Automated Pupillometry Improves Care in Neuro ICU

Article: Enhancing Reliability with Automated Pupillometry
Source: Vanderbilt University Medical Center
Published: May 19, 2021

Assessing pupil size and reactivity provides vital information about the care of patients in the neurology ICU. Although manual methods based on visual estimates via penlight remain established practice, in large part due to convenience and equipment availability, they also present obstacles in terms of reliability, varying among operators and patient eye colors. Intubation and intravenous lines blocking a clear line of sight, as well as cases of sedation and pharmacologic paralysis, can also present challenges. The Neurology Department at Vanderbilt University Medical Center is assessing the use of an automated handheld pupillometer by NeurOptics for more accurate and objective measurements of pupillary size, shape, and light reactivity. These measurements are quantified as a Neurological Pupil index (NPi), which provides valuable information regarding subtle changes before visible changes in pupil size are seen. As an assistant professor of the program remarks, “The impact of accurate versus slightly inaccurate serial measurement can be profound...Pupillometry may allow for more urgent medical or surgical intervention in some of our sickest patients, particularly those with rising intracranial pressures that can result in permanent damage, like brain herniation.” Similarly, they report that quantitative pupillometry outperformed manual measurements in comatose cardiac arrest patients, especially in predicting unfavorable outcomes, as well as successfully identified early changes in neurologic function, intracranial pressure, and treatment response to osmotherapy, among other neurologic conditions. Automated pupillometry, even at VUMC, is not indicated for all patients, but rather for patients with the highest risk, such as patients with intracranial injury or patients who experience neurologic decline. The team anticipates automated pupillometers becoming standard of care for units that treat trauma and critical illness.

My rating of this article: ⭐⭐⭐

Social Interaction as Seen through Pupils

Article: Window to Mind: Pupils Mirror Perception of Social Interaction
Source: Chinese Academy of Sciences (China)
Published: July 30, 2021

As part of the autonomic sympathetic nervous system, the pupils of our eyes change size in response to arousing emotional stimuli. Psychologists in China were interested in exploring whether pupil size could also serve as a window to social motivations, particularly social interaction. In a set of three experiments, the scientists tested pupillary response to second-person social interaction, observation of third-person social interaction, and communicative social interaction. They found that pupil size enlarged when the participants perceived a single agent sending interactive intention toward them as compared to toward others, and when they viewed two agents interacting with each other as compared to facing away from each other. These pupil dilation effects, however, relied on correct understanding of the communicative intentions of the interacting agents. The experiments show that, perhaps related to well-documented relationships between pupils and emotional response, pupil size could also indicate perception of social interaction. In brief, humans are social beings possessing intrinsic motivations toward interacting with others and maintaining social relationships. The study adds insight to the visual system's sensitivity to social interaction, with pupils being a potential biomarker for early detection of social cognitive disorders.

Personal commentary: Information about the study design is limited based on the news article.

My rating of this article: <⭐

Cheng Y, Liu W, Yuan X, et al. "The Eyes Have It: Perception of Social Interaction Unfolds Through Pupil Dilation." Neuroscience Bulletin.  37:1595–1598. 1 July 2021. https://doi.org/10.1007/s12264-021-00739-z

Framing Strategies Stabilize Visual Perception

Article: How Do We Know Where Things Are?
Source: Dartmouth College
Published: June 24, 2021

When we move our eyes to look around a scene, the image of the world projected onto our retina also moves, which in turn changes the image that is sent to the brain. Yet, our brains perceive a stabilized view of the world. Psychologists studying this process, known as "visual stabilization," tested the brain's inherent "steady cam" through two experiments, conducted both in person and online. The first experiment is an example of “paradoxical stabilization,” in this case demonstrating how a stabilized view is produced by a moving frame replicated on a computer monitor. A second experiment demonstrated that participants perceived the location of objects in relation to (moving) frames, even when the objects themselves were stationary. This effect held true across a wide range of frame speeds, sizes, and path lengths tested. In other words, even though the image of what we see "moves" on our retina when our eyes move, (1) the presence of a frame in the scene stabilizes our judgments of location, and (2) our brain has a tendency to perceive objects in relation to available frames. As the senior author of the study states, “Our results show that a framing strategy is at work behind the scenes all the time, which helps stabilize our visual experience.”

My rating of this study: ⭐

Özkan M, Anstis S, Hart BM, et al. "Paradoxical stabilization of relative position in moving frames." PNAS.  18(25):e2102167118. 22 June 2021. https://doi.org/10.1073/pnas.2102167118

Binocular Connectivity with Selective Monocular Function in the Mouse Retinogeniculate Pathway

Article: Picky neurons: In the visual thalamus, neurons are in contact with both eyes but respond to only one
Source: Max Planck Institute of Neurobiology (Germany)
Published: June 18, 2021
Article: Neurons Simplify Visual Signals by Responding to Only One Retina
Source: The Scientist
Published: October 1, 2021

Ipsilateral nerve fibers (red) and contralateral nerve
fibers (green) in the mouse visual thalamus

The visual thalamus—in humans, comprised of the lateral geniculate nucleus (LGN), the thalamic reticular nucleus (TRN), and the pulvinar—relays visual stimuli from the retina to the primary visual cortex. The retinogeniculate pathway, involving the LGN, is of greatest interest to visual perception. According to a long-standing theory, signals from the two eyes are separated in the visual thalamus before being transmitted to the visual cortex. However, investigations into the visual thalamus of mice showed that a large number of neurons form synapses with retinal ganglion cells (RGCs) of both eyes. Using optogenetics, researchers confirmed this finding. However, they also discovered that very few of the neurons actually receive equal signal strength from both eyes. Rather, in most neurons, signal strength from one eye dominates over the other, with the weaker signals from the non-dominant eye not reaching threshold to trigger an action potential. The researchers hypothesize that they do not play a major role in processing visual information. In other words, although demonstrating structural binocular connectivity, these cells in the mouse visual thalamus were functionally monocular, resolving the contradictory findings in the earlier study. From a basic science standpoint, the findings showed that anatomy does not necessarily confer function; in this case, neurons in contact with one another do not necessarily communicate extensively. From the perspective of function, the study showed that even with equal access to both eyes, thalamic cells selectively establish functional connections with only one eye. Monocular connections are explained by synaptic selection rather than by anatomical overlap between RGC axons and dLGN neuron dendrites alone. Furthermore, synapses with the dominant eye strengthen while those of the nondominant eye remain immature. The scientists next plan to study how eye dominance is determined, whether there are variations in different RGC types, and whether the immature contact sites could be activated when needed, for example to treat eye conditions such as amblyopia.

My rating of this study: ⭐⭐⭐

Bauer J, Weiler S, Fernholz MHP, et al. "Limited functional convergence of eye-specific inputs in the retinogeniculate pathway of the mouse." Neuron.  18 June 2021. https://doi.org/10.1016/j.neuron.2021.05.036

Week in Review: Number 33

Visual Impairment May Increase Risk of Dementia
A study using data from the World Health Organization's Study on Global Ageing and Adult Health (SAGE) found that older people with visual impairment were significantly more likely to suffer mild cognitive impairment (MCI), a potential precursor to dementia, which in turn is a major cause of disability and dependency among older individuals. Based on population data of 32,715 people older than 50 years of age from China, India, Russia, South Africa, Ghana and Mexico, the researchers found that people with visual impairment at both distance and near vision were 1.7 times more likely to suffer from mild cognitive impairment than those without visual impairment. Similarly, people with near visual impairment were 1.3 times more likely to suffer from mild cognitive impairment than those without. However, those individuals who reported only distance visual impairment did not appear to exhibit increased risk. The overall prevalence of mild cognitive impairment was 15.3% in the study sample, and 44% of the study population reported no visual impairment at all, suggesting that the connection to cognitive impairment is not strictly due to age. One of the authors comments, “Research now needs to focus on whether intervention to improve quality of vision can reduce the risk of mild cognitive impairment, and ultimately dementia. More work needs to be done to examine any possible causation, and what the reasons might be behind it.”

