), consistent with Salzmann's nodular degeneration.

Figure 2.

Figure 2.

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Forty-seven-year-old black male with conjunctival and corneal lesion on left eye. A. Slit lamp image with a temporal corneal and conjunctival lesion (arrow). Dotted black line demonstrates the orientation of the AS OCT raster. B. High resolution AS OCT showing normal thickness epithelium (arrow) with linear subepithelial scarring (asterisk) consistent with pterygium.

In addition to its in-office clinical use, AS OCT is also greatly helpful as an intraoperative imaging tool. Several studies have showcased the utility of intraoperative AS OCT during Descemet membrane endothelial keratoplasty (DMEK) (12, 13), Descemet stripping automated endothelial keratoplasty (DSAEK) (14), deep anterior lamellar keratoplasty (DALK) (15), and other surgical procedures (16). Intraoperative AS OCT provides the surgeon with valuable insight into the positioning of the graft in endothelial procedures, guidance of depth in lamellar procedures, and additional information that can greatly influence surgical outcomes.

Recent developments

While already a powerful tool, technology for AS OCT continues to evolve. A recent article by Wartak et al (17) demonstrated the use of a polarization-sensitive “micro” OCT boasting the highest resolution know to date: 1.5×1.5×1 μm. The team was able to use this new “μOCT” to visualize corneal cellular and nervous structures in both cross-sectional B-scans and en face maximum intensity projections at various depths. Although this technology is still in development and not yet widely available, it is still an exciting indication of the future of imaging tools, as the resolution and imaging capabilities of μOCT rival those of in vivo confocal microscopy and other high-resolution imaging modalities. μOCT will surely be a great asset to clinicians in the visualization, diagnosis, and management of ocular surface pathologies .

Other recent advances involving AS OCT may involve novel or improved methods to visualize, diagnose, or manage ocular surface pathologies. Liang and associates (18) used AS OCT to measure corneal epithelial thickness in patients with and without limbal stem cell deficiency (LSCD). They found that patients with LSCD had decreased corneal epithelial thickness and that a three-point OCT thickness measurement is a reliable measure to confirm LSCD diagnosis. These findings suggest that AS OCT may have clinical value in the diagnosis of LSCD, which can be difficult to confirm clinically. Additionally, it suggests that future imaging studies may find novel ways to track the progression of LSCD or detect it in early stages.

Another study by Tran et al (19) used high resolution (HR) AS OCT to identify subclinical lesions of ocular surface squamous neoplasia (OSSN). The study analyzed patients that underwent treatment with topical chemotherapy for OSSN. They found that 17% of patients whose disease was clinically resolved had residual disease detected by HR AS OCT. This study is an excellent example of how the powerful imaging capacity of HR AS OCT can make a significant difference in the management and treatment of ocular surface diseases like OSSN. A quick scan with HR AS OCT can avert premature termination of topical therapy, and thus avoid undertreatment of OSSN.

Kaliki et al (20) used AS OCT to compare OSSN to pseudoepitheliomatous hyperplasia (PEH) of the ocular surface. They found that on AS OCT, PEH showed irregular hyperreflective epithelium, epithelial dipping, no evidence of abrupt transition from normal to abnormal epithelium, and subepithelial hyperreflective lesions with posterior shadowing in all nine cases observed. These findings were used to rule out the initial referral diagnosis of OSSN and instead diagnose PEH, which was confirmed by histopathology in all cases. This study highlights that while PEH and OSSN may share some similarities on AS OCT (hyperreflective and thickened epithelium), there are other features that can aid clinicians in narrowing the differential diagnosis.

Karp et al (21) used HR AS OCT to predict the margins of OSSN lesions undergoing surgical excision. In a series of eight cases, they used HR AS OCT preoperatively to map the borders of the lesions to be excised. During the surgery, they used an anatomical reference point to map the margins of the lesion based on the OCT imagery and then excised the lesions using a no-touch technique with 4 mm margins. Histopathology confirmed accurate margin predictions in all cases. This study is a promising indication of the significance of OCT for the surgical management of OSSN. Using such a technique, surgeons can further reduce the risk of leaving residual tumor, thereby minimizing the risk of recurrence and need for further treatment.

