Age-related macular degeneration (AMD) is a leading cause of irreversible visual impairment in people over the age of 50 years.1 The global prevalence of any type of AMD has been reported to be 8.7%.2 Although approximately 170 million individuals are afflicted, the global prevalence of AMD is expected to increase to 288 million by 2040.2–4 AMD can be classified into early-stage, intermediate-stage, and advanced-stage AMD. Early- or intermediate-stage AMD is characterized by the presence of drusen and retinal pigment epithelial changes, and these may not affect vision significantly at these stages. Advanced-stage AMD, however, tends to be vision threatening and these individuals may present with either geographic atrophy (nonexudative AMD) or choroidal neovascularization (exudative AMD).
The management of AMD spans a large spectrum, from a simple screening of early AMD to complex, repeated treatments with intravitreal vascular endothelial growth factor (VEGF) inhibitors that require close monitoring and frequent visits in neovascular AMD (nAMD). Current management strategies in nAMD have evolved from the fixed monthly regimens proposed by the initial registration trials (CATT, MARINA, ANCHOR) to regimens such as treat and extend AMD (TREX-AMD).5–9 These regimens that take into account real-world clinical considerations, attempt to mitigate high treatment burdens but still require frequent interactions between patients and doctors in hospital settings for investigations and treatments. These management strategies have worked well to date to prevent vision loss in patients with AMD but need to adapt to face the potentially life-threatening challenges from a pandemic such as the coronavirus disease 2019 (COVID-19).
The COVID-19 was declared by the World Health Organization (WHO) as a pandemic on March 11, 2020.10–13 Ophthalmologists, like other healthcare providers, are faced with the responsibility of providing essential care while ensuring they are not vectors of the disease. In response to the crisis, many international ophthalmology societies and colleges quickly published guidelines and recommendations for best practices.14–16 Earlier this year, these ophthalmology societies recommended that ophthalmologists cease to provide any treatment other than urgent or emergent care. Several measures have been proposed to minimize COVID-19 spread among ophthalmic care providers and patients: administrative control to lower patient attendance and suspension of elective services, patient triage system at entrances to identify at-risk patients, and the promotion of the use of personal protective equipment.17–19 Although these measures were important to reduce the risk of COVID-19 spread, these measures are unsustainable in the long-term especially because we have yet to see an “end” to this pandemic.
Hence, in order to cope with these measures and the high burden of care associated with the management of nAMD, retina subspecialty clinics have been forced to adopt practices that differed from traditional treatment patterns.20 Although many of these strategies are practical and safe, there is an opportunity to further improve the management of AMD through the use of digital technology. Here, we review the current and future options of digital technology and how these may improve the management of AMD in the post-COVID world.
IMPACT OF COVID-19 WORLDWIDE
The COVID-19 pandemic that has plagued 2020 has affected people from all corners of the globe. As of December 29, 2020, over 79 million individuals globally have been infected with the novel coronavirus and over 1.7 million people people have lost their lives to it.21 The sudden surge of patients has strained healthcare infrastructure across the world, with resources stretched to the breaking point while the mortality from COVID-19 has risen steadily.22 With global recognition of the need to suppress spread, travel restrictions and social distancing were mandated by most countries in the world.23 This lock-down of movement has triggered widespread acceptance and adoption of digital communication with the intention of mitigating the social, economic, and political impact of the pandemic.24–26
DIGITAL TECHNOLOGY DURING THE COVID-19 PANDEMIC