AI for the Diagnosis of Retinopathy of Prematurity
An artificial intelligence technology used in the United States to diagnose retinopathy of prematurity (ROP) was successfully applied in India, according to researchers at OHSU and Massachusetts General Hospital. Retinopathy of prematurity develops in premature infants who are given high levels of oxygen to sustain them after birth; the high amount of oxygen causes abnormal blood vessel growth in the retina, potentially leading to blindness. Retinopathy of prematurity affects 20,000 babies worldwide, especially in developing countries where there are fewer trained ophthalmologists. According to an earlier study published in JAMA Ophthalmology, the use of this technology to diagnose ROP via images showed a 91% accuracy rate compared to expertly trained ophthalmologists. The new study applied the algorithms to 1,253 eye exams from an ROP telemedicine program in India, and correctly identified 100% of severe cases requiring treatment. The researchers also report that their i-ROP DL system is less susceptible to racial bias by implementing a two-step process, first identifying blood vessel patterns in the original eye image, then turning the image into a black-and-white blood vessel map. It is this second image in black-and-white that is analyzed for ROP, the greyscale colors reducing ethnicity-related differences in retinal image appearance. The technology has been granted breakthrough status by the FDA in 2020 and is licensed to a company called Boston AI Labs for further development. The study authors conclude, "Integration of AI into ROP screening programs may lead to improved access to care for secondary prevention of ROP and may facilitate assessment of disease epidemiology and NCU resources."

RPE Proliferation as a Novel Cause of Uveal Coloboma
Colobomas are congenital ocular malformations resulting from the incomplete closure of the optic fissure during embryonic development. Although most commonly visualized as incomplete formation of the iris, colobomas can occur in a variety of ocular structures, including the lens, choroid, retina, optic disc, and eyelid. Depending on the eye tissue affected and the extent of malformation, colobomas can cause blindness. Prior research demonstrated that mutations in the gene encoding neurofibromin 2 (NF2), a tumor suppressor protein important in tissue development and regeneration, can cause colobomas, among other contributing causes. Researchers studying the role of the gene Nf2 found that silencing the gene in developing mouse eyes led to proliferation of the retinal pigment epithelium (RPE) in the optic fissure region, with RPE cells not forming a monolayer but multiple layers. The cellular crowding from RPE proliferation prevents the cells from transitioning to a cuboidal shape. This leads to improper alignment and orientation of the RPE cells, failure of optic fissure fusion/closure, and ultimately persistent coloboma. The researchers also note that, interestingly, these cells retain their RPE character, rather than transforming into other tissues of the retina. The authors write, "Our findings indicate that limiting proliferation particularly in the RPE layer is a critical mechanism during OF [optic fissure] closure." They hope that studying the underlying mechanism of RPE proliferation during development may help to understand factors preventing regeneration of adult RPE and inform therapeutics for RPE-related eye diseases.

Shared Mutations in Skin & Conjunctival Melanomas
Researchers in the U.K. studying how ultraviolet radiation contributes to cutaneous melanomas found that the same genes that cause these skin cancers also cause a rarer form of melanoma of the eye, namely, conjunctival melanoma, of the mucous membrane that lines the sclera of the eye and inner lids. In particular, the researchers applied whole genome sequencing to 10 samples of conjunctival melanomas and found UVR-associated single base substitution signature 7 (SBS7) genetic mutations in 9 of the conjunctival melanomas, as compared to 1 sample of conjunctival melanoma and 8 samples of other mucosal melanomas that did not show these features related to ultraviolet radiation. They argue that SBS7 dominance in mucosal melanoma is a better indicator of UVR-exposure than tumor site. Furthermore, they found that ultraviolet radiation-induced conjunctival melanomas contain the same cancer mutations in the BRAF and NRAS genes. This contrasts with earlier understanding that the KIT and SF3B1 mutations are more common in mucosal melanomas and the BRAF and NRAS mutations are more common in cutaneous melanomas. Although uveal melanomas, another rare melanoma of the eye, are less related to ultraviolet radiation, the researchers report that their findings complement an earlier study showing that ultraviolet exposure can present SBS7 predominance if it arises on the iris. A common driver of both cutaneous and conjunctival melanoma, the researchers argue, facilitates the application of therapies developed primarily for cutaneous melanoma in the context of ocular melanomas, such as the BRAF inhibitor vemurafenib used to treat skin melanoma. The lead author of the study comments, “Our work shows the importance of delving into the underlying biology in rare cancers, which could identify new tailored treatment avenues for people. In this case we have identified mutations in a rare type of eye cancer that could be targeted by drugs used to treat skin cancer.”

Effects of Dual Sensory Impairment in Women & Men
Two studies from researchers in the U.K. examined the effects of vision, hearing, and dual sensory impairment or loss in women and men, with attention to gender differences. The survey data in the first study, from a database of 23,089 adults in the Spanish National Health Survey, showed that women were between 2 and 2.5 times as likely as men to report experiencing depression and anxiety. Compared to women without sensory impairment, women with dual sensory impairment were almost 3.5 times more likely to report depression or anxiety. Compared to men with no sensory impairment, men with dual sensory loss were almost 2.8 times more likely to report depression and almost 1.8 times as likely to report anxiety. Finally, as expected, dual sensory loss was associated with higher levels of depression and anxiety compared to single sensory loss. In this study, although both genders report experiencing mental health effects, the association was stronger in women. The lead author of the study comments, "This highlights the importance of interventions to address vision and hearing loss, especially in women. Some sensory loss is preventable or treatable, and clearly these issues are taking their toll not just on physical health, but mental health too."

In a second study, using the same Spanish National Health Survey database, the same lead researcher explored associations between physical inactivity and obesity in women and men with vision, hearing , and dual sensory impairment or loss. They found that in people with vision loss, the likelihood of obesity was about 1.4 times higher than those who did not report vision loss. Furthermore, in people with vision loss, the prevalence of obesity was roughly 1.5 times higher in inactive men than in inactive women. Again, as expected, those with combined hearing and vision impairment were more likely to experience inactivity and obesity compared to those with single sensory impairment. The researchers note that although women were overall less physically active than men, an association between physical inactivity and obesity was found in men but not in women. Similar to interventions for depression and anxiety, they conclude that active steps should be taken to reduce the risk of weight gain in people with sensory impairments.

