Methods of protecting vision, foveal architecture, and eyeball shape in children exposed to near work and screentime

Abstract

The present invention relates to methods of administering ocular nutrients, such as the carotenoids lutein and / or zeaxanthin, to individuals to protect eyeball shape, foveal architecture, vision, and other eye conditions. Another aspect of the present invention relates to the administration of lutein and / or zeaxanthin to individuals, especially during the adolescent years, in order to address the negative effects associated with prolonged periods of near work and / or screentime.

Description

[0001]METHODS OF PROTECTING VISION, FOVEAL ARCHITECTURE, AND EYEBALL SHAPE IN CHILDREN EXPOSED TO NEAR WORK AND SCREENTIMECROSS REFERENCE TO RELATED APPLICATIONSThe present invention claims the benefit of priority to United States ProvisionalPatent Application No. 63 / 689,434, filed August 30, 2024, entitled “METHODS OFPROTECTING VISION, FOVEAL ARCHITECTURE, AND EYEBALL SHAPE IN CHILDENEXPOSED TO NEAR-WORK AND SCREENTIME,” the entire disclosure of which isincorporated herein by reference in its entirety.BACKGROUND OF THE INVENTIONBefore the COVID-19 pandemic affected digital lifestyles, roughly 19% of childrenbetween the ages of 0 and 17 years, were estimated to spend 4 or more hours in front of adigital screen, or approximately 13 million individuals (Child and Adolescent HealthMeasurement Initiative. 2018-2019 National Survey of Children’s Health (NSCH) data query).The prevalence of digital eye strain prior to the pandemic was estimated to be between 22%and 40% (Sheppard & Wolffsohn, 2018). Researchers conducting an open online surveyreported that screen time since the pandemic has increased by an average of four hours perday (Bahkir & Grandee, 2020).Digital eye strain and accommodative fatigue are emerging public health concern,particularly in view of the increased amount of time children are spending in front of digitalscreens following the COVID-19 pandemic (Bhattacharya et al., 2020). (Lakey-Beitia et al.,2019; Pérez-Gálvez et al., 2018). These issues have become exacerbated as children arespending well over the recommended two hours screen time per day and, excessiveexposure to the high energy blue light associated with digital devices has been shown tocause both short term and long term visual damage as well as disruption to the sleep cycle(Jaadane et al., 2015; Knell et al., 2019; Krigel et al., 2016; Maisons-Alfort, 2019; Rideout,2010; Walsh et al., 2018). A study looking at the effects of screen time via video game playingin over 300 children found that eye strain, including headaches and dizziness wassignificantly higher in the children reporting higher frequency of video game playing(Rechichi et al., 2017).Digital eye strain and accommodative fatigue may present in a number of ways,including stress on the foveal architecture and eyeball shape, which in turn may affect vision,visual function, and eye comfort. Improper foveal architecture and eyeball shape canultimately lead to retinal cell damage, potentially resulting in disorders or conditions, suchas macular degeneration, glaucoma, cataracts, retinal detachment, vision loss, and blindness.This is of particular concern for children during the adolescent and teenage years, where ithas been observed that the eyes undergo a critical period of rapid growth.Thus, there remains a need in the art to address, counter, delay, and prevent thenegative consequences of increased digital device use and digital eye strain, particularly inchildren.BRIEF DESCRIPTION OF THE INVENTIONThe present invention relates to methods of administering ocular nutrients, such ascarotenoids (e.g., zeaxanthin, and / or meso-zeaxanthin) to individuals in order to protecttheir foveal architecture, eyeball shape, vision, and other eye conditions. Another aspect ofthe present invention relates to methods to address, counter, delay, or prevent the negativeeffects of prolonged near work and screentime in individuals, especially teenagers.BRIEF DESCRIPTION OF THE DRAWINGSFig. 1 provides an overview of the study outline.Figs.2A-2E describe the baseline characteristics of participants for (A) age, (B) screentime, (C) digital eye strain, (D) macular pigment-HFP, and (E) macular pigment-HB. N=59.Fig. 3 represents the final data set used for the mixed model repeated measuresstatistical analyses (CONSORT Diagram).Figs.4A-4B shows the mean change in macular pigment values over time assessed via(A) heterochromatic flicker photometry and (B) Haidinger’s Brush degree of polarization.Error bars indicate ± 1 standard error of the mean. N=54. Asterisk (*) indicates statisticallysignificant difference between groups at p<0.05.Fig.5 shows the mean change in digital eye strain values over time assessed via VisualFatigue Scale. Error bars indicate ± 1 standard error of the mean. N=54. Asterisk (*) indicatesstatistically significant difference between groups at p<0.05. Figs. 6A-6F shows the mean change in digital eye strain values over time assessed viaVisual Fatigue Scale: (A) problems seeing, (B) strange feeling, (C) tired eyes, (D) feelingnumb, (E) headache, (F) feeling dizzy. Error bars indicate ± 1 standard error of the mean.N=54. Caret (^) indicates a significant trend between groups at p<0.10 from post-hocindependent samples t-test of change from baseline to day 180.DETAILED DESCRIPTION OF THE INVENTIONGlobally, the adolescent population appears to be at high-risk for near work relatedeye health conditions. As used herein “near work” describes any activity that includesfocusing on an object within an arm’s length from the eyes (e.g., use of a smart phone orelectronic device, reading a book). For instance, research have identified that near workincreases the risk of myopia. As described in greater detail herein, the adolescent populationpresents a unique opportunity for potential intervention. Of all of the age groups,adolescents spend the greatest amount of time on digital devices, with recent studiesshowing teenagers in the United States spending over 8 hours per day on recreational digitaldevices such as phones, computers, and gaming consoles. Additionally, adolescence is a timeof rapid neuronal development and plasticity, meaning that the neural tissues of the eye andbrain are potentially susceptible to small environmental changes and that theseenvironmental influences during this age can have a life-long impact regarding anindividual’s health trajectory.Macular carotenoids from the diet represent one approach to protecting the retinafrom long term damage caused by excessive near work. One important and lesser knownmacular carotenoid that comes from fruits and vegetables is lutein (Bernstein et al., 2016).Lutein is an orange-colored pigment found in many of the brightly colored fruits andvegetables in the human diet (Eisenhauer et al., 2017). The human body cannot producelutein on its own and must obtain lutein from either the diet or supplementation (Bernsteinet al., 2016). Some of the fruits and vegetables with the highest concentrations of luteininclude dark green leafy vegetables such as kale, spinach, broccoli and collard greens, as wellas beans, butternut squash and oranges (Humphries & Khachik, 2003). When lutein isconsumed from the diet or supplementation, the colored molecule gets deposited in the eye,skin and brain where it has been found to play a key role as an antioxidant, anti-inflammatory, and blue light absorber and / or filter (Bernstein & Ranganathan, 2021).Research has shown that a daily intake of at least 10 mg of lutein from the diet isbeneficial for both the eyes and the brain (Age-Related Eye Disease Study 2 Research et al.,2014; Hammond et al., 2014; Jia et al., 2017; Mares, 2016). Unfortunately, due to the lack ofclinical trials with children, there is currently no recommended daily intake values forindividuals under