Wertheimer and associates (22) used AS OCT to measure optical density in corneas of patients with Fuchs’ dystrophy as a way to grade corneal stromal opacification. They found that the corneal optical densities obtained by AS OCT were significantly increased compared to a control group. This finding is particularly valuable because it suggests a possibility for a new objective method of diagnosing and measuring progression of Fuchs’ dystrophy. Further studies could build on these findings to develop a standardized method of measuring progression of Fuchs’ dystrophy through AS OCT. Such a method could aid the clinician by complementing measurements such as pachymetry, visual acuity, and observations upon examination.

Finally, other exciting developments in OCT technology involve the use of artificial intelligence systems. In a recent study, Eleiwa et al (23) designed a deep learning algorithm to detect different stages of Fuchs’ dystrophy based on ultra-high resolution OCT scans. The algorithm had a 91% sensitivity and 97% specificity for early stage Fuchs’, a 92% specificity and 100% sensitivity for late stage Fuchs’, and a 98% specificity and 99% sensitivity for healthy corneas. This study presents the exciting prospect of having a deep learning system with great diagnostic utility. Such a system could greatly aid clinicians in diagnosing Fuchs’ in its early stages when it may otherwise go undetected, as well as aid in the monitoring of the progression of the disease.

Zéboulon et al (24) combined artificial intelligence with OCT technology by using a deep learning algorithm with AS OCT to identify and visualize corneal edema. The model they designed had an accuracy of 98.7%, a sensitivity of 96.4%, and a specificity of 100%. Additionally, it provided colored heat maps of edema presence on OCT. This study presents an exciting new tool for the management of corneal edema. An automated system to detect and visualize corneal edema could greatly facilitate the management and diagnosis of a number of ocular surface pathologies. Such a tool could allow clinicians to objectively track its progression or improvement through heat maps and other visual models.

Perspective

Since its emergence in the 1990s, OCT has become an incredibly powerful and useful imaging tool in ophthalmology. The studies reviewed here reveal that AS OCT is a continually changing technology with an ever-increasing scope of use. With the powerful resolution that current technology allows, AS OCT is especially useful for imaging finer details of the ocular surface, such as subclinical cases of OSSN, corneal edema, and other pathologies. In our experience, OCT is particularly useful for the management of OSSN, as it allows for the visualization of subtle cases and lesions that may be masquerading as another pathology. Additionally, AS OCT is valuable because it produces high-resolution, contactless imagery that can be easily interpreted by even novice clinicians (25). Several ocular surface pathologies with similar clinical presentations can be effectively differentiated on AS OCT [Figure 1, Figure 2]. However, AS OCT does have limitations, as it can have poor penetrance beyond large or darkly pigmented lesions. In such cases, imaging with ultrasound biomicroscopy may be better suited. Regardless, AS OCT is an indispensable tool for the ocular surface clinician.

Optical coherence tomography angiography

Background

Optical coherence tomography angiography (OCTA) is a relatively new imaging modality that provides noninvasive, high-resolution images of vascular tissues (26). OCTA is most commonly used for retinal imaging, but it has found increasing use in anterior segment imaging as well (27). Because it is noninvasive, OCTA also offers the benefit of avoiding possible side effects or reactions associated with injected dyes for traditional angiography like fluorescein or indocyanine green (28, 29). OCTA collects a series of consecutive B-scans at one location and creates a visualization of the only moving part, which is assumed to be cells inside blood vessels (30, 31). Available models offer excellent resolutions of about 5 microns (30).

Recent developments

Several recent studies have shown the increasing applicability of OCTA to imaging of ocular surface pathologies. Binotti et al (32) used AS OCTA to assess the progression of limbal stem cell deficiency (LSCD). They found that AS OCTA can identify significant differences in corneal vascular extension and thickness as early as stage I LSCD. This study is a promising example of how AS OCTA could be useful to clinicians in identifying and tracking the progression of pathologies like LSCD.

Similarly, another study by Binotti et al (33) used AS OCTA to assess different levels of corneal neovascularization. In this study, the authors found that on AS OCTA, severe corneal neovascularization showed increased area, volume, depth, and posterior limit when compared to mild cases. Additionally, they found that volume and depth of corneal neovascularization correlated strongly to best corrected visual acuity.

Liu and associates (34) used AS OCTA to characterize the vasculature of ocular surface squamous neoplasia (OSSN). They found that on AS OCTA, the highest vessel area densities (VAD) were highest in the conjunctival tumors, followed by the subepithelial tissues adjacent to tumors, and then the tissue 200 microns under tumors. They also found that OSSN with both corneal and conjunctival involvement showed significantly more VAD on the conjunctival areas than on the corneal areas, and more involvement on subepithelial conjunctival areas than in subepithelial corneal areas. In this study, AS OCTA provides insight into tumor pathogenesis, and can provide helpful information about the lesion in question and the surrounding area [Figure 4].