Attentional Blink Phenomenon in Infants
Spatial and temporal attention are primary cognitive processes that enable higher order thinking. Spatial attention is an aspect of visual working memory that develops dramatically during the first year of life and has been previously demonstrated to be similar between infants and adults. Researchers were curious to know whether the temporal element of visual working memory was also similar between adults and preverbal infants. They explored this question through testing the attentional blink effect, a temporal limitation in processing visual information when perception of images occurs less than half a second apart. In other words, if two images occur less than 500 ms apart, visual working memory would "blink" and not register the perception of one of the images. The sample comprised of forty 7- to 8-month-old infants, who were presented with rapid serial visual streams of two female faces as targets at a rate of 100 ms per image and temporally separated by either 200 ms or 800 ms. The scientists took advantage of infants' preferential looking at novelty to identify whether the infants could perceive an image. They found that the babies could identify targets at 800 ms, but not identify targets at 200 ms. They could consolidate items into visual working memory at the longer lag, within a second, but not at the shorter lag of less than half a second. In other words, for targets that were temporally separated by less than half a second, the infants demonstrated attentional blink. Like the similarities between adult and infant spatial visual attention, this study points to similar patterns in temporal visual attention, and the same temporal limitations, between adults and infants that take place as early as within the first year of life. The researchers argue that in addition to being the first study to demonstrate attentional blink in preverbal infants, study of this phenomenon is also relevant as it relates to consciousness.

In Other News
(1) Serious visual impairment declines among older Americans
(2) Added features in VR headset-based vision testing
(3) How newborn mammals dream the world they're entering (Related)

Attentional Blink Phenomenon in Infants

Article: Infants recognize rapid images, just like adults
Source: Hokkaido University (Japan)
Published: May 22, 2021

Infants could identify two faces when the temporal interval was 800 ms,
but they could identify only the first target (overlooking the second)
when the separation was 200 ms.

Spatial and temporal attention are primary cognitive processes that enable higher order thinking. Spatial attention is an aspect of visual working memory that develops dramatically during the first year of life and has been previously demonstrated to be similar between infants and adults. Researchers were curious to know whether the temporal element of visual working memory was also similar between adults and preverbal infants. They explored this question through testing the attentional blink effect, a temporal limitation in processing visual information when perception of images occurs less than half a second apart. In other words, if two images occur less than 500 ms apart, visual working memory would "blink" and not register the perception of one of the images. The sample comprised of forty 7- to 8-month-old infants, who were presented with rapid serial visual streams of two female faces as targets at a rate of 100 ms per image and temporally separated by either 200 ms or 800 ms. The scientists took advantage of infants' preferential looking at novelty to identify whether the infants could perceive an image. They found that the babies could identify targets at 800 ms, but not identify targets at 200 ms. They could consolidate items into visual working memory at the longer lag, within a second, but not at the shorter lag of less than half a second. In other words, for targets that were temporally separated by less than half a second, the infants demonstrated attentional blink. Like the similarities between adult and infant spatial visual attention, this study points to similar patterns in temporal visual attention, and the same temporal limitations, between adults and infants that take place as early as within the first year of life. The researchers argue that in addition to being the first study to demonstrate attentional blink in preverbal infants, study of this phenomenon is also relevant as it relates to consciousness.

My rating of this study: ⭐⭐

Tsurumiab S, Kanazawac S, Yamaguchi MK, et al. "Attentional blink in preverbal infants." Cognition.  214:104749. September 2021. https://doi.org/10.1016/j.cognition.2021.104749

Visual Impairment May Increase Risk of Dementia

Article: Partially sighted may be at higher risk of dementia
Source: Anglia Ruskin University (U.K.)
Published: April 30, 2021

A study using data from the World Health Organization's Study on Global Ageing and Adult Health (SAGE) found that older people with visual impairment were significantly more likely to suffer mild cognitive impairment (MCI), a potential precursor to dementia, which in turn is a major cause of disability and dependency among older individuals. Based on population data of 32,715 people older than 50 years of age from China, India, Russia, South Africa, Ghana and Mexico, the researchers found that people with visual impairment at both distance and near vision were 1.7 times more likely to suffer from mild cognitive impairment than those without visual impairment. Similarly, people with near visual impairment were 1.3 times more likely to suffer from mild cognitive impairment than those without. However, those individuals who reported only distance visual impairment did not appear to exhibit increased risk. The overall prevalence of mild cognitive impairment was 15.3% in the study sample, and 44% of the study population reported no visual impairment at all, suggesting that the connection to cognitive impairment is not strictly due to age. One of the authors comments, “Research now needs to focus on whether intervention to improve quality of vision can reduce the risk of mild cognitive impairment, and ultimately dementia. More work needs to be done to examine any possible causation, and what the reasons might be behind it.”

My rating of this study: ⭐⭐⭐🌸

Smith L, Shin JI, Jacob L, et al. "The association between objective vision impairment and mild cognitive impairment among older adults in low- and middle-income countries." Aging Clinical and Experimental Research.  4 March 2021. https://doi.org/10.1007/s40520-021-01814-1

RPE Proliferation as a Novel Cause of Uveal Coloboma

Article: Genetic Clues in Uveal Coloboma
Source: Vanderbilt University Medical Center
Published: April 27, 2021

Proliferation is upregulated in the RPE layer in the Nf2 knockout optic cup.
The ventral-most region harboring the optic fissure shows cells (red)
in the G2/M stage of cell division increased in B compared to A.
Arrows indicate a thickened RPE layer in F compared to E.

Colobomas are congenital ocular malformations resulting from the incomplete closure of the optic fissure during embryonic development. Although most commonly visualized as incomplete formation of the iris, colobomas can occur in a variety of ocular structures, including the lens, choroid, retina, optic disc, and eyelid. Depending on the eye tissue affected and the extent of malformation, colobomas can cause blindness. Prior research demonstrated that mutations in the gene encoding neurofibromin 2 (NF2), a tumor suppressor protein important in tissue development and regeneration, can cause colobomas, among other contributing causes. Researchers studying the role of the gene Nf2 found that silencing the gene in developing mouse eyes led to proliferation of the retinal pigment epithelium (RPE) in the optic fissure region, with RPE cells not forming a monolayer but multiple layers. The cellular crowding from RPE proliferation prevents the cells from transitioning to a cuboidal shape. This leads to improper alignment and orientation of the RPE cells, failure of optic fissure fusion/closure, and ultimately persistent coloboma. The researchers also note that, interestingly, these cells retain their RPE character, rather than transforming into other tissues of the retina. The authors write, "Our findings indicate that limiting proliferation particularly in the RPE layer is a critical mechanism during OF [optic fissure] closure." They hope that studying the underlying mechanism of RPE proliferation during development may help to understand factors preventing regeneration of adult RPE and inform therapeutics for RPE-related eye diseases.

My rating of this study: ⭐⭐⭐

Sun WR, Ramirez S, Spiller KE, et al. "Nf2 fine-tunes proliferation and tissue alignment during closure of the optic fissure in the embryonic mouse eye." Human Molecular Genetics.  29(20):3373–3387. 15 October 2020. https://doi.org/10.1093/hmg/ddaa228

Effects of Dual Sensory Impairment in Women & Men

Article: Women with sensory loss twice as likely to suffer depression
Source: Anglia Ruskin University (U.K.)
Published: March 26, 2021
Article: Men with sensory loss are more likely to be obese
Source: Anglia Ruskin University (U.K.)
Published: 8 June 2021

Two studies from researchers in the U.K. examined the effects of vision, hearing, and dual sensory impairment or loss in women and men, with attention to gender differences. The survey data in the first study, from a database of 23,089 adults in the Spanish National Health Survey, showed that women were between 2 and 2.5 times as likely as men to report experiencing depression and anxiety. Compared to women without sensory impairment, women with dual sensory impairment were almost 3.5 times more likely to report depression or anxiety. Compared to men with no sensory impairment, men with dual sensory loss were almost 2.8 times more likely to report depression and almost 1.8 times as likely to report anxiety. Finally, as expected, dual sensory loss was associated with higher levels of depression and anxiety compared to single sensory loss. In this study, although both genders report experiencing mental health effects, the association was stronger in women. The lead author of the study comments, "This highlights the importance of interventions to address vision and hearing loss, especially in women. Some sensory loss is preventable or treatable, and clearly these issues are taking their toll not just on physical health, but mental health too."