the age of 18 years. However, studies indicate that in the United States,the average daily intake of lutein is around only 1 mg per day (Johnson et al., 2010). Thesituation is not much better globally, with average intakes in the European Union rangingfrom 0.5 mg to 4 mg, for example (Granado et al., 2007).In a survey of almost 200,000 individuals 15 years of age and older, only 18% of thesample met the World Health Organization’s recommended daily intake of at least fiveservings of fruit and vegetables which contain lutein (Frank et al., 2019). Accordingly, thereis an unresolved need to address the fact that children are not getting enough lutein in theirdiets which can lead to age related eye and brain impairment (Age-Related Eye Disease Study2 Research et al., 2014; Christensen et al., 2018; Eisenhauer et al., 2017; Amy C. Long et al.,2019). The recommended daily intake of 10 mg of the nutrient lutein (required for eye andbrain function) is not being met by most children (Kim et al., 2014; Thurnham, 2007). In theUnited States alone, 99% of children between the ages of 2 to 18 years are not eating therecommended daily amount of dark, green leafy vegetables. (Krebs-Smith et al., 2010). Evenmore alarming, over 90% of children in the United States do not eat the recommended dailyamount of vegetables (Kim et al., 2014). The intake does not appear to be better from a globalperspective with a recent national survey conducted in England found that only eight percentof children between the ages of 11 and 18 consumed the 5-a-day recommended daily intakeof fruits and vegetables (Bates, 2016). In fact, a study of 28 low and middle income countriesfound that the over eighty percent of individuals 15 years and older failed to meet the dailyrecommended intake levels (Frank et al., 2019).There are approximately 21.4 million children between the ages of 10 and 14 yearscurrently living in the United States (ACS Demographic and housing estimates, 2019). Thisage group represents the U.S. demographic with the lowest healthy eating index (HEI) of allage groups with an average 52 out of a possible 100 along with a reported approximatevegetable intake of only ½ cup per week of dark green leafy vegetables, known for their highcontent of lutein and zeaxanthin (Abdel-Aal el et al., 2013; Dietary Guidelines for Americans,2020-2025., December 2020.; Eisenhauer et al., 2017).Against this backdrop of increased exposure to digital devices and eye strain and adiet with the lowest healthy eating index, the inventors have further determined that in thisadolescent population, lutein and / or zeaxanthin may be even more important in thedeveloping eye and brain than in the adult body. Existing data suggest preferential uptakeof lutein in juvenile tissue and developing organisms. Furthermore, there is compellingevidence that increased levels of lutein and / or zeaxanthin at an early age can result inpositive long-term benefits. For example, multiple cross-sectional studies conducted inchildren have found that higher levels of lutein and / or zeaxanthin in the eye, measured asmacular pigment optical density (MPOD) was strongly correlated with measures ofintelligence, academic achievement and cognitive control (Hassevoort et al., 2017; Saint etal., 2018; Walk et al., 2017). In addition, a series of studies conducted in primatesdemonstrated that a diet deficient in lutein led to fundamental deficits in eye developmentand visual function while restoring lutein to the diet was able to correct many of theproblems (Leung et al., 2004; Neuringer et al., 2004). High levels of lutein in the retina arealso predicted to lead to positive health outcomes later in life, and in fact, studies have shownthat MPOD levels tend to decrease with age, making it all the more critical to ensure highlevels of lutein from as early age as possible (Arunkumar et al., 2018; Ji et al., 2015).Even more alarming, studies have shown a strong correlation between low intake oflutein and age-related macular degeneration (Wu et al., 2015), as well as with cognitivedecline and Alzheimer’s disease later in life. With a globally aging population, if this deficitis not addressed adequately early on in life, there will be substantial public healthconsequences. One study predicted that if individuals were to consume the recommendedlevels of lutein daily, there would be a seven percent reduced risk for age related eye diseaseand a potential savings of over five billion US dollars annually due to costs of requiredmedical care (Frost & Sullivan, October 2017).Despite these alarming trends, there are limited interventional studies in children tooffer guidance on lutein and / or zeaxanthin intake, either through diet or supplementation.To the inventors’ knowledge, there are no published studies to date investigating the impactof lutein and / or zeaxanthin supplementation on vision and eye health in healthy adolescentsor confirmation that lutein and / or zeaxanthin intake will result in increased macularpigment levels in the eye. The inventors have for the first-time identified and describedpreviously unknown benefits of lutein supplementation in children, namely, protectingvision, reducing abnormal eyeball shape changes, and preserving foveal architecture ofchildren exposed to digital screens and near work. And, namely, the benefits of lutein and / orzeaxanthin supplementation for supporting foveal architecture and integrity to preserveocular shape and structure, which reduces biomechanical stress and perception of eye strain,accommodative fatigue and ultimately vision.These conditions include but are not limited to damage to the retinal nerve layer,improper eyeball elongation, eyeball shape change, impaired vision, eye strain,accommodative fatigue, screentime fatigue, biomechanical stress, dry eye, strabismus,and / or irregular anatomical development or damage of the fovea or foveal architecture areall problematic issues that are exacerbated by exposure to digital screens and near work.The methods disclosed herein help prevent, reduce, delay, and mitigate these conditions.One proposed benefit of lutein and / or zeaxanthin accumulation within the retina isthe protection from short-wavelength high energy blue light present in both sunlight anddigital device screens. Due to the high energy nature of blue light, excessive exposure canlead to oxidative stress in the retina and damage to photoreceptor cells. A study in primatesshowed that when the animal was deficient in lutein, blue light exposure significantlydamaged the retina and, subsequently, the macula. (Barker et al., 2011).One aspect of the present invention relates to administering carotenoids, such aslutein and / or zeaxanthin, to an individual in order to protect and maintain the integrity ofan individual’s eyes, including the eye structure, such as preserving eyeball shape and / orpreventing elongation. Administration of carotenoids, such as lutein and / or zeaxanthin, alsobenefits the surround ocular tissues that may affect vision such as the uveal tissues, sclera,and the foveal architecture.In certain embodiments, the administration of one or more ocular nutrients, such aslutein and / or zeaxanthin, protects the eye by mechanisms of reduced oxidative stress,reduced inflammation, cellular signaling, neurotrophin support, and gene regulation.In certain embodiments, eyeball elongation is prevented by the accumulation ofcarotenoids in the uveal tissues, which include the choroid, the iris and the ciliary bodies.The choroid sits between the retina and sclera. A thickened choroid is correlated with areduced risk and reduced progression of eyeball shape lengthening. Thus, by increasing thelevel of carotenoids, the choroid is strengthened and protected.The foveal architecture refers to the specialized structure of fovea, which is thecentral part of the retina. The fovea is responsible for visual acuity—allowing