Figure 4.

Figure 4.

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Seventy-year-old white female with ocular surface squamous neoplasia (OSSN) described in Figure 1. A. Slit lamp image of the left eye with OSSN of the conjunctiva and corneal surface. Black box shows area of AS OCT angiography scan. B. En face AS OCT angiography image showing the vasculature of the tumor covering the conjunctiva and cornea.

Additionally, Nampei et al (35) used AS OCTA to compare the vasculature in two cases of OSSN and one case of pterygium. They found that the two OSSN lesions (one conjunctival intraepithelial neoplasia, one squamous cell carcinoma) showed increased “zigzag vessel patterns” in superficial and deep layers, while the pterygium showed more “straight vessel patterns” in the superficial later and an “avascular pattern” in the deep layer of the head. While only based on three cases, this study indicates possible additional features that can aid the clinician in differentiating OSSN and pterygia. The use of AS OCTA in these cases may not be necessary, as a standard AS OCT can already provide information necessary to discriminate between OSSN and other ocular surface pathologies. AS OCTA, however, may provide insights into the pathophysiology and tumorigenesis of these ocular surface entities.

Brouwer et al (36) used AS OCTA to study the vasculature of conjunctival and iris melanocytic lesions. They found that conjunctival melanoma and nevi showed the same “tortuous” vasculature on AS OCTA, while primary acquired melanosis showed similar vasculature to normal conjunctiva. Additionally, iris nevi and melanoma also showed “tortuous” vasculature patterns. To our knowledge, this is the first paper to study melanocytic lesions of the conjunctiva on AS OCTA. Unfortunately, they study did not yield a valuable measure to differentiate between benign and malignant melanocytic lesions using AS OCTA. However, further technological developments could build on these findings to increase the diagnostic value of AS OCTA for these lesions.

Perspective

Anterior segment OCTA (AS OCTA) is a newer development of OCT technology. While highly useful for the visualization of retinal vasculature, its use for ocular surface imaging remains somewhat limited but is growing nonetheless. As several pathologies of the ocular surface can already be identified based on AS OCT alone, the vascular information provided by AS OCTA may not be of independent significance. However, AS OCTA may provide valuable information about the pathophysiology of several ocular surface lesions. Additionally, because AS OCTA is uniquely designed for imaging vascularity, it may be especially valuable for imaging corneal neovascularization and limbal stem cell deficiency.

Ultrasound biomicroscopy

Background

Ultrasound biomicroscopy (UBM) was first used in vivo for ophthalmic purposes by Pavlin et al in 1990 (37), who adapted it from existing ultrasound technology. They used high frequency ultrasound transducers of 100 MHz to obtain cross sections of up to 4 mm depth and a lateral resolution of 20 microns (37). Throughout the rest of the 1990s, UBM continued evolving and improving and became more widely used for imaging of the anterior segment and anterior segment tumors [Figure 5], anterior chamber, angle, iris, ciliary body, and other structures (38-40). Today, UBM systems typically use transducers of 35-50 MHz, with resolutions ranging from about 30-70 microns and scan depths of 4-6 mm (41).

Figure 5.

Figure 5.

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Sixty-six-year-old black male with history of renal transplant and lesion of the conjunctiva temporally right eye, with history of a pterygium excision in the same area previously. A. Slit lamp image of conjunctival-corneal lesion (arrow). B. High-resolution ultrasound biomicroscopy (UBM) of the lesion showing thickened conjunctiva (asterisk) and normal underlying sclera and no vitreous membranes attached. Biopsy confirmed ocular surface squamous neoplasia.

Recent developments

Nahum et al (42) used intraoperative UBM to confirm graft orientation during Descemet membrane endothelial keratoplasty (DMEK) in eight cases. They found that UBM allowed for accurate graft orientation in all cases. In one case, while the blue cannula tip sign indicated correct orientation of the graft, UBM indicated that the graft was upside down. The graft was inverted and correct orientation was then confirmed by both UBM and the blue cannula tip sign. Postoperative AS OCT was used to confirm correct graft orientation in all cases. This study indicates that in addition to AS OCT, intraoperative UBM may be a useful adjunct to confirm correct graft orientation during DMEK.