In a second study, using the same Spanish National Health Survey database, the same lead researcher explored associations between physical inactivity and obesity in women and men with vision, hearing , and dual sensory impairment or loss. They found that in people with vision loss, the likelihood of obesity was about 1.4 times higher than those who did not report vision loss. Furthermore, in people with vision loss, the prevalence of obesity was roughly 1.5 times higher in inactive men than in inactive women. Again, as expected, those with combined hearing and vision impairment were more likely to experience inactivity and obesity compared to those with single sensory impairment. The researchers note that although women were overall less physically active than men, an association between physical inactivity and obesity was found in men but not in women. Similar to interventions for depression and anxiety, they conclude that active steps should be taken to reduce the risk of weight gain in people with sensory impairments.

My rating of these studies:  ⭐⭐⭐

Pardhan S, López Sánchez GF, Bourne R, et al. "Visual, hearing, and dual sensory impairment are associated with higher depression and anxiety in women." International Journal of Geriatric Psychiatry.  10 March 2021. https://doi.org/10.1002/gps.5534

Pardhan S, Smith L, Davis A, et al. "Gender differences in the association between physical activity and obesity in adults with vision and hearing losses." European Journal of Public Health.  31(4):835–840. 10 May 2021. https://doi.org/10.1093/eurpub/ckab077

AI for the Diagnosis of Retinopathy of Prematurity

Article: AI correctly diagnoses vision-threatening condition in babies in India
Source: Oregon Health & Science University
Published: March 22, 2021

A normal retina (left) and a retina with ROP showing dilated, tortuous blood vessels (right)

 

An artificial intelligence technology used in the United States to diagnose retinopathy of prematurity (ROP) was successfully applied in India, according to researchers at OHSU and Massachusetts General Hospital. Retinopathy of prematurity develops in premature infants who are given high levels of oxygen to sustain them after birth; the high amount of oxygen causes abnormal blood vessel growth in the retina, potentially leading to blindness. Retinopathy of prematurity affects 20,000 babies worldwide, especially in developing countries where there are fewer trained ophthalmologists. According to an earlier study published in JAMA Ophthalmology, the use of this technology to diagnose ROP via images showed a 91% accuracy rate compared to expertly trained ophthalmologists. The new study applied the algorithms to 1,253 eye exams from an ROP telemedicine program in India, and correctly identified 100% of severe cases requiring treatment. The researchers also report that their i-ROP DL system is less susceptible to racial bias by implementing a two-step process, first identifying blood vessel patterns in the original eye image, then turning the image into a black-and-white blood vessel map. It is this second image in black-and-white that is analyzed for ROP, the greyscale colors reducing ethnicity-related differences in retinal image appearance. The technology has been granted breakthrough status by the FDA in 2020 and is licensed to a company called Boston AI Labs for further development. The study authors conclude, "Integration of AI into ROP screening programs may lead to improved access to care for secondary prevention of ROP and may facilitate assessment of disease epidemiology and NCU resources."

My rating of this study: ⭐⭐⭐

Campbell JP, Singh P, Redd TK, et al. "Applications of Artificial Intelligence for Retinopathy of Prematurity Screening." Pediatrics.  147(3):e2020016618. 1 March 2021. https://doi.org/10.1542/peds.2020-016618

Shared Mutations in Skin & Conjunctival Melanomas

Article: Ultraviolet radiation causes rare type of eye cancer
Source: University of Manchester (U.K.)
Published: January 11, 2021

Mutation spectra in mucosal and common cutaneous melanomas

Researchers in the U.K. studying how ultraviolet radiation contributes to cutaneous melanomas found that the same genes that cause these skin cancers also cause a rarer form of melanoma of the eye, namely, conjunctival melanoma, of the mucous membrane that lines the sclera of the eye and inner lids. In particular, the researchers applied whole genome sequencing to 10 samples of conjunctival melanomas and found UVR-associated single base substitution signature 7 (SBS7) genetic mutations in 9 of the conjunctival melanomas, as compared to 1 sample of conjunctival melanoma and 8 samples of other mucosal melanomas that did not show these features related to ultraviolet radiation. They argue that SBS7 dominance in mucosal melanoma is a better indicator of UVR-exposure than tumor site. Furthermore, they found that ultraviolet radiation-induced conjunctival melanomas contain the same cancer mutations in the BRAF and NRAS genes. This contrasts with earlier understanding that the KIT and SF3B1 mutations are more common in mucosal melanomas and the BRAF and NRAS mutations are more common in cutaneous melanomas. Although uveal melanomas, another rare melanoma of the eye, are less related to ultraviolet radiation, the researchers report that their findings complement an earlier study showing that ultraviolet exposure can present SBS7 predominance if it arises on the iris. A common driver of both cutaneous and conjunctival melanoma, the researchers argue, facilitates the application of therapies developed primarily for cutaneous melanoma in the context of ocular melanomas, such as the BRAF inhibitor vemurafenib used to treat skin melanoma. The lead author of the study comments, “Our work shows the importance of delving into the underlying biology in rare cancers, which could identify new tailored treatment avenues for people. In this case we have identified mutations in a rare type of eye cancer that could be targeted by drugs used to treat skin cancer.”

My rating of this study: ⭐⭐

Mundra P, Dhomen N, Rodrigues M, et al. "Ultraviolet radiation drives mutations in a subset of mucosal melanomas." Nature Communications.  12:259. 11 January 2021. https://doi.org/10.1038/s41467-020-20432-5

Week in Review: Number 32

Increased Risk of High Refractive Error in Children of Mothers with Diabetic Complications
A nationwide population-based cohort study comprised of more than 2.4 million individuals born in Denmark between 1977 and 2016, with follow-up spanning up to 25 years, found that mothers who have diabetes before or during their pregnancy were at an increased risk of having children who go on to develop high refractive error (RE). Including conditions such as myopia, hyperopia, and astigmatism, refractive errors collectively result in defocus of the retinal image and if the degree of refractive error is high enough, can contribute to visual impairment. Based on earlier studies showing links between refractive error and congenital eye defects, the researchers suspected that maternal hyperglycemia during pregnancy could lead to elevated fetal blood glucose levels, which in turn can damage the retina and optic nerve and lead to changes in the shape of the eyes that ultimately cause RE. The results indicate that among the study population, 2.3% were exposed to maternal diabetes, with 0.9% and 0.3% being type 1 and type 2 pre-gestational diabetes respectively, and 1.1% involving gestational diabetes. Exposure to maternal diabetes was associated with a 39% greater risk of high RE compared to unexposed offspring, with elevated risk observed in all three types of refractive error. There was also a difference between type 1 and type 2 diabetes; compared to unexposed offspring, rates of high RE were 32% higher in offspring of mothers with type 1 diabetes and 68% higher in offspring of mothers with type 2 diabetes. Most notably, offspring of mothers with complications arising from diabetes were twice as likely (200%) to have high RE, compared to 18% in unexposed offspring. All this being said, the actual numbers of incidence were low. For example, the authors report, "During up to 25 years of follow-up, 553 offspring of mothers with diabetes and 19,695 offspring of mothers without diabetes were diagnosed with high RE." Although 553 individuals is a tiny number in a sample size of 2,470,580, the authors stress the importance of early screening and prevention, stating, "[A]ny tiny improvement in this low-risk preventable factor will contribute to a huge reduction in absolute numbers of these eye conditions."