for fine detailsand color to be distinguished. The fovea is devoid of rod photoreceptors, but contains coneswhich are directly stimulated to achieve this visual acuity. Carotenoid pigments, such aslutein and / or zeaxanthin may accumulate in the fovea. Irregular anatomical development ofthe fovea is detrimental to eye health and vision, and may cause irregular eyeball shape.Proper regulation of dopamine also plays a role in controlling eye growth andmaintaining correct eyeball shape. Extended periods of near work, such as using digitaldevices and screen time are associated with dopamine deficiency in the eye. This disclosurecontemplates that carotenoids can help preserve and regulate dopamine in the eye and helpprevent a dopamine deficiency in the eye.As described above, the eyes of adolescents, or teens and pre-teens, undergosignificant development and growth during this critical stage of life. The inventors havesurprisingly discovered for the first time that this developmental phase appears to affect theaccumulation of lutein and / or zeaxanthin. Specifically, the accumulation of lutein and / orzeaxanthin happens rapidly—more quickly than seen in other age groups and populations.The accumulation of lutein may also be more rapid due to a compromised or stretched retinaresulting from the high amount of digital device use or near work. Thus, both thedevelopmental time frame and a compromised retina may “prime” the retina to receivelutein and / or zeaxanthin. Additionally, a lower dose of lutein and / or zeaxanthin may berequired when compared with other age groups and populations. This disclosure furthercontemplates that lutein and / or zeaxanthin supplementation can be used as a preventativemeasure to intervene before damage occurs in children.Ocular nutrients may be used for the methods described herein. Such ocular nutrientsmay include antioxidant vitamins, carotenoids, antioxidant minerals, natural antioxidantextracts, and fatty acids alone or in combination. Such antioxidant vitamins may includevitamins A, C, and / or E. Such carotenoids may include lutein, zeaxanthin, betacryptoxanthin, beta carotene, astaxanthin, retinoids, retinal, retinaldehyde, capsanthin,astaxanthin, and / or meso-zeaxanthin, and esters thereof. Such antioxidant minerals mayinclude zinc, copper, and / or selenium. Such natural antioxidant extract may includepolyphenols, quercetagetin, quercetin, anthocyanidins, and / or turmeric (containingrosmarinic acid). Such fatty acids may include omega 3 fatty acids and / or short chain fattyacids.One aspect of the present invention relates to the supplementation of ocular nutrientsto a population in need thereof, which includes but is not limited all children, and accordingto at least one embodiment, the population includes one or more subjects experiencingadolescence, such as teenagers (i.e., 13 to 18 years of age), pre-teenagers (i.e., 8 to 12 yearsof age), and younger children (i.e., 7 years of age or younger).In certain embodiments, the supplementation should be added in a therapeuticallyeffective amount in a subject. In an embodiment, a therapeutically effective amount of thenutrient, antioxidant, or vitamin is between about 0.02 (1 IU) and 15 mg (150 IU) perkilogram of body weight of the subject per day. In an embodiment, a therapeutically effectiveamount of the nutrient, such as lutein and / or zeaxanthin, is between about 0.0001 and 2 mgper kilogram of body weight of the subject per day. In an embodiment, a therapeuticallyeffective amount of nutrient, such as lutein and / or zeaxanthin, is in the range of betweenabout 0.0001 and 5 mg per kilogram of body weight of the subject per day.In certain embodiments, an effective amount of ocular nutrient supplementation is inthe range of about 0.1 mg / day to about 30 mg / day, for instance between about 0.5 to about15 mg / day, 0.5 to about 10 mg / day, or about 5 to 10 mg / day, such as about 0.5 mg / day, 0.6mg / day, 0.7 mg / day, 0.8 mg / day, 0.9 mg / day, 1 mg / day, 2 mg / day, 3 mg / day, 4 mg / day, 5mg / day, 6 mg / day, 7 mg / day, 8 mg / day, 9 mg / day, 10 mg / day, 11 mg / day, 12 mg / day, 13mg / day, 14 mg / day, 15 mg / day, 20 mg / day, 25 mg / day, or 30 mg / day.In certain embodiments the ocular nutrient supplementation dose provided for thedisclosed methods is at least 0.5 mg / day, 1 mg / day, at least 2 mg / day, at least 3 mg / day, atleast 5 mg / day, at least 6 mg / day, at least 7 mg / day, at least 8 mg / day, at least 9 mg / day, atleast 10 mg / day, at least 11 mg / day, at least 12 mg / day, at least 13 mg / day, at least 14mg / day, at least 15 mg / day, at least 20 mg / day, at least 25 mg / day, or at least 30 mg / day.According to one aspect of the invention, the subjects receiving supplementationunder the methods described herein may be children. In certain embodiments, thepopulation includes individuals during adolescence (typically, spanning 9 to 19 years of age)and young adulthood (typically, up to 24 years of age), and includes but is not limited toteenagers (i.e., 13 to 18 years of age), pre-teenagers (i.e., 8 to 12 years of age), and in someinstances younger than 8 years of age. It should be appreciated that young adults and adultsmay also benefit from the methods described herein.In certain embodiments, the individuals or subjects with high usage of digital devices(i.e., greater than 4 hours average per day) may particularly benefit from the methodsdescribed herein.In certain embodiments, the method comprises carotenoid supplementation oradministration to an individual or subject provides protection through anti-oxidantproperties, anti-inflammatory properties, blue light filtering, and an increase in dopaminelevels in an individual or subject, which may slow shape change within an eyeball.In certain embodiments, the administration of one or more ocular nutrients, such aslutein and / or zeaxanthin, to an individual or subject prevents or delays damage associatedwith digital screens, near work, and blue light. In an embodiment, the administration of oneor more ocular nutrients to an individual or subject, such as lutein and / or zeaxanthin,reverses damage to the eye from exposure to digital screens, near work, and blue light.In certain embodiments, the administration of one or more ocular nutrients, such aslutein and / or zeaxanthin, to an individual or subject protects the vision of an individual orsubject with exposure to digital screens and near work, including under conditions causingdamage to the retinal nerve layer, improper eyeball elongation, improper eyeball shape,biomechanical stress, damage to the foveal architecture, and / or irregular anatomicaldevelopment of the fovea.In certain embodiments, the administration of one or more ocular nutrients, such aslutein and / or zeaxanthin, to an individual or subject reduces abnormal eyeball shapechanges of an individual or subject with exposure to digital screens and near work, includingunder conditions causing damage to the retinal nerve layer, and / or irregular anatomicaldevelopment of the fovea.In certain embodiments, the administration of one or more ocular nutrients, such aslutein and / or zeaxanthin, to an individual or subject prevents or delays abnormal eyeballshape changes of an individual or subject person with exposure to digital screens and nearwork, including under conditions causing damage to the retinal nerve layer, impropereyeball elongation, improper eyeball shape, biomechanical stress, damage to the fovealarchitecture, and / or irregular anatomical development of the fovea.In certain embodiments, the administration of one or more ocular nutrients, such aslutein and / or zeaxanthin, to an individual or subject preserves the foveal architecture of anindividual or subject with exposure to digital screens and near work, including underconditions causing damage to the retinal nerve layer, improper eyeball