Teleconferencing has become an essential daily tool for remote communication for purposes of work, social interaction, and medical consultations.27 Notably, Zoom Video Communications’ stock price rose dramatically with the implementation of social distancing measures, from US$68.04 on 31 December 2019 to $259.51 on 26 June 2020 on the US stock market.13 In addition, the e-commerce giants’ growth during this pandemic is proving to be substantial and multifactorial. Amazon's net sales have increased this year by 26% to US$75.5 billion in the first quarter of 2020 compared to US$59.7 billion in the first quarter of 2019.28 Alibaba Group's revenue for this year's first quarter amounting to a total of US$16.1 million compared to its counterpart in 2019 where US$13.9 million revenue was generated.29 This is contributed by a forced change in consumers’ spending behavior to online retail, which also generates demand for small businesses to utilize online retail as a platform to overcome financial difficulty during the current economic decline.30 Digital payments have also gained traction during this period. An analysis by Bain & Company estimated that there will be a 5% increase in digital payments compared to pre-COVID and e-commerce digital payments will increase by 1–2%.31 As quarantine orders have eased and people have ventured out of their homes, contactless payments have risen especially since initial reports from the World Health Organization carried warnings to the public that banknotes were capable of carrying and spreading the virus.32,33 Mastercard reacted by raising contactless payment limits across 29 countries.34
DIGITAL TECHNOLOGY IN MEDICINE
Virtual clinics and teleconsultation frameworks have been the means of provision of acute specialist care to rural areas.35 Among the first premises that encouraged the development of telemedicine was the recognition of the need to provide medical assistance to remotest areas. In the 1960s, along with the development of The Space Program in preparation for space missions, the National Aeronautic and Space Administration in the United States initiated the monitoring of astronauts’ health to provide medical aid if needed through remote teleconsultations.35,36 Since then, the use of teleconsultations has increased in medicine and ophthalmology. Australia has largely capitalized on teleconsultations and implemented schemes to review acute ophthalmological conditions remotely.37 These measures have resulted in improved patient convenience by cutting the need for extensive travel for medical advice and are also cost saving by reducing unnecessary acute transfers.38 Virtual clinics have reduced the workload on tertiary centers and improved the efficiency of eye clinics, particularly for glaucoma services.39 There has been increased adoption of digital platforms around the globe alongside the internet of things (IoT) that further allows for wider access to healthcare, eye care, and increased efficiency.40,41
In this global health emergency where medical resources outweigh demand, telemedicine has enabled the triaging of at-risk populations (Table 1). Teleconsultations have allowed patients’ symptoms to be evaluated for possible COVID-19 infections while reducing the risk of exposure to other patients, healthcare professionals, and the community.42,43 With the need for rapid detection of patients with COVID-19, several groups have also harnessed the automation of artificial intelligence (AI) to enable rapid automated diagnosis of COVID-19 through analysis of radiological imaging of the respiratory system.44–46 To enable monitoring and surveillance of this pandemic, public agencies have embraced digital technologies such as IoT, big data analytics, AI, and Blockchain.47 Use of digital tools utilizing GPS or Bluetooth tracking has been critical to aid contact tracing to identify exposed individuals and sever the chain of transmission.21 Easily accessible databases such as “Worldometer” show real-time live updates on the global number of positive cases, deaths, and recovered cases.48 Thermal camera setups at access points also provide fever screening areas, and when coupled with facial recognition software, allows rapid identification of COVID-19 suspect individuals in the community.49,50
TABLE 1 -
Digital Techniques Used by Health Symptoms and Government to Aid in Tackling COVID-19 Pandemic
|Strategy to Tackle COVID-19
||Digital Tool Employed
|Monitoring community cases
||Thermal cameras with facial recognition software49,50
||Thermal imaging, AI, IoT, big data
||Contact tracing with digital footprint90
||IoT, big data
||Real-time live updates of pandemic48
||IoT, big data
||Virtual clinics for remote consultations to reduce traffic into hospitals91
||Home monitoring of non-urgent diseases92
||IoT, big data
||Quarantine, remote working27
||Delivery of medications47
||Teleconsultations for symptomatic individuals with systemic or respiratory symptoms42
||Screening of high-risk individuals based on travel and contact history42
||AI, big data
||Home monitoring and triage of unstable patients93
||IoT, big data
|Diagnosis of confirmed cases
||Automated diagnosis of COVID-19 from chest imaging44,46
||Multimodal automated analysis of symptoms, exposure history, laboratory test, and imaging45
|Interventions and treatment of COVID-19 patients
∗Electronic Intensive Care Unit monitoring programs42
AI indicates artificial intelligence; IoT, internet of things.