Case Report: Acute Vision Loss from IgG4-Related and Bacterial Rhinosinusitis after COVID-19
A recent case report involving a COVID-19 patient who experienced acute loss of vision in one eye provides insight into how SARS-CoV-2 infection could affect the immune system. Specifically, the patient was diagnosed with immunoglobulin G4-related disease (IgG4-RD) concurrent with bacterial rhinosinusitis, the first such case reported in the literature. The patient experienced complete resolution of symptoms after treatment with surgery, antibiotics, and corticosteroids; however, the unusual coinciding factors in this case, including a possible connection to preceding COVID-19 infection and ocular involvement, highlight its relevance for discussion. The male patient in his 70s initially presented to the emergency department with a headache for 2 weeks and vision loss in the right eye for 2 days; he reported no history of rhinosinusitis but did have rhinorrhea (a runny nose) 3 weeks prior and was diagnosed with COVID-19. Although he recovered from COVID-19, the patient developed a worsening right-sided headache 1 week later and right vision loss 2 days prior to presentation. The patient's right eye visual acuity at presentation was limited to hand-motion detection, with severe pain on ocular motion. CT scans revealed opacification with diffuse inflammation in all sinuses on the right side of his face, as well as erosion of the medial orbital apex bone. Emergency surgery and antibiotics were initiated. Bacterial cultures showed that this particular infection involved Streptococcus constellatus, which is associated with orbital invasion.

Histopathologic analysis of sinus samples showed dense infiltrate of IgG-containing plasma cells, with most being IgG4 positive; this finding was confirmed with elevated serum IgG4. IgG4-related rhinosinusitis was diagnosed and the patient was additionally prescribed prednisone and amoxicillin-clavulanate. At 3-week follow-up, the patient's vision had returned to baseline and his headaches had completely resolved. "Although rare, rheumatological workup for IgG4-RD in patients with severe rhinosinusitis and acute vision loss is critical because treatment of IgG4-RD differs from that of bacterial rhinosinusitis," the authors emphasize, "Hence, corticosteroids and antibiotics may be indicated in patients with severe rhinosinusitis until either IgG4-related or bacterial rhinosinusitis can be ruled out." They further state, "Importantly, this patient’s prior SARS-CoV-2 infection suggests a possible relationship between COVID-19 and IgG4-RD. Immunoglobulin G4-RD is mediated by cytotoxic CD4-positive T-cells, an atypical subset of helper T-cells with cytotoxic ability. Increased representation of cytotoxic CD4-positive T-cells was recently discovered in SARS-CoV-2 reactive T-cells, with higher levels associated with hospitalization. This finding signals a possible link between COVID-19 and IgG4-RD," although additional cases would be needed to differentiate between coincidence and connection between the two diseases.

Progress in Augmented Reality Contact Lenses
A start-up company, Mojo Vision, recently announced progress in the design of augmented reality (AR) displays embedded into contact lenses, adding a layer of information onto real world images. Although a long ways from clinical implementation or hitting the shelves, the Mojo Lens boasts features such as a hexagonal display less than a millimeter wide, with pixels each merely a quarter of the width of a red blood cell, and a "femtoprojector" that beams images directly onto the central retina. Electronic features include a camera that captures the outside world; a computer chip that processes imagery, controls the display, and communicates wirelessly with external devices; a motion tracker that incorporates accelerometer and gyroscope technology to compensate for eye movement, and a wirelessly charging battery. Current challenges include extending battery life and "making these things small enough to be socially acceptable," since social discomfort related to recording and sharing information were problems encountered by earlier AR systems such as the Google Glass eyeglasses. When asked why they chose contact lenses as an AR display technology, the start-up emphasizes that contact lenses are worn by 150 million people worldwide, they are lightweight and don't fog up, and AR technology on contact lenses would work even with the eyes closed. At this stage, the team reports that prototypes have passed toxicology tests and they have all the hardware and software components to start assembling fully featured prototypes.

Scientists Develop Brain Organoids with Optic Cups
Organoids are miniature organs grown from induced pluripotent stem cells (iPSCs) that share enough characteristics with the source organ to serve as models to study tissue and embryonic development, disease pathophysiology, and personalized therapies/therapeutics. Researchers studying the connection between the eyes and the brain have grown brain organoids that developed bilateral optic cups, the rudimentary structures that later become the eyes. Previous studies by other research teams had used human embryonic stem cells or alternatively iPSCs (which are derived from adult cells that have been genetically reprogrammed back into an embryonic-like pluripotent state) to generate the optic cup; these studies focused on generating only the retina. The present research instead seeks to study the interorgan interaction of optic cups as they are functionally integrated into brain organoids. Using cells from four iPSC donors, they developed 16 independent batches and generated 314 brain organoids, 72% of which formed optic cups (showing that the method is reproducible). Their lab protocol, such as adding retinol acetate to the culture medium to encourage eye development, produced brain organoids that formed optic cups as early as 30 days, with more mature visible structures appearing within 60 days, a time frame that parallels retinal development in human embryos. The optic cups matured enough to contain primitive corneal epithelial and lens-like cells, as well as retinal pigment epithelia, retinal progenitor cells, synapsin-1, CTIP-positive myelinated cortical neurons, microglia, and axon-like projections that formed electrically active neuronal networks. Furthermore, these organoids exhibited photosensitive response to various light intensities and connectivity to brain regions. Because the formation of optic cups within brain organoids is novel, the researchers report this being the first time observing nerve fibers of retinal ganglion cells reach out to connect with their brain targets in an in vitro system. The team is working on strategies to extend the viability of the organoids and hopes that these organoids will aid in the study of retinopathies, neurodevelopmental disorders, and tissue transplantation.

Blind People Understand Color Through Language
How we learn what we know—whether through direct sensory experience, talking with others, or reasoning through our own thoughts—is a puzzle for empirical philosophy, whose subject matter centers on the idea that to truly know something, one must experience it directly. Recent research sheds light on this question through comparing the understanding of visual phenomena, in this case color, between congenitally blind and sighted people, only the latter of whom have personally experienced color. Contrary to what was predicted by empiricist philosophers such as John Locke, who argued that although individuals who are born blind might grasp arbitrary color facts without an understanding of color, cognitive neuroscientists found that both congenitally blind and sighted individuals possess in-depth understanding of object color, often making similar generative inferences for novel objects and giving similar causal explanations, although they do not necessarily agree about arbitrary color facts. For example, both blind and sighted people can infer that two natural kinds, e.g., two bananas, are more likely to have the same color. Similarly, both blind and sighted people can infer that two objects with functional colors, e.g., two stops signs, are more likely to have the same color than two objects with nonfunctional colors, e.g., two cars. However, relative to sighted people, blind people are less likely to infer that bananas are yellow or that stop signs are red. Even more surprising, blind people can sometimes generate independent, coherent causal explanations for object color. For example, when asked to predict the color of a polar bear, while sighted individuals said that polar bears are white to camouflage with the snow, some blind individuals said that polar bears are black in order to absorb heat and stay warm. The intuitions applied to novel scenarios, independent of memory, such as when asked to predict the color of objects on an imaginary island. These examples revealed that people develop intuitive and inferentially rich “theories” of color regardless of visual experience, and in turn illustrates the effectiveness of linguistic exposure and communication with people who talk about color as sufficient for forming intuitive theories and understanding of color. The researchers next plan to study how and when color understanding develops in the brain among blind and sighted children.