elongation, and / orirregular anatomical development of the fovea. In an embodiment, the preservation occursprior to damage of the foveal architecture. In certain embodiments, the preservation occursprior to irreversible damage of the foveal architecture.In certain embodiments, the administration of one or more ocular nutrients, such aslutein and / or zeaxanthin, to an individual or subject minimizes or mitigates damage to thefoveal architecture of a person with exposure to digital screens and near work, includingunder conditions causing damage to the retinal nerve layer, improper eyeball elongation,and / or irregular anatomical development of the fovea.In certain embodiments, the administration of one or more ocular nutrients, such aslutein and / or zeaxanthin, to an individual or subject prevents, delays, minimizes, ormitigates eye strain and / or screentime fatigue of a person with exposure to digital screensand near work, including under conditions causing damage to the retinal nerve layer,improper eyeball elongation, and / or irregular anatomical development of the fovea.Another aspect of the present invention relates to healthy lifestyle interventions, i.e.,supplementation or administration of carotenoids, such as lutein and / or zeaxanthin, toensure adequate macular pigment levels in a vulnerable population, such as children duringthe adolescence phase, wherein the supplementation or administration of carotenoids is inan amount effective to provide protection against potential damage due to exposure todigital screens, blue light, and near work that can lead to eye conditions including vision(myopia or hyperopia), eye strain, biomechanical stress, dry eye, strabismus, damage tofoveal architecture, irregular development of fovea, eyeball shape change, improper eyeballelongation, screentime fatigue, and retinal nerve cell layer damage.In certain embodiments, the methods described herein include subjects with one ormore conditions. For instance, where the subject is experiencing one eye condition, but nota second eye condition, the administration of a carotenoid may prevent or delay the secondeye condition from developing or progressing. Simultaneously, the first eye condition maybe reduced or mitigated from the same administration.In certain embodiments, the administration of the ocular nutrient, such as luteinand / or zeaxanthin, may be distributed in any suitable medium or form, including, but notlimited to a gummy, tablet, capsules, soft gel, chewing gum, yogurt, or carbonated beverage.In certain embodiments, the carotenoid, such as lutein and / or zeaxanthin, may besourced from a natural source, including but not limited to the group consisting of marigold,paprika, Chinese lantern, spinach, kale, collard greens, yellow sweet corn, peas, brusselsprouts, broccoli rabe, asparagus, arugula, avocado, eggs, pistachios, winter squash,pumpkin, sweet potatoes, carrots, or goji berries.In certain embodiments, the carotenoid, such as lutein and / or zeaxanthin, may beadministered with other important nutrients and vitamins, such as omega 3 fatty acids,which may provide a synergistic effect on eye and brain benefits.Example 1: The “LuTEEN” Trial: Effects of Daily Lutein Supplementation on Macular Pigment and Digital Eye Strain in Healthy Youth (Pre-Teen and Teen) – A Randomized, Placebo-Controlled Study The objective of this study was to determine the effects of daily supplementation with5 mg lutein or placebo on the macular pigment density of healthy participants between theages of 8 and 16 years who were exposed to four hours or more of daily digital screens. Inaddition, the study was designed to track changes in digital eye strain over the course as wellas baseline values of health literacy and vegetable self-efficacy.The population of teens and pre-teens was identified to investigate the impact ofsupplemental lutein on macular pigment density in the retina and related effects on eye andbrain health, where the age group has a reported low level of dietary lutein (DietaryGuidelines for Americans, 2020-2025., December 2020) intake along with excessive screentime exposure. In addition, this age group can easily perform the non-invasive tests designedto measure lutein levels in the eye (Temple et al. 2015; Wooten et al., 1999) and to theinventors’ knowledge would be the first teenage youth population to be studied via aninterventional study with supplemental lutein.Importantly, macular pigment composed of both lutein and zeaxanthin can bemeasured via non-invasive methods to indicate the amount of lutein and zeaxanthindeposited in the eye and correlates with lutein levels in the brain (Bernstein et al., 2016;Vishwanathan et al., 2016). Heterochromatic flicker photometry (HFP) is the mostcommonly used psychophysical technique used to measure macular pigment optical density(MPOD) clinically and works by comparing flicker perception of two lights at differentwavelengths. The participant response provides an estimate of macular pigment opticaldensity (MPOD) which is an indication of macular pigment levels in the fovea center of oneeye. HFP measures macular pigment at a single point in the retina and can be challengingfor younger participants to perform with typical standard deviations of 0.2 to 0.3 opticaldensity units (McCorkle et al. 2015). Commercially available devices such as the MPSIIQuantifEye Macular Pigment Device can be used to implement the HFP technique. A newerpsychophysical measurement tool is the MPEye. The MPEye is a device that uses the entopticphenomenon of Haidinger’s brushes (HB) to measure lutein and zeaxanthin concentrationsin the eye (Temple et al., 2015). The participant looks through a view finder with both eyesand indicates the direction of a spinning yellow bowtie shape. The ability to see the image isdetermined by macular pigment concentration along the henle fibers and provides ameasure of macular pigment density across the entire macula. While both methods arevalidated, HFP is reliant on a participants’ ability to perceive flickering lights in a single eyewhile MPEye measures macular pigment density across the entire retina in both eyes andrelies on the participants ability to observe a spinning yellow light. In addition, the MPEyedetects macular pigment levels across the entire retina whereas HFP assesses macularpigment at a single point in the retina. The distribution of macular pigment following luteinsupplementation in healthy pre-teen and teen youth has not yet been studied and thereforeit is not known if HFP or MPEye is the more sensitive measure to detect changes in macularcarotenoids over time. Therefore, depending on the age of the child one method may beeasier to administer and may capture developmental changes more completely.Nonetheless, both MPOD measurement methods are painless, can be completed inapproximately 5-10 minutes of time and have been shown to be valid and reliable measuresof macular pigment in school-aged children (Cannavale et al., 2019; Hassevoort et al., 2017;Saint et al., 2018; Walk et al., 2017).METHODS Study DesignThis was a six-month, prospective, randomized, double-blind, placebo-controlledparallel trial in healthy children and adolescents with daily digital screen exposureconducted at a single site (Des Moines, IA). The study consisted of three visits to the studysite (baseline, 90 and 180-day) along with bi-weekly text check-ins. All visits conformed tostandards of the use of human participants in research as outlined in the Helsinki Declarationand all study procedures were reviewed and approved by an external Institutional ReviewBoard (Salus IRB No. IRB00013544). The study was prospectively registered atClinicalTrials.gov (NCT05314647).Study Participants Fifty-nine participants between 8 and 16 years of age were recruited for this study.The inclusion criteria included being between the ages of 8 and 16 years on the day