DIGITAL TECHNOLOGY IN OPHTHALMOLOGY
Although digitalization has been more widely accepted with recent pressures, this fourth industrial revolution had already begun to transform various sectors with no exception to healthcare.51 Ophthalmology has been at the forefront of this foray and with its culture of innovation, it was quick to adopt these novel digital technologies, including virtual health, AI, and digital home-monitoring applications to aid in improving patient care.52 Telemedicine has been integral in improving screening programs of ophthalmological diseases.35 As the availability of experienced ophthalmologists may be scarce especially in developing countries, telemedicine may allow for more appropriate distribution of resources.53,54 This is through more people screened at an early stage of disease by specialty-trained nurses and graders, allowing ophthalmologists to focus their efforts toward managing difficult and severe cases.53,54 Telemedicine has also facilitated the management of more than 10,000 potentially complex cases in low- and middle-income countries via the Orbis Cyber-Sight telemedicine program.55 The portal provides a platform for ophthalmologists in developing countries to transmit patient data and images safely, and to consult with expert mentors in the field. With the increasing development of AI, automated diagnosis of ophthalmological conditions has helped to address concerns of limited resources by providing an automated way of triage common causes of vision-threatening conditions. There is a keen global interest in AI to detect diabetic retinopathy, a major worldwide cause of preventable blindness. Products of this are multiple algorithms able to detect not only diabetic retinopathy from fundus photographs with high sensitivity and specificity, but in addition, other related eye conditions such as diabetic macular edema, glaucoma, and age-related macular degeneration.56 With retinopathy of prematurity being the leading cause of childhood blindness causing lifelong morbidity, AI algorithms for retinopathy of prematurity has been developed to address concerns of reliability and accuracy of screening of at-risk babies especially in low- or middle-income countries, usually limited by inadequate equipment, training, and personnel.57 As the retina is the only organ in which direct observation of blood vessels in vivo is possible, studies have shown correlations with the health of the microvasculature of the heart and brain. Therefore, future developments in teleophthalmology are likely to provide opportunities to use retinal vascular health screening to identify cardiac, neurovascular, and systemic diseases.58,59
DIGITAL TECHNOLOGY IN AMD
AMD typically affects elderly patients who are also at risk of morbidity and mortality related to COVID-19. We envisage that with current and future digital tools, the management of AMD can be streamlined and adapted to reduce patients’ risk of exposure to COVID-19. This digital revolution can address all aspects of AMD management. First, AMD screening can be readily performed using fundus and Optical coherence tomography (OCT) imaging in the community. Next, patients with abnormalities detected can be referred to virtual AMD clinics for expert evaluation and a clinic visit only if treatment with intravitreal VEGF inhibitor therapy is required. Finally, once stability of the disease has been achieved, home-monitoring using digital applications or devices can be implemented to avoid unnecessary hospital visits.
AI for AMD Screening and Treatment
In the past few years, several deep learning systems (DLS) have been developed for detecting and classifying the severity of AMD based on color fundus photographs. Although the majority of these algorithms were built using the Age-related Eye Disease Study (AREDS) materials,60–62 others have come from population-based studies and diabetic retinopathy screening programs.56,63 Because the color fundus images in the AREDS dataset were captured as analog photographs, they were subsequently digitized. Whether the DLSs trained using digitized images will show similar analyzing capability if presented with images that were acquired using digital cameras has not yet been established; however, there are available and increasing number of DLS trained to identify AMD from digital camera images. Most Deep learning (DL) algorithms have demonstrated the potential to perform different AMD classification tasks at high accuracy and noninferiority when compared with retinal specialists or professional human graders.56,60–62 The DLSs utilizing AREDS dataset for both training and testing purposes obtained high performance. To exemplify, Grassmann et al obtained a sensitivity of 84.20% and specificity of 94.30%, and Burlina et al obtained an area under the curve of receiver operating curve (AUC) of 0.94–0.96. Ting et al confirmed these findings in multiethnic real-world datasets allowing for broader applications of this technique.56,60,61