In Other News
(1) Evolution of color vision in lampreys
(2) Bionic eye brings blind patient new sight
(3) Collaboration between optometry and computer science

Case Report: Acute Vision Loss from IgG4-Related and Bacterial Rhinosinusitis after COVID-19

Article: A COVID-19 Patient Lost Vision in One Eye. Here's How They Could Be Connected
Source: ScienceAlert
Published: August 27, 2021

Complete opacification of (A) the right frontal sinus, (B) the right ethmoid sinus
with erosion of the medial orbital apex bone,and (C) the right maxillary sinus

A recent case report involving a COVID-19 patient who experienced acute loss of vision in one eye provides insight into how SARS-CoV-2 infection could affect the immune system. Specifically, the patient was diagnosed with immunoglobulin G4-related disease (IgG4-RD) concurrent with bacterial rhinosinusitis, the first such case reported in the literature. The patient experienced complete resolution of symptoms after treatment with surgery, antibiotics, and corticosteroids; however, the unusual coinciding factors in this case, including a possible connection to preceding COVID-19 infection and ocular involvement, highlight its relevance for discussion. The male patient in his 70s initially presented to the emergency department with a headache for 2 weeks and vision loss in the right eye for 2 days; he reported no history of rhinosinusitis but did have rhinorrhea (a runny nose) 3 weeks prior and was diagnosed with COVID-19. Although he recovered from COVID-19, the patient developed a worsening right-sided headache 1 week later and right vision loss 2 days prior to presentation. The patient's right eye visual acuity at presentation was limited to hand-motion detection, with severe pain on ocular motion. CT scans revealed opacification with diffuse inflammation in all sinuses on the right side of his face, as well as erosion of the medial orbital apex bone. Emergency surgery and antibiotics were initiated. Bacterial cultures showed that this particular infection involved Streptococcus constellatus, which is associated with orbital invasion.

Histopathology images showsing (A) lymphocytes and plasma cells,
(B) IgG staining, and (C) mostly positive IgG4 staining

Histopathologic analysis of sinus samples showed dense infiltrate of IgG-containing plasma cells, with most being IgG4 positive; this finding was confirmed with elevated serum IgG4. IgG4-related rhinosinusitis was diagnosed and the patient was additionally prescribed prednisone and amoxicillin-clavulanate. At 3-week follow-up, the patient's vision had returned to baseline and his headaches had completely resolved. "Although rare, rheumatological workup for IgG4-RD in patients with severe rhinosinusitis and acute vision loss is critical because treatment of IgG4-RD differs from that of bacterial rhinosinusitis," the authors emphasize, "Hence, corticosteroids and antibiotics may be indicated in patients with severe rhinosinusitis until either IgG4-related or bacterial rhinosinusitis can be ruled out." They further state, "Importantly, this patient’s prior SARS-CoV-2 infection suggests a possible relationship between COVID-19 and IgG4-RD. Immunoglobulin G4-RD is mediated by cytotoxic CD4-positive T-cells, an atypical subset of helper T-cells with cytotoxic ability. Increased representation of cytotoxic CD4-positive T-cells was recently discovered in SARS-CoV-2 reactive T-cells, with higher levels associated with hospitalization. This finding signals a possible link between COVID-19 and IgG4-RD," although additional cases would be needed to differentiate between coincidence and connection between the two diseases.

My rating of this study: ⭐⭐⭐

Harb AA, Chen Y, Ben-Ami JR, et al. "Acute Vision Loss From IgG4-Related and Bacterial Rhinosinusitis After COVID-19." JAMA Otolaryngology Head Neck Surgery.  26 August 2021. https://doi.org/10.1001/jamaoto.2021.2121

Progress in Augmented Reality Contact Lenses

Article: Mojo Vision crams its contact lens with AR display, processor and wireless tech
Source: CNET, via EyeWire News
Published: August 24, 2021

CMOS backbone of the electronic display

A start-up company, Mojo Vision, recently announced progress in the design of augmented reality (AR) displays embedded into contact lenses, adding a layer of information onto real world images. Although a long ways from clinical implementation or hitting the shelves, the Mojo Lens boasts features such as a hexagonal display less than a millimeter wide, with pixels each merely a quarter of the width of a red blood cell, and a "femtoprojector" that beams images directly onto the central retina. Electronic features include a camera that captures the outside world; a computer chip that processes imagery, controls the display, and communicates wirelessly with external devices; a motion tracker that incorporates accelerometer and gyroscope technology to compensate for eye movement, and a wirelessly charging battery. Current challenges include extending battery life and "making these things small enough to be socially acceptable," since social discomfort related to recording and sharing information were problems encountered by earlier AR systems such as the Google Glass eyeglasses. When asked why they chose contact lenses as an AR display technology, the start-up emphasizes that contact lenses are worn by 150 million people worldwide, they are lightweight and don't fog up, and AR technology on contact lenses would work even with the eyes closed. At this stage, the team reports that prototypes have passed toxicology tests and they have all the hardware and software components to start assembling fully featured prototypes.

My rating of this article: ⭐⭐

Increased Risk of High Refractive Error in Children of Mothers with Diabetic Complications

Article: New study reveals that children of mothers with diabetes during pregnancy have an increased risk of eye problems
Source: Diabetologia, European Association for the Study of Diabetes (EASD), via ScienceDaily
Published: August 17, 2021

A nationwide population-based cohort study comprised of more than 2.4 million individuals born in Denmark between 1977 and 2016, with follow-up spanning up to 25 years, found that mothers who have diabetes before or during their pregnancy were at an increased risk of having children who go on to develop high refractive error (RE). Including conditions such as myopia, hyperopia, and astigmatism, refractive errors collectively result in defocus of the retinal image and if the degree of refractive error is high enough, can contribute to visual impairment. Based on earlier studies showing links between refractive error and congenital eye defects, the researchers suspected that maternal hyperglycemia during pregnancy could lead to elevated fetal blood glucose levels, which in turn can damage the retina and optic nerve and lead to changes in the shape of the eyes that ultimately cause RE. The results indicate that among the study population, 2.3% were exposed to maternal diabetes, with 0.9% and 0.3% being type 1 and type 2 pre-gestational diabetes respectively, and 1.1% involving gestational diabetes. Exposure to maternal diabetes was associated with a 39% greater risk of high RE compared to unexposed offspring, with elevated risk observed in all three types of refractive error. There was also a difference between type 1 and type 2 diabetes; compared to unexposed offspring, rates of high RE were 32% higher in offspring of mothers with type 1 diabetes and 68% higher in offspring of mothers with type 2 diabetes. Most notably, offspring of mothers with complications arising from diabetes were twice as likely (200%) to have high RE, compared to 18% in unexposed offspring. All this being said, the actual numbers of incidence were low. For example, the authors report, "During up to 25 years of follow-up, 553 offspring of mothers with diabetes and 19,695 offspring of mothers without diabetes were diagnosed with high RE." Although 553 individuals is a tiny number in a sample size of 2,470,580, the authors stress the importance of early screening and prevention, stating, "[A]ny tiny improvement in this low-risk preventable factor will contribute to a huge reduction in absolute numbers of these eye conditions."