ofenrollment, with self-reported exposure to digital screens of four hours or more per day onaverage, and were in good general health and with no lutein or zeaxanthin supplement useduring the prior six months. The four hours or more digital screen inclusion criteria wasselected based on research showing that screen time greater than 4-6 hours daily maydegrade eye function significantly (Yang et al., 2020). In addition, a recent study in childrenwith a mean age of 13 years revealed that the average screen time per day was 3.9 hours, amajor jump from the pre-COVID pandemic average of 1.9 hours (Mohan et al., 2021).Furthermore, researchers have found that children with greater than 5 hours of screen timeper day were at a significantly increased risk for digital eye strain (Mohan et al., 2021).Sample SizeThe study was designed to have a power of 80% (β = 0.20) assuming a moderate effectsize of 0.6 with lutein supplementation compared to placebo. The power analyses werebased on related studies (Hassevoort et al., 2017; Renzi-Hammond et al., 2017; Saint et al.,2018; Stringham et al., 2017; Walk et al., 2017). Specifically, data from Stringham et al., 2017reporting significant improvements in MPOD values in healthy young adults with four hoursof screen time or more per day after six months of supplementation assessed viaheterochromatic flicker photometry (0.383 and 0.472 for placebo and treatment MPODvalues respectively and 0.132 for placebo standard deviation) was used to inform theanalyses. The power analyses suggested a total sample size of 70 (35 per group) to accountfor possible attrition was required to reach power of 80% (β = 0.20) with a two-sided alphaof 0.05.Study Intervention The participants were randomized to receive either 5 mg lutein (FloraGLO® Lutein,Kemin Industries, Des Moines, IA, LOT No. UT20100010) or an identical placebo without theactive in a sugar-free gummy format. The pectin gummies were manufactured in a GMPfacility by TopGum Industries, LTD, Sderot, Israel No lutein or zeaxanthin was detected inthe placebo gummies at any time point, as expected. The lutein gummies were found tocontain, on average, 6.89 mg lutein and 0.53 mg zeaxanthin per gummy at time zero, whichslightly exceeds the target of 5 mg lutein per gummy most likely due to overage added duringproduction. The lutein gummies contained a ratio of 13:1 lutein to zeaxanthin, which isconsistent with the ratio found in FloraGLO® Lutein material (Kemin Industries, Des Moines,IA). Gummies were analyzed at both 5 months and 8 months after time zero (equivalent to7 months and 10 months after gummy manufacture date). Lutein was found to be 102% and101% of time zero content at the measured time points, respectively. Zeaxanthin wasmeasured at 104% and 102% of time zero content at the measured time points, respectively.These data confirm that the active components in the gummies used for the clinical trial haveremained stable throughout the study.Randomization and Study Procedures The study consisted of three visits to the study site (baseline, 90 and 180-day) alongwith bi-weekly text check-ins. Figure 1 provides an overview of the study outline. Screeningphone calls were made to potential participants to determine eligibility for inclusion in thestudy. The phones calls were conducted with the parent or guardian of the children andincluded questions on age, digital device use, lutein / zeaxanthin supplement use and overallhealth. If eligibility criteria were met, the parent and participant were invited to come to thestudy site for baseline assessment and enrollment in the study. At the baseline visit, bothparents and participants completed the health literacy assessment. Participants took themacular pigment measurements and digital eye strain survey.After completing the baseline screening, each participant was assigned to a groupbased on a simple randomization procedure using a computer generated random numbersequence (Kim & Shin, 2014). Randomization was based on a variable block randomizationalgorithm via Castor EDC Software (Castor v2024.2.0.1, Castor Research Inc, Amsterdam,The Netherlands). Block sizes were set to 4, 6, and 8 and participants were stratified basedon age group (8-10, 11-13 and 14-16 year olds) and sex (female, male). Based onrandomization, participants were provided with an opaque Bottle A or Bottle B of gummieswith a total of 100 gummies to last for the next 90 days. They were instructed to take onegummy per day with food. Bi-weekly text messages were sent to the participant’s parents tocheck on compliance and any potential adverse events to the study product. Participantsreturned to the lab on days 90 and 180 and the same measurements were made with theparticipants. Product bottles were collected, and the remaining gummies were counted todetermine compliance. No additional data were collected from parents at either of the twosubsequent time points.Compliance percentage was defined as the number of gummies remaining in thebottle divided by the number of gummies when the bottle was dispersed and then multipliedby 100 to give a percentage. Compliance was assessed by counting the number of gummiesreturned in the product bottles on days 90 and 180 and was encouraged via weekly textmessages to the participants. Compliance was defined as between 80% and 120% ofgummies consumed at the two assessment time points.Outcome Measures Primary Outcome The primary outcome of the clinical trial was the change in macular pigment densityobserved at 90 and 180 day compared to baseline using two different validated instruments;the QuanitfEye based on heterochromatic flicker photometry (HFP) (EyePromise,Chesterfield MO, USA) and the MPEye based on the concept of Haidinger’s brushes (HB)(Azul Optics, Bristol UK). Both methodologies utilize a psychometric approach to determinethe density of the macular pigment and allow for repeated non-invasive assessments of thelutein and zeaxanthin content of the retina (Wooten et al., 1999: Temple et al., 2015). Bothprocedures have been carried out in children and adults (Chew et al., 2004; Saint et al., 2018;Walk et al., 2017: Sangani et al. 2024) and have been shown to be safe, comfortable, andpainless.Secondary Outcomes The secondary outcomes assessed included health literacy, veggie efficacy and digitaleye strain. Health literacy was assessed in both the children and parents using the NewestVital Sign (NVS) assessment tool (Driessnack et al., 2014; Weiss et al., 2005). Theassessment, which takes approximately three minutes, requires the participant to look overa nutrition facts panel for ice cream and answer six questions about the informationprovided in the facts panel. The instrument has been found to have high internal consistencyand to correlate well with other measures of health literacy (Weiss et al., 2005). Theinstrument has been studied in children and found to perform well (Chari et al., 2014;Driessnack et al., 2014; Guo et al., 2018; Okan et al., 2018; Warsh et al., 2014). Overall, theNVS has demonstrated sensitivity as an assessment of health literacy in parents and foundto correlate well with real life health outcomes such as emergency room visits and adolescentobesity (Chari et al., 2014; Morrison et al., 2014). Veggie self-efficacy was assessed via a 20-point questionnaire asking about the participants habits related to vegetable consumption.The survey takes approximately three minutes to complete with a minimum possible scoreof 20 and maximum of 120. The instrument has been validated in populations as young as 8years of age (Sharma et al. 2014).The instrument for digital eye strain consisted of a six question validated assessmentmeasured on a frequency scale, similar to the visual fatigue scale used in adults (Benedettoet al., 2013; Saoji et al. 2024; Cavusoglu et al, 2023; Swathi et al. 2022). The six itemsassessed on a 4-point Likert scale consisted of the