Apart from digital fundus photographs, OCT can also play an important role in AMD screening. DL algorithms have been built to deliver automated segmentation and classification tasks using OCT images that are key for detecting the new onset of nAMD. The clinical application of DL on OCT scans was described by De Fauw et al.64 Using 14,884 three-dimensional OCT scan volumes, they built a two-stage framework by decoupling the segmentation and classification network, which provides 1 of 4 referral suggestions, that is, urgent, semi-urgent, routine, and observation only. This framework was tested for patient triage in an ophthalmology clinic based on more than 50 common diagnoses that can be derived from OCT, compared with retinal specialists and optometrists. The DL algorithm was comparable to the decision for “urgent referral” made by 2 expert retina specialists and was better in making this decision as compared to 2 other retinal specialists and 4 optometrists with an AUC of 0.99. A key advantage of this two-stage framework is that the model can be generalized to a new OCT device by retraining the segmentation stage with manually annotated slices, whereas the classification network remains unchanged. The error rate of the framework tested on Spectralis OCT scanner with adapted segmentation network was 3.4%, not significantly different from the error rate of 5.5% on the original device type.64
Lack of confidence in the feasibility of integration of these systems and the “black box” unaccountable nature of DLS garnered some resistance to adoption during initial proposals. However, the development of “heatmaps,” areas of focus of the DLS, provided clinicians and policymakers more understanding of the neural networks’ learning and decision-making. Figure 1 shows examples of heatmaps of our DLS showing eyes with advanced AMD compared to a normal fundus. This demonstrates that the DLS is able to identify pathology in the macula suggestive of AMD and thus classify it to have AMD. The cost-effectiveness of integrating AI solutions into screening programs have also been a considerable factor for policymakers determining widespread adoption. Xie et al explored the cost-effectiveness of a fully-automated, semi-automated model for diabetic retinopathy, a vision-threatening ophthalmological condition with national screening in many countries, which demonstrated reduced cost per patient per year, providing economic rationale to integrate AI into the screening program.65
A recent feasibility study adapted the multimodal retinal image analysis consisting of fundus photographs, OCT, and OCT angiography scans. Although the training dataset was relatively small (75 participants), Vaghefi et al showed that by combining multiple modalities, the DLS accuracy increased from 91% to 96% in detecting intermediate AMD, compared to using OCT alone.66 With methods to mitigate the common problem of small datasets required for training of algorithms such as generating new images through the use of Generative Adversarial Networks, further studies could even show improvement in outcomes. Figure 2 shows examples of Generative Adversarial Network-created images of AMD compared to actual images taken of eyes with AMD, showing the ability for realistic images of AMD to be created for the benefit of future studies and DLS development. Another method to overcome the problem of small datasets is to adopt “live” clinical databases that will accumulate an increasing amount of datapoint and allow interactive improvement and refinement of DLS for patients that may have heterogeneous factors for genetic and environmental susceptibility. Thus, further research should note that it is crucial to use large multicenter datasets with various macular diseases and to incorporate a multimodal approach with clinical data, color fundus photographs, and OCT imaging, in order to enhance the generalizability of the AMD DL framework.
Although the DLS is able to screen for AMD, there are potential limitations in its clinical use as a screening tool for some ocular conditions as it does not address comorbid conditions or risk factors before the development of ophthalmoscopic findings. For example, elevated intraocular pressure before glaucomatous optic neuropathy and elevated glycated hemoglobin before worsening diabetic retinopathy. Thus, one would be cautious to interpret DLS screening results in the isolation of these risk factors.
In the management of nAMD, OCT monitoring of morphology of retinal lesions and disease activity forms an integral part of monitoring and decision for retreatment. With increasing demands for effective and accurate OCT monitoring, automated techniques have been explored.67,68 These include the Notal OCT Analyzer that reports high-concordance rates when comparing to retinal specialists with an accuracy of 91%, sensitivity of 92%, and specificity of 91%.68 A recent study utilizing the AREDS2 10-year Follow-On study (AREDS2-10Y) with 1127 eyes with longitudinal data showed that the AI-based algorithm achieved a higher level of performance at detecting the presence of retinal fluid than human retinal specialists (accuracy 0.851 versus 0.805, sensitivity 0.822 versus 0.468, specificity 0.865 versus 0.970, respectively) when compared to the ground truth of expert graders at the University of Wisconsin Fundus Photograph Reading Center.67