My rating of this study: ⭐⭐⭐⭐

Du J, Li J, Liu X, et al. "Association of maternal diabetes during pregnancy with high refractive error in offspring: a nationwide population-based cohort study." Diabetologia.  17 August 2021. https://doi.org/10.1007/s00125-021-05526-z

Scientists Develop Brain Organoids with Optic Cups

Article: Brain organoids develop optic cups that respond to light
Source: Cell Press, via EurekAlert
Published: August 17, 2021
Article: Scientists Grew Stem Cell 'Mini Brains'. Then, The Brains Sort-of Developed Eyes
Source: ScienceAlert
Published: August 17, 2021
Article: Human Brain Organoids Develop Optic Vesicles, Respond to Light
Source: Genetic Engineering & Biotechnology News
Published: August 18, 2021

Brain organoids with optic cups

Organoids are miniature organs grown from induced pluripotent stem cells (iPSCs) that share enough characteristics with the source organ to serve as models to study tissue and embryonic development, disease pathophysiology, and personalized therapies/therapeutics. Researchers studying the connection between the eyes and the brain have grown brain organoids that developed bilateral optic cups, the rudimentary structures that later become the eyes. Previous studies by other research teams had used human embryonic stem cells or alternatively iPSCs (which are derived from adult cells that have been genetically reprogrammed back into an embryonic-like pluripotent state) to generate the optic cup; these studies focused on generating only the retina. The present research instead seeks to study the interorgan interaction of optic cups as they are functionally integrated into brain organoids. Using cells from four iPSC donors, they developed 16 independent batches and generated 314 brain organoids, 72% of which formed optic cups (showing that the method is reproducible). Their lab protocol, such as adding retinol acetate to the culture medium to encourage eye development, produced brain organoids that formed optic cups as early as 30 days, with more mature visible structures appearing within 60 days, a time frame that parallels retinal development in human embryos. The optic cups matured enough to contain primitive corneal epithelial and lens-like cells, as well as retinal pigment epithelia, retinal progenitor cells, synapsin-1, CTIP-positive myelinated cortical neurons, microglia, and axon-like projections that formed electrically active neuronal networks. Furthermore, these organoids exhibited photosensitive response to various light intensities and connectivity to brain regions. Because the formation of optic cups within brain organoids is novel, the researchers report this being the first time observing nerve fibers of retinal ganglion cells reach out to connect with their brain targets in an in vitro system. The team is working on strategies to extend the viability of the organoids and hopes that these organoids will aid in the study of retinopathies, neurodevelopmental disorders, and tissue transplantation.

My rating of this study: ⭐⭐

Gabriel E, Albanna W, Pasquini G, et al. "Human brain organoids assemble functionally integrated bilateral optic vesicles." Cell Stem Cell.  17 August 2021. https://doi.org/10.1016/j.stem.2021.07.010

Blind People Understand Color Through Language

Article: Blind People Can’t See Color but Understand It the Same Way as Sighted People
Source: Johns Hopkins University, via ScienceDaily, Technology Networks  and NEI
Published: August 16, 2021

How we learn what we know—whether through direct sensory experience, talking with others, or reasoning through our own thoughts—is a puzzle for empirical philosophy, whose subject matter centers on the idea that to truly know something, one must experience it directly. Recent research sheds light on this question through comparing the understanding of visual phenomena, in this case color, between congenitally blind and sighted people, only the latter of whom have personally experienced color. Contrary to what was predicted by empiricist philosophers such as John Locke, who argued that although individuals who are born blind might grasp arbitrary color facts without an understanding of color, cognitive neuroscientists found that both congenitally blind and sighted individuals possess in-depth understanding of object color, often making similar generative inferences for novel objects and giving similar causal explanations, although they do not necessarily agree about arbitrary color facts. For example, both blind and sighted people can infer that two natural kinds, e.g., two bananas, are more likely to have the same color. Similarly, both blind and sighted people can infer that two objects with functional colors, e.g., two stops signs, are more likely to have the same color than two objects with nonfunctional colors, e.g., two cars. However, relative to sighted people, blind people are less likely to infer that bananas are yellow or that stop signs are red. Even more surprising, blind people can sometimes generate independent, coherent causal explanations for object color. For example, when asked to predict the color of a polar bear, while sighted individuals said that polar bears are white to camouflage with the snow, some blind individuals said that polar bears are black in order to absorb heat and stay warm. The intuitions applied to novel scenarios, independent of memory, such as when asked to predict the color of objects on an imaginary island. These examples revealed that people develop intuitive and inferentially rich “theories” of color regardless of visual experience, and in turn illustrates the effectiveness of linguistic exposure and communication with people who talk about color as sufficient for forming intuitive theories and understanding of color. The researchers next plan to study how and when color understanding develops in the brain among blind and sighted children.

My rating of this study: ⭐⭐

Kim JS, Aheimer B, Manrara VM, et al. "Shared understanding of color among sighted and blind adults." PNAS.  118(33):e2020192118. 17 August 2021. https://doi.org/10.1073/pnas.2020192118

Week in Review: Number 31

CRISPR-Cas9 Treatment for Fuchs' Corneal Dystrophy
Fuchs' endothelial corneal dystrophy (FECD) is the leading cause of corneal transplant in the U.S. and although there is no shortage of donor corneal tissue in this country, corneal transplant is surgery that comes with many risks. Even a successful surgery that restores clear vision with a donor cornea commits the patient to many office visits, co-pays, and post-operative eye drops. A treatment that could be administered prior to or in place of surgery could therefore provide patients with additional options and benefits. As part of an eight-year study, a team of researchers is exploring the use of CRISPR-Cas9 gene editing to knockdown the expression of a mutant protein responsible for a form of Fuchs' endothelial corneal dystrophy. In particular, they are focusing on a single-point mutation in a collagen protein known as COL8A2, or collagen type VIII alpha 2 chain, which causes an early-onset subset of the disease that typically affects patients in their late 30s or early 40s. Notably, previous research in mice showed that silencing the COL8A2  gene did not adversely affect the cornea; rather, it is the mutant variant, a missense mutation, of the protein that causes problems.

The researchers developed a new technique, called start codon disruption, in which they disrupt the initiation site of transcription, the start codon, thereby preventing protein synthesis. While other techniques that disrupt gene expression farther down the gene can also result in termination of protein expression, the farther downstream along the gene, the more likely a viable protein would still be produced that instead has unknown, and possibly unwanted, activity. This research is also novel in the sense that it applies CRISPR gene editing to post-mitotic cells, in this case the corneal endothelium, the cells of which are not replenished as a person ages. Significant loss of corneal endothelial cells leads to loss of pumping function, and in this case results in corneal edema leading to impaired vision. The treatment has so far been tested in mice by intracameral delivery of the gene therapy via adenovirus viral vector. The team reports both preservation of endothelial cells as well as rescue of endothelium pump function with no adverse effects to the surrounding tissues and a safe drug profile for the retina, iris, and other parts of the eye at the maximum tolerated dose. The researchers will continue studies in small animals and non-human primates before moving on to clinical trials. However, the study's senior researcher is hopeful that the therapy will one day reduce the need for corneal transplants for Fuchs’ dystrophy patients, thereby both directly benefiting those patients as well as indirectly helping other patients in need of corneal tissue.