following questions: 1) I have difficultiesin seeing; 2) I have a strange feeling around the eyes; 3) My eyes feel tired; 4) I feel numb; 5)I have a headache; 6) I feel dizzy looking at the screen (Benedetto et al., 2013; Stringham etal., 2017). These questions represent a sub-set of symptoms assessed in the Computer VisionSyndrome Questionnaire, a validated instrument for use in measuring digital eye strain inadults (Cantó-Sancho et al., 2020; Seguí Mdel et al., 2015; Sheppard & Wolffsohn, 2018)because research shows that children and adolescents are unable to correctly report on allthe symptoms identified in the Computer Vision Syndrome Questionnaire (Hu et al., 2013;De-Hita-Cantalejo et al., 2020; Ichhpujani et al., 2019).Statistical Analysis Data were analyzed using SPSS statistical software package (IBM Corp. Version29.0.1.0 (171)) with p<0.05 set as the criterion for significance. Only participants who metthe compliance criteria were included in the analysis. A mixed model repeated measures(MMRM) was conducted on the per protocol population of 54 participants with the removalof 5 participants from the intent to treat population due to a gummy compliance level lessthan 80%. For each subject, change from baseline was calculated for the 90 day and 180-dayvisits with treatment, visit, and treatment by visit interaction treated as fixed effects,participant as a random effect and baseline macular pigment values as a covariate. Avariance components covariance structure was used with a maximum likelihood estimationand Satterthwaite approximation for degrees of freedom. Pairwise comparisons on theestimated marginal means were conducted using Bonferroni tests to account for multiplecomparisons. Identical analyses were conducted on digital eye strain scores using baselineVFS score as a covariate. Descriptive statistics were used to assess subject characteristicsat baseline with all participants included (n=59) and independent samples t-tests or Pearsonchi-square tests were used to determine if any group differences were present at baseline.RESULTS Participant characteristics and compliance All 59 participants screened for the study between the ages of 8 and 16 years weredeemed eligible to participate and were recruited for the study. The average age of theparticipants was 12.3 years (SD=2.23) with 59% of the participants in the pre-teen / youthcategory (8-12 years) and 41% in the adolescent age range (13-16 years). Participants wereevenly split between female (n=30) and male (n=29) with White or Caucasian making up theprimary racial / ethnic category (n=48). Table 1 provides detailed demographics of theparticipants at baseline.Table 1: Participant Demographics at baseline (n=59)Overall Total Placebo Lutein p-valueAge in yearsMean (±SD) y 12.3 (±2.23) 12.25 (±2.31) 12.43 (±2.18) 0.75518-10 y 25.4% (n=15) n=8 n=711-13 y 45.8% (n=27) n=14 n=1314-16 y 28.8% (n=17) n=9 n=8GenderFemale 50.8% (n=30) 53.3% (n=16) 46.7% (n=14) 0.9022Male 49.2% (n-29) 51.7% (n=15) 48.2% (n=14)Hours Screen time (h)Mean (±SD) h 5.51 h (±1.5) 5.61 h (±1.7) 5.44 h (±1.3) 0.5871 Racial / Ethnic groupWhite 81.4% (n=48) n=23 n=25 0.3582Asian 11.9% (n=7) n=5 n=2Hispanic or Latino 3.4% (n=2) n=1 n=1Mixed 3.4% (n=2) n=2 n=0Black or African American 0% (n=0) n=0 n=0American Indian or Alaska 0% (n=0) n=0 n=0NativeNative Hawaiian / Other 0% (n=0) n=0 n=0Pacific IslanderBaseline Macular Pigment ValuesHeterochromatic Flicker 0.547 ± 0.144 0.555 ± 0.160 0.539 ± 0.129 0.6841Photometry: Mean (±SD) (n=58) (n=30) (n=28)Haidinger’s Brush degree 5.136 ± 2.4563 5.32 ± 2.257 4.93 ± 2.721 0.5461of polarization: Mean (n=59) (n=31) (n=28)(±SD)Eye StrainDigital Eye Strain (VFS) 10.88 ± 3.09 10.81 ± 2.70 10.61 ± 2.74 0.847(n=59) (n=31) (n=31)Health KnowledgeParent Health Literacy (NVS) (n=41) (n=21) (n=20)Child Health Literacy 3.65 ± 2.16 3.71 ± 2.23 3.58 ±2.12 0.8181(NVS) (n=54) (n=28) (n=20)12Two-sided p-values from independent samples t-test with equal variances assumedPearson Chi-square test with two-sided p-valueIndependent sample t-tests were conducted to determine any baseline differences indemographic data between the treatment and placebo groups and all tests resulted in non-significant probabilities (p>0.35 for all). Mean self-reported screen time for all participantsat baseline was 5.4 hours (SD=1.3) and mean digital eye strain was 10.9 (SD=3.1). Thefrequency distributions for age, screen time, digital eye strain and baseline macular pigmentvalues can be seen in Figures 2A-2E.Based on the gummy count, the participants were 94.56% compliant with a standarddeviation of 10.3%. However, five participants did not reach the threshold of inclusion bymaintaining a compliance greater than 80% and less than 120%. All five participants hadless than 80% compliance (49.7%, 76.41%, 77.49%, 77.84% and 78.92%). As such, theseparticipants were removed from the per protocol analysis, bringing the average compliancein the per protocol population to 96.65% with a standard deviation of 7.3%. Of the fiveparticipants removed from further analysis, four were in the placebo group and one was inthe treatment group. The CONSORT diagram (Figure 3) represents the final data set usedfor the mixed model repeated measures statistical analyses.Health Literacy and Veggie Self-Efficacy Table 1 shows that health literacy was approximately two points higher for parentscompared to the children’s NVS scores out of a total possible of six points. However, neitherparent nor child health literacy scores varied between the two groups at baseline. Veggieself-efficacy was approximately 65 out of a possible 120 for the total participant group atbaseline. There was also no significant difference in Veggie Self-Efficacy scores betweengroups at baseline.Macular Pigment Changes (HFP and MPEYE assessments) Macular pigment density across the entire macula, assessed utilizing Haidinger’sBrushes degree of polarization showed a significant increase for participants taking a daily5 mg lutein gummy compared to the placebo group, F(1,73.4)=6.86, p=.011. Pairwisecomparison analyses revealed that the group of participants receiving lutein demonstrateda mean marginal estimate increase in MP-eye values of 1.5 while the group receiving theplacebo showed a mean marginal estimate increase of only 0.07 resulting in a marginal meanestimate increase in the treatment group of approximately 1.45 MP-eye units (95%confidence interval is 0.346 to 2.554, Cohen’s d = 1.85). Based on the absolute changes inmeans from baseline, the participants taking lutein showed a 13.7% improvement in HBmeasured macular pigment compared to participants taking placebo. On the other hand,macular pigment peak volume at the center of the fovea, measured as MPOD viaheterochromatic flicker photometry, did not demonstrate any increase based on luteinsupplementation and in fact remained fairly constant throughout the course of the study forboth the lutein and placebo groups, F(1,59.07)=.044,p=.835, Marginal mean estimatesshowed a mean change of 0.044 and 0.039 for the lutein and placebo groups respectively,yielding a marginal mean estimate difference of 0.005 between both groups (95% confidenceinterval of -0.052 to 0.042, Cohen’s d =0.15). Based on the absolute changes in means frombaseline, the participants taking lutein showed a 0.05% improvement in HFP measuredmacular pigment compared to participants taking placebo.The means ± SD of MPOD measurements by HFP are summarized in Table 2 andFigure 4A. Using HFP, there was no difference between groups at baseline (PL 0.532 ± 0.158vs. LuT 0.549 ± 0.122), and no significant difference between the interventions at day 90 (PL0.554 ± 0.156 vs. LuT 0.580 ± 0.116) and day 180 (PL 0.566 ± 0.179 vs. LuT 0.588 ± 0.141).Marginal mean estimates showed a mean change of 0.044 and 0.039 for the lutein andplacebo groups respectively, yielding a mean difference of 0.005 between both groups(p=0.835). While