AI has lent its ability to develop further tools to aid the management of nAMD by defining the disease and detection of biomarkers of nAMD. Various algorithms have been developed to monitor nAMD using biomarkers including but not limited to intraretinal fluid, subretinal fluid, pigment epithelial detachment, drusen, and geographical atrophy.69 The development of systems to better quantify and measure retinal fluid will enable a reliable assessment of response to anti-VEGF treatment compared to the qualitative evaluation currently used in clinical practice.70 Schmidt-Erfurth et al utilized automated segmentation methods in deep learning to ascertain volumes of intraretinal fluid, subretinal fluid, and pigment epithelial detachment, and applied this algorithm to a phase III HARBOR clinical trial.70 This study demonstrated that the stricter treatment arm with a higher dose and regular monthly dosing of anti-VEGF resulted in the least residual fluid, exemplifying how these AI algorithms are enabling improving therapeutic regimes for nAMD.70
Personalized medicine has been highly regarded as the gold standard of treatment options for an individual where treatment is optimized to minimize side effects and maximize efficacy. Development of AI algorithms aiming to predict progression to late dry and late wet AMD based on color fundus photographs allows higher-risk individuals who may benefit from closer follow surveillance and may guide management by advising on better control of risk factors and for alternative advanced treatment.71,72 In the current technological climate, models have been having high-accuracy rates with detection, but accuracy in prediction of progression of AMD has not achieved such high rates yet that proves to be a difficult task with few groups attempting this.71 In addition, predicting the onset of the disease is currently difficult with limited images of asymptomatic patients. Prognostication of functional improvement from treatment through algorithms has been explored to provide predictive information that can assist in patients’ autonomous decision-making. A study utilizing machine learning to predict visual acuity (VA) after the commencement of anti-VEGF treatment at 3- and 12-month intervals showed that the difference between algorithmic prediction and actual VA was between 0.11 and 0.18 logMAR for 3-month forecast and 0.16 and 0.22 logMAR.73 This demonstrates the utility that AI may provide in the creation of personalized medicine.
Virtual AMD Clinics for Diagnosis and Treatment
The concept of “virtual” (without actual consultation) medical retina clinics emerged in 2015.74 In this “virtual” clinic,” all patients had VA tests and OCT scan performed and reviewed asynchronously by the medical team without a face to face specialist consultation. The implementation of these virtual AMD clinics not only assisted with a reduction in mean time between consecutive appointments and waiting times, but also resulted in significant visual gains.74 Furthermore, previous studies have demonstrated high inter-reader and intrareader agreement for OCT scans.75,76 In another study, a reduction in healthcare burden was demonstrated when up to 44% of patients were found to be suitable for virtual clinics where only OCT and ultra-widefield imaging were performed.77
With the advances in imaging coupled with potential AI-driven decision making, we expect that the monitoring of treatment response, recurrence during maintenance phase or after cessation of treatment, and observation of the fellow eye for incipient neovascularization can be managed using “virtual” clinics. This concept adheres to the principles of social distancing, which is imperative for the prevention of COVID-19 spread, by allowing the acquisition of images and subsequent decision making to be separated in time and space.
By far the largest survey of patients’ attitudes regarding attending virtual clinics revealed that more than 86% of patients were supportive of a “virtual” clinic review in place of face-to-face clinic appointments.78
Real-World AMD Retina Clinics
nAMD is a sight-threatening condition that requires prompt and regular intravitreal anti-VEGF injections. Retina subspecialists treating nAMD have developed various strategies during the initial “lockdown phase.” The aim was to reduce the contact time between ophthalmic care providers and patients and congestion within the clinic, while maintaining visual improvement and/or visual stability. One of the strategies we implemented (Table 2) included a variation of the “Treat-and-Plan” regime as described by Antaki et al.20
TABLE 2 -
The Clinical Protocol for New Referral Visits Versus Follow-Up Assessment Visits Versus Treatment-Only Visit
|Type of Visit
||New Referral Visit
||Follow-Up Assessment Visit
||VA, OCT, DFE
||- If VA and symptomatically stable: VA, OCT, or DFE- If VA and symptomatically worse: VA, OCT, DFE ± FA, ICG, OCTA
||Loading dose phase – 3 monthly intravitreal injections
||No disease activity: allocate to fixed-interval regime based on last stable treatment intervalPresence of disease activity: decrease treatment interval by 2 weeks
||For intravitreal injection
DFE indicates dilated fundal examination; ICG,Indocyanine green angiography; OCT, Optical coherence tomography; OCTA, Optical coherence tomography angiography; VA, visual acuity.