Another study used UBM to detect intraocular involvement of ocular surface squamous neoplasia (OSSN). In a series of seven cases, Meel et al (43) found that intraocular involvement was clinically observed in three cases. In the remaining four cases, intraocular involvement was observed only through UBM. This study highlights the utility of UBM for detecting intraocular involvement in extensive, high-risk cases of OSSN.

Finally, Vizvári et al (44) compared conjunctival melanocytic nevi on AS OCT and UBM. They evaluated 56 eyes with slit lamp examination and AS OCT. Of these 56 cases, 21 patients were also imaged with UBM. In this imaged group of 21, in eight patients’ cysts were clinically evident upon slit lamp examination. Interestingly, AS OCT detected cysts in 12 patients, identifying subclinical cysts in four additional patients. Comparatively, despite visualization of the cysts clinically in eight patients, the UBM detected cysts in only six patients. However, UBM was able to show the posterior margins of all of the conjunctival nevi, while AS OCT was unable to show posterior margins in six nevi due to shadowing. This study is of particular value because it shows some of the strengths and weaknesses of these two imaging modalities with regard to imaging nevi. It shows that AS OCT can be more effective in visualizing details of nevi such as cysts, while UBM can be more useful for studying posterior margins.

Perspective

For imaging the ocular surface, UBM can provide fast and useful imaging. While the technology has existed for decades, studies such as these show that its applications in ocular surface imaging continue to expand. As demonstrated by these studies, UBM may be helpful in visualizing gross anatomical changes, such as intraocular involvements of ocular surface tumors, iris lesions and perhaps DMEK graft orientation. However, AS OCT can now produce images of much higher resolution than UBM, proving more useful in visualizing finer structures and details. As AS OCT has limited penetrance and issues with shadowing, the penetrative power and of UBM can complement AS OCT images.

In vivo confocal microscopy

Background

The first use of confocal microscopy to study corneas ex vivo was in 1985 by Lemp et al, who suggested its in vivo use (45). The first use of in vivo confocal microscopy (IVCM) of the cornea was by Cavanagh et al in 1990 (46). IVCM focuses on a small sample of tissue and eliminates visual noise by using a pinhole on a focal plan conjugate to the specimen, yielding high-resolution, high-contrast images, several of which can be combined to produce three-dimensional models of the sample tissue (47). IVCM is a powerful technology that allows for 800x magnification and visualization of microscopic and cellular structures (48). Currently available models offer high resolutions of four microns of axial resolutions and one to two microns of lateral resolution (49). Since its creation, IVCM has become widely used for imaging the ocular surface in the diagnosis and management of various pathologies such as corneal dystrophies, pterygia, ocular trauma, ocular surface squamous neoplasia, and more (50-54).

Recent developments

Schneider et al (55) used IVCM to measure Langerhans cell density in patients undergoing topical cyclosporine 0.05% eye drops twice daily for dry eye disease (DED). The confocal microscope was able to identify Langerhans cells to allow for quantification of cell density. They found significantly decreased Langerhans cell density after cyclosporine treatment. These findings are significant for ocular surface clinicians who may regularly encounter DED patients in their practices. It shows the utility of IVCM for measuring the effectiveness of therapy for DED.

Additionally, Takhar et al (56) used IVCM with a novel standardizing technique to evaluate corneal nerve metrics in patients with DED vs a control group. They were able to evaluate corneal nerve fiber length, corneal nerve fiber area, and fractal dimension of the corneal nerves. While they did not find significant differences between the DED and controls groups, their findings are valuable as it indicates that IVCM can play a role in reliably measuring corneal nerve metrics, which may be of great use for the management of other ocular surface pathologies.

Similarly, Dermer et al (57) used IVCM to evaluate the frequency of corneal sub-basal nerve plexus (SBNP) microneuromas (MN) among patients with and without dry eye (DE) symptoms. Nerve abnormalities like MN may cause neuropathic corneal pain similar to what is observed in some cases of DE. They found no significant difference in MN frequencies between patients with DE symptoms with a history of refractive surgery, patients with DE symptoms without a history of refractive surgery, and patients without DE symptoms. This study also demonstrates the role IVCM can play in evaluating corneal nerve health and imaging fine corneal lesions such as MN.