MPOD values did increase for both groups over the course of treatment(mean change of LuT 0.039 and PL 0.034), the improvement did not reach statisticalsignificance (p=0.543).Table 2: Macular Pigment Scores Over the Course of the Study Using HFPHFP Placebo LuteinBaseline 0.532 ± 0.158 0.549 ± 0.122(n=26) (n=27)Day 90 0.554 ± 0.156 0.580 ± 0.116(n=27) (n=26)Day 180 0.566 ± 0.179 0.588 ± 0.141 The means ± SD of MPOD measurements by MPEYE are summarized in Table 3 andFigure 4B. Using MPEYE, there was no significant difference between the interventions atbaseline (PL 5.15 ± 2.35 vs. LuT 4.89 ± 2.76, p=0.023). However, statistically significantdifferences emerged between the interventions at day 90 (PL 5.26 ± 2.84 vs. LuT 5.85 ± 2.45)and day 180 (PL 4.81 ± 3.10 vs. LuT 5.78 ± 2.68).Table 3: Macular Pigment Scores Over the Course of the Study Using MPEYEMPEYE Placebo Lutein5.15 ± 2.35 4.89 ± 2.76Baseline (n=27) (n=27)Day 90 5.26 ± 2.84 5.85 ± 2.45(n=27) (n=27)Day 180 4.81 ± 3.10 5.78 ± 2.68(n=27) (n=27)The MMRM revealed a statistically significant effect for treatment but not for visit orthe treatment by visit interaction (Table 4). Further, pairwise comparison analysesrevealed that the group of participants receiving lutein demonstrated an average increase inMPEYE values of 1.5 while the group receiving the placebo showed an overall change of 0.07resulting in an increase in the treatment group of approximately 1.45 units, p=0.011 with a95% confidence interval of 0.346 to 2.554 based on estimated marginal means and amoderate effect size (Cohen’s d = 0.31) based on mean group differences at Day 180.Table 4: Mixed Models Repeated Measures Analysis of Macular PigmentFixed Effect Fixed Effect Standard p-value 95%Parameter Estimate Error (based on t- Confidencestatistic) IntervalTreatment -.013 .030 .663 -.073 to .047Visit -.019 .026 .460 -.071 to .033Treatment x .017 .037 .655 -.057 to .090VisitTreatment -1.635 .707 .023* -3.036 to -.234Visit .074 .621 .905 -1.173 to1.321Treatment x .370 .878 .675 -1.393 toVisit 2.134* statistically significantParticipant scores on both of the psychophysical methods for measuring macularpigment (HFP and HB) were correlated at baseline, r(58)=0.335, p=.010, but were no longercorrelated following the six months of supplementation, r(52)=0.180, p=.201, indicating thatthe two methods may be measuring different underlying physiological parameters.Digital Eye Strain Evaluation of the results revealed that participants supplemented with 5 mg of luteinover the six-month study showed an overall treatment effect demonstrating a statisticallysignificant reduction in digital eye strain compared to the participants taking only a placebo,F(1,107)=6.798, p=0.010. Evaluation of the estimated marginal means revealed a reductionin visual fatigue of 1.184 (SE=0.280) in the group taking lutein and a much smaller decreasein visual fatigue of 0.148 (SE=0.282) in the participants taking the placebo gummy for a meandifference of 1.036 between the two groups (95% confidence interval of 0.249 to 1.823,Cohen’s d=1.85). As a reference, a study in healthy adults found a one-to-two-point decreasein visual fatigue following approximately one hour of reading on LCD, e-ink or paper formatsusing the same VFS measurement tool (Benedetto et al., 2013). For the current study, theparticipants taking lutein showed a 5.56% improvement in visual fatigue compared toparticipants taking placebo based on the absolute changes in means from baseline (Figure5). There was no significant visit or treatment by visit effect. Post hoc independent sample t-tests of each individual question of the VFS, indicatesthat the responses to “I have problems seeing” and “I have headaches” could potentially bedriving the benefits observed with the lutein supplementation (Figures 6A-6F).Health Awareness Participants’ abilities to obtain and use information to make informed healthdecisions was significantly correlated with the same capabilities of their parents as seen bythe significant correlations of parents’ and participants’ health literacy scores, r(41)=0.568,p<.001. Interestingly, parents’ health literacy scores, but not the children’s scores weresignificantly correlated with baseline macular pigment values, indicating that parents maystill play a pivotal role in adolescent nutrient intake. Of special note, the parents’ scores wereonly significantly related to HB baseline macular pigment values and not to HFP baselinevalues, again indicating that the HB methodology may be a more sensitive technique forassessing total macular pigment quantities, r(41)=0.350, p=.025 and r(40)=-0.105, p=.521,for parent health literacy and baseline macular pigment HB and HFP values respectively.DISCUSSION The present study evaluated the effects of a six-month daily intervention of 5 mglutein on macular pigment levels and digital eye strain in a healthy adolescent populationexposed to four hours or more of daily digital device use. The findings demonstrate that amoderate nutritional intervention of 5 mg lutein (the equivalent of 1 / 4 cup of cookedspinach) was able to increase macular pigment levels in a healthy adolescent population.Following six-months of daily supplementation, participants consuming a 5 mg luteingummy demonstrated a 14% increase in macular pigment density compared to those takinga placebo gummy. Along with the macular pigment increase, participants in the treatmentgroup reported a 6% decrease in digital eye strain compared to the levels reported byparticipants in the placebo group. Health literacy was assessed at baseline for both theparticipant and the parent guardian as one potential indicator of healthy lifestyle habits.Measures of health literacy point to the possible influence of parents’ health knowledge andutilization on a child's macular pigment levels even into the teenage years. While the parentand child’s health literacy scores were significantly correlated with each other at baseline, itwas the parent’s health literacy score and not the child’s that was significantly correlatedwith the participant’s baseline macular pigment levels while the child's own scores were not.The relationship between parent health knowledge and child macular pigment levels was nolonger statistically significant by the end of the nutritional intervention study. Finally, theresults indicate that a simple, non-invasive method for assessing macular pigment levelsbased on the principles of Haidinger’s brushes degree of polarization may provide a practicaland cost-effective method for tracking macular carotenoid levels in children, pre-teens andteenagers and is sensitive to moderate lifestyle changes such as a small increase in dailycarotenoid intake.To the inventors’ knowledge, this is the first study to show that luteinsupplementation of 5 mg per day in healthy preteen and teenage children leads to anincrease in macular pigment levels and reduced digital eye strain compared to a placebogroup. While more than 30 studies have shown increases in macular pigment followinglutein supplementation in adults, no intervention trials have been conducted to date inhealthy children and adolescents (Hu et al., 2023b; Ponce-García et al., 2024). A meta-analysis of clinical studies on macular pigment and children identified a total of 13 studiesin children between the ages of 0 and 12 years old but failed to find any studies conductedin children older than 12 years of age (Ponce-García et al., 2024). Even more importantly,none of the 13 studies reported were interventional trials. While the cross-sectional studiesuncovered important relationships between macular pigment levels and visual and cognitiveoutcomes, an interventional trial is required to build the causal relationship between luteinand health outcomes. To date, only one published study is available reporting luteinsupplementation in children (Parekh et al., 2024). The study was