This involved 3 types of visits, new referral visit, follow-up assessment visit, and treatment only visits (Table 2). In our setting, we performed similar tests (VA, dilation, and OCT) during the new referral visits, with FA, Indocyanine green angiography, and Optical coherence tomography angiography performed only upon request of the treating physician. Patients on active treatment who attended follow-up assessment visits had VA tests with either OCT or dilated fundal examination. If these patients were deemed stable by the treating physician the patients then proceeded directly for treatment. However, if vision had declined by 1 line from the previous visit or the patient reported worse vision, both OCT and dilated fundal examination were required and treatment interval titrated based on activity status. We also instituted treatment-only visits in which patients on fixed or regular intervals attended for treatment only without further tests or investigations. Although these measures help reduce contact time and congestion, a potential downside exists for stable patients due to the inability to extend treatment intervals.
The future development of a pandemic-ready, robust clinical management must address new referrals and follow-up protocols, patient treatment compliance, tracking of clinical outcomes, and also data security.
Digital monitoring devices for AMD – ForeseeHome, myVisionTrack, Alleye
Since the late 1960s, self-monitoring in AMD patients has traditionally involved the use of an Amsler chart (grid). The Amsler grid can evaluate the central 20° visual field when used at a 30-cm testing distance.79 The identification of subtle changes in visual function (such as distortion) may suggest AMD disease activity or recurrence. The limitations of the Amsler chart include its subjective and qualitative nature, crowding effects, and perceptual completion phenomenon, hence limiting its sensitivity in detecting AMD-related visual changes.80
There are several alternatives to the Amsler chart. In an effort to improve AMD disease monitoring and recurrence preferential hyperacuity perimetry (PHP) was developed by Loewenstein et al.81 The initial technique was more sensitive than the traditional Amsler chart but had a relatively high rate of false positives. Further iterations of PHP was able to differentiate recent-onset nAMD from intermediate AMD with higher sensitivity and specificity.82 Recently, portable home monitoring devices such as the ForeseeHome AMD monitor utilizes PHP testing to detect new choroidal neovascularization development at an earlier stage83 (Fig. 3).
The shape discrimination hyperacuity (SDH) testing is another method of early identification of AMD and its progression.84 Wang et al found that a mobile version of the SDH test, myVisionTrack (mVT) developed by Genentech USA, Inc, was comparable to the previously established desktop SDH. This provides patients with a new tool that is intuitive and readily accessible to monitor macular diseases at home.85 A subsequent study by the same group also showed that elderly patients were willing to comply with this novel method of self-monitoring.86
Another recently developed novel mobile application, Alleye developed by Oculocare medical Inc. in Switzerland, uses an alignment hyperacuity task (dot alignment) to monitor visual function.87 In contrast to mVT that detects and characterizes the central 3° of metamorphopsia, Alleye screens 12.7 thus covering almost the entire macular region. The extended area of screening is useful when considering macular pathology typically extends within the vascular arcades (Fig. 4). Further studies are currently underway for evaluating the reliability of different tests for monitoring disease progression and for early detection of fellow eye involvement.88,89
Real-World Experience with Alleye Home Monitoring Application
In Singapore National Eye Center, we deployed the Alleye application to patients who had their appointments deferred over the COVID-19 pandemic lockdown in Singapore. Patients scheduled for a follow-up in the retina clinic for any condition over the lockdown period (end April 2020 to middle June 2020) were deferred based on electronic chart review by treating physicians. All deferred patients were subsequently invited to participate in a pilot test of the Alleye app with an aim to detect early changes in vision due to reactivation of disease.
COVID-19 was an unexpected catalyst for digitalization progression in this century and transformation of people's daily lives. Although digital strategies were employed to monitor and curb the community spread of the virus, these initiatives were also extended to address preexisting demands on healthcare. This has become part and parcel of our “new normal” in healthcare provision and has become essential in the fight against this pandemic. In the ophthalmology community, the management of AMD has been profoundly affected as these patients are not only most vulnerable to COVID-19 infections but also require regular monitoring and treatment to slow the progression of the disease. There is an urgent unmet need to transform the way care is provisioned for AMD during this crisis and beyond. Digital transformation may be the solution for ensuring safety in all aspects of AMD management. This transformation includes advanced analytic techniques such as AI to detect and screen for disease, novel models of care that ensure minimal contact and social interactions, treatment strategies such as the “Treat-and-Plan” regime, and digital home monitoring initiatives that can detect early changes of AMD. In the post-COVID-19 new normal, we may see these strategies become more prevalent as evidence of their effectiveness to provide safe care materializes. With the continued evolution and improvement of digitalization, we will be better equipped to face the next challenge.
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