DARC Imaging Predicts Risk of Geographic Atrophy
Geographic atrophy (GA) is an advanced form of age-related macular degeneration (AMD), the leading cause of visual impairment in individuals over 55 years of age. In an effort to detect early signs of the disease, when interventions and treatments might be more effective, researchers are investigating a retinal imaging technology called Detection of Apoptosing Retinal Cells (DARC), which had previously shown clinical success in predicting the progression of glaucoma and detecting wet AMD. Performed with an intravenous injection of a fluorescent dye (ANX776, fluorescently labelled Annexin A5), DARC detects areas of the retina that are undergoing cellular stress or apoptosis (cellular death), which show up as areas of hypefluorescence when viewed on fundus exam. These areas of damage can be quantified with an AI algorithm, resulting in a "DARC count" that can be monitored over time for progression or prediction. The present phase 2 clinical trial involved 113 participants, 19 of whom had early signs of neovascular AMD and 13 of whom had early signs of geographic atrophy. The research team also recruited healthy volunteers and patients with progressive glaucoma, optic neuritis, and other eye conditions representative of neurodegeneration. All patients were screened with DARC and followed up with ocular coherence tomography (OCT) every six months over three years, the latter condition to assess DARC's validity against OCT. The results showed that patients with a DARC count of more than 10 on initial examination had increased expansion of GA three years later. The researchers plan on larger clinical trials and are exploring a nasal delivery of the fluorescent dye for a less invasive screening tool.

Retinal Organoids as Lab Models for Retinoblastoma
Retinoblastoma is a rare pediatric eye cancer driven by biallelic inactivation of the RB1  gene. Research into the pathophysiology of retinoblastoma, however, has had many limitations. First, rare eye diseases such as retinoblastoma have a small pool of patients to sample from. Genetically engineered mouse models of retinoblastoma do not express the abnormalities seen in humans when the RB1  gene is silenced, and are therefore not always reliable predictors for preclinical drug development. Biopsies in living patients are also contraindicated, since the act of biopsy can further spread the tumor cells. As such, tumor samples have been derived from more advanced stages requiring removal of the eyeball. Scientists are investigating the use of retinal organoid to more accurately model retinoblastoma to study the early stages of the disease as well as to screen for potential therapies. The researchers hope that these organoids could also shed light on other drivers of tumor development beyond the RB1  gene. In this case, the samples were collected from 15 retinoblastoma patients who had germline mutations in RB1, from which 3D cultures of cells were grown from induced pluripotent stem cells (iPSCs). These iPSCs developed into retinal organoids and were then injected into mouse eyes, where retinoblastomas subsequently formed. Whole-genome sequencing, RNA sequencing, and methylation analysis of these retinoblastoma tumors showed that they were indistinguishable from patient samples. The first author of the study comments on the novelty of the research, saying, “The ability of the organoid models to [successfully grow into organoids and later spontaneously developed into tumors] is unique, because cell lines with RB1  mutations do not spontaneously develop into retinoblastoma tumors.” Data from the project is freely available in the Childhood Solid Tumor Network at St. Jude Children's Research Hospital.

Head and Eye Movements & Gaze Tracking in Baseball
Researchers in sports vision conducted a review of film- and lab-based studies pertaining to batters' gaze in baseball to answer the question "Do batters actually keep their eye on the ball?" and if so, whether there is any advantage in strategy with regard to head and eye movements. Their study suggests that while batters do indeed keep their eyes on the ball, they direct their gaze by moving their heads rather than their eyes. Some of the batters were also seen to make what is suspected to be an anticipatory shift in gaze toward home plate. While the two authors of this study found no consensus in head and eye movements among baseball batters, they did uncover a consistent finding that batters move their heads rather than their eyes to direct their gaze at the ball. They speculate that given the time pressure during the half-a-second journey of a pitched ball to home plate, head movement reduces the complexity of negotiating visual and neural signals. However, head movement also leads to an interesting paradox, namely, suppression of the vestibular ocular reflex (VOR). Responsible for turning our eyes in the opposite direction of a head turn, the vestibular ocular reflex allows us to maintain a stabilized view of our surroundings despite head movement. As one of the authors explains, “When it comes to something like batting, when I’m rotating my head to follow the ball, the VOR is telling my eyes to go in the opposite direction. … So that VOR has to be canceled if the eyes are going to stay on the ball.” After confirming that batters do keep their eyes on the ball, the researchers next look to study whether anticipatory saccades away from the ball improved batting success, a pertinent question to sports training. Thus far, they report no conclusive data, but highlight both athletic interest in the topic as well as the need for larger studies under game conditions. While baseball serves as a model situation in this case, the authors posit that questions such as how we organize our thoughts when pressed for time and whether to fix our gaze on the focus of our attention or direct our gaze based on predictions are questions that apply to everyday life. “Ultimately, once we understand how and why the hand, eye and head are coordinated in a certain way, then training these patterns is the next step," one of the researchers concludes.

Myopia and the COVID-19 Pandemic in Hong Kong
The COVID-19 pandemic has brought attention to the increased global incidence of myopia in the pediatric population, as adjustment to lockdown led to less time spent outdoors and more time spent interacting with screens and near work. An often-cited study published in JAMA Ophthalmology  reported overall increased rates of myopia among more than 120,000 homebound children in China. Researchers in Hong Kong expanded upon the topic, as reported in a smaller cohort study involving 1793 children between the ages of 6 and 8, 1084 of whom were recruited before the COVID-19 pandemic and compared with 709 children who were recruited at the beginning of the COVID-19 pandemic. The authors report, "The overall incidence was 19.44% in the COVID-19 cohort, and 36.57% in [the] pre-COVID-19 cohort. During the COVID-19 pandemic, the change in SER [spherical equivalent refraction] and axial length was –0.50±0.51 D and 0.29±0.35 mm, respectively." Note that the incidence is actually reported to be higher in the pre-COVID-19 cohort.

However, because these are two different cohorts, recruited at two different time periods (and over different durations), the authors caution against a direct comparison between them. Instead, they "estimated the risk ratio of incidence of myopia between the two groups using a relative risk regression model (log-binomial model)," and based on that model, they found that "myopia incidence in the COVID-19 cohort was higher than in the pre-COVID-19 cohort (p=0.03) after adjusting for age, gender, follow-up duration, parental myopia, time of outdoor activity and near work." The authors also compared this study to an earlier study from 2004 to further support their data, stating, "The myopia incidence (13.15% over 1 year) in the previous cohort was lower than that of our COVID-19 cohort (19.44% over 8 months, p<0.001) despite having a longer follow-up of 1 year compared with 8 months in the COVID-19 cohort, indicating that the incidence of myopia increased during the COVID-19 pandemic." They attribute this to a decrease in outdoor activities from approximately 1 hour 15 minutes to merely 25 minutes per day and an increase in screen time from 2.5 to nearly 7 hours per day. Despite very indirect methodology in this study, based on comparison with similar studies in Asia, it is reasonable to extrapolate, with caution, that their model captures trends consistent with a global increase in myopia incidence during the COVID-19 pandemic. The researchers conclude with a motivation for the study, saying, "Our results serve to warn eye care professionals, and also policy makers, educators and parents, that collective efforts are needed to prevent childhood myopia—a potential public health crisis as a result of COVID-19."

In Other News
(1) Neuroscientists investigate the cause of Fuchs' corneal dystrophy
(2) A blind paraolympian runner and his guide
(3) Scientists study vision and motion in fruit flies