Guillon-Rolf et al (58) used IVCM to evaluate the SBNP morphology in patients with congenital corneal anesthesia. They found that, compared to a control group, patients with congenital corneal anesthesia had significantly decreased SBNP nerve fiber density, fiber length, and branch density, as well as significantly increased dendritiform cell density in the superficial cornea. These findings also show that IVCM can be useful for measuring corneal nerve metrics for the diagnosis of congenital corneal anesthesia as well as the management of other corneal pathologies.

Leonardi et al (59) compared slit lamp examination (SLE) and IVCM in the detection of corneal epithelial deposits in patients with Fabry disease. They found that only nine of 28 (32%) of Fabry disease patients showed cornea verticillate on SLE, while 25 (89%) showed epithelial hyperreflective deposits on IVCM. Additionally, 16 of the 19 eyes with no cornea verticillate detected on SLE did show epithelial deposits on IVCM. This study highlights the power of IVCM and that it can be significantly more effective at detecting corneal epithelial deposits than even an experienced clinician at the slit lamp.

Finally, one study also applied artificial intelligence models in combination with imaging technology. Wei et al (60) used a deep learning model to evaluate and segment the sub-basal corneal nerve fiber (CNF) with IVCM. The model had a mean average precision of 94%, sensitivity of 96%, specificity of 75%, and area under curve of .96 for corneal nerve segmentation. This study shows how deep learning models could allow for faster segmentation and evaluation of CNF in a standardized, reproducible method. Such technology could greatly facilitate how clinicians track and manage CNF health.

Perspective

The studies reviewed within show that the utility of IVCM continues to grow, due to both newfound applications for imaging ocular surface structures and pathologies and new advances in IVCM technology. With its powerful resolution and contrast, IVCM allows for evaluation of minute structures in virtual models. Its high resolution makes it especially well-suited for visualizing fine ocular surface details like corneal nerves, corneal epithelial deposits, cell densities, and more. IVCM is not an ideal imaging tool for visualizing whole lesions, several layers of the ocular surface, or gross ocular anatomy.

Conclusions

Optical coherence tomography, optical coherence tomography angiography, ultrasound biomicroscopy, and in vivo confocal microscopy are four of the most important imaging methods for the ocular surface. Recent studies reveal that these imaging modalities for ocular surface pathologies continue to evolve and provide new insights into pathology to aid the clinician. Studies reviewed within demonstrate how imaging technology can assist in the diagnosis and management of numerous ocular surface pathologies. Cutting edge developments such as μOCT and deep learning algorithms for imaging may be increasingly available in the near future and can greatly impact the way clinicians detect and evaluate the ocular surface.

Figure 3.

Figure 3.

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Seventy-year-old white female with an ocular surface squamous neoplasia (OSSN) of the left eye. A. Slit lamp image shows an OSSN covering the bulbar conjunctiva and cornea from 12-6 o'clock. The black dotted line marks the orientation of the high resolution OCT raster. B. High resolution AS OCT showing thickened hyperreflective epithelium (asterisk) with an abrupt transition (arrow). C. Slit lamp image of the same eye after medical treatment with topical 5-fluorouracil and interferon α-2b. The black dotted line marks the orientation of the AS OCT raster. D. High resolution AS OCT of the same eye after treatment showing normal thickness epithelium (arrow), with underlying subepithelial scarring noted.

Financial support:

NIH Center Core Grant P30EY014801, RPB Unrestricted Award, Dr. Ronald and Alicia Lepke Grant, The Lee and Claire Hager Grant, The Robert Farr Family Grant, The Grant and Diana Stanton-Thornbrough ,The Robert Baer Family Grant, The Emilyn Page and Mark Feldberg Grant, The Calvin and Flavia Oak Support Fund, The Robert Farr Family Grant, The Jose Ferreira de Melo Grant, The Richard and Kathy Lesser Grant, The Michele and Ted Kaplan Grant and the Richard Azar Family Grant(institutional grants).

Footnotes

Publisher's Disclaimer: This Author Accepted Manuscript is a PDF file of a an unedited peer-reviewed manuscript that has been accepted for publication but has not been copyedited or corrected. The official version of record that is published in the journal is kept up to date and so may therefore differ from this version.

Human and Animal Rights

All reported studies/experiments with human or animal subjects performed by the authors have been previously published and complied with all applicable ethical standards (including the Helsinki declaration and its amendments, institutional/national research committee standards, and international/national/institutional guidelines).

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