conducted withundernourished Indian children between 5 and 12 years of age and investigated the effectsof 10 mg lutein and 2 mg zeaxanthin per day for 6 months on visual and cognitive outcomes(Parekh et al., 2024). The findings from the present study differ in that the current studyutilized a lower dose of 5 mg lutein and supplemented healthy older children and teenagersbetween 8 and 16 years of age. This is significant in that it is the first study to investigatethis question and be able to show a significant improvement in macular pigment and digitaleye strain compared to a placebo group in this age group and with a low dose of luteinsupplementation. Additionally, this is the first study to compare the two psychophysicalmeasurement techniques of HB and HFP, the first to find differences in outcomes betweenthe two groups and the first to use the MPeye device in a human interventional study with aplacebo group. To date, the MPeye device, which relies on the HB technique for assessingmacular pigment in the retina, has only been utilized in cross-sectional, epidemiologicalsingle arm studies (Sangani et al., 2024; Temple et al., 2019a).More than 30 clinical studies have shown macular pigment increases with luteinsupplementation in adults (Hu et al., 2023b). However, not all studies in adults have beenable to demonstrate macular pigment improvements even at doses as high as 20 mg per day(Yoshida et al., 2023). In the present study, participants exhibited a 14% increase in macularpigment at a daily dosage level of 5 mg lutein compared to participants taking only placebo.There are several potential explanations for this finding. It is possible that the deliveryformat of a daily gummy provides a more bioavailable system for the fat-soluble lutein to bedigested and absorbed by the body, thus resulting in the significant outcomes observed (Bhat& Mamatha, 2021; Böhm et al., 2021; Olmedilla-Alonso et al., 2021; Thürmann et al., 2005).In addition, the specific source of the lutein could be a higher-quality ingredient comparedto lutein sources used in other human clinicals that failed to report significant improvements(Chung et al., 2004; Dai et al., 2021; Lim et al., 2021; Sheshappa et al., 2015). In addition, it ispossible that the preteen and teenage eye is in a state of rapid growth and development andmay be better able to absorb all sources of supplemental lutein more readily than the fullyformed adult retina (Cheng & Tian, 2024; Ho et al., 2024). For example, it is possible that thepreteen and teenage eye have higher amounts of the lutein transporter protein, StAR-relatedlipid-transfer protein 3 (StARD3), and therefore are able to absorb higher amounts of luteincirculating in the serum (Arunkumar et al., 2020b; Horvath et al., 2016; Sluchanko et al.,2022; Tanprasertsuk et al., 2016). Whatever the underlying mechanism, the data from thepresent study indicate that supplementing healthy preteen and teenage children with at least5 mg lutein a day may be an effective way to increase macular pigment levels in children’seyes. Furthermore, given that the macular pigment increases were seen across the breadthof the macula as measured with the HB device and not necessarily just in the center peak asassessed by the HFP method (Forster, 1954; Manion & Stokkermans, 2024; Mottes et al.,2022; Temple et al., 2019a), the results of the study point to the possibility that lutein mayaccumulate differently in the retina of children compared to macular accumulation in theadult eye. Additionally, as the first study to use the HB technique via the MPeye device toassess macular pigment levels following lutein supplementation, the current findings couldmean that the MPeye device is more sensitive to changes in overall macular pigment levelsand may serve as an ideal device for rapid screening of lutein levels in both children andadults.Asecondary research question in the current study was whether luteinsupplementation could lead to a reduction in digital eye strain in healthy teen and preteenchildren exposed to digital devices for four hours or more per day. Digital eye strain wasassessed via the Visual Fatigue Scale (VFS), a validated tool that measures digital stress on ascale from 6 to 24. In the present study, participants taking 5 mg of lutein daily demonstrateda one-point improvement on the VFS scale, corresponding to a reduction in digital eye strainof 5.56% compared to the change seen in the placebo group. For comparison, a study inhealthy adults found a one-to-two-point worsening of visual fatigue following approximately1 hour of reading on LCD, e-ink or paper formats using the same VFS measurement tool(Benedetto et al., 2013). Researchers have suggested the 20 / 20 / 20 rule as an interventionto reduce digital eye strain in which a person takes a break every 20 minutes and spends atleast 20 seconds looking at something 20 feet away (Bin Maneea et al., 2024; Datta et al.,2023). Multiple research studies have been conducted to measure visual fatigue using asimilar survey tool known as the Computer Vision Syndrome questionnaire (CVS-Q;SeguíMdel et al., 2015). One interventional study of the 20 / 20 / 20 rule found a 2-pointimprovement in the CVS-Q score for individuals following the 20 / 20 / 20 rule for a 2-weekduration indicating that the 1-point difference observed in the present study may beclinically meaningful in an individual’s daily life experience (Seguí Mdel et al., 2015; Talens-Estarelles et al., 2023). However, other research investigations have failed to demonstratesignificant improvements in digital eye strain based on various intervention techniques. Forexample, a study using blue blocking lenses failed to find reductions in subjective symptomscores for visual fatigue among healthy adults (Palavets & Rosenfield, 2019; Singh et al.,2021). Visual fatigue and digital eye strain have been recognized as a serious health problemfor over 20 years (Rosenfield, 2016; Sheppard & Wolffsohn, 2018) with increased concernsfollowing the rise in digital device exposure in more recent years (Jaadane et al., 2015b;Mylona et al., 2023). For instance, a study of 10,000 medical students conducted in 2024revealed a computer vision syndrome prevalence rate of approximately 57% (Iqbal et al.,2024).One key finding of the study was that parents’ health literacy scores were significantlyand positively correlated with their children’s health literacy scores as well as to the child’smacular pigment levels at baseline. It’s important to note that the children’s own healthliteracy scores were not correlated to their macular pigment levels, indicating that parentsof children between 8 and 16 years of age may play a more significant role in healthy eatinghabits of kids than the children themselves. This finding implies that efforts to get kids to eatmore vegetables may be more effective if directed at the parents and not necessarily to thechildren. This also indicates the importance of the family as a social factor for the overallhealth and wellbeing of the child. Additionally, only macular pigment scores using the HBmethodologically were significantly correlated to the parent’s health literacy values,indicating that the HB method may be a more sensitive measure of macular pigment in thepreteen and teenage eye and perhaps even in the eye across the lifespan.CONCLUSION The purpose of this study was to determine the effects of daily lutein supplementationon eye and brain outcomes in healthy preteen and teenage children exposed to daily digitaldevices. In addition, baseline data were collected to better understand the potential roles ofsocial, biological, and psychological factors on healthy eating behaviors, specificallyincluding lutein-rich fruits and vegetables in the daily diet. Understanding the benefits ofsupplemental lutein intake in a gummy format is important since the preteen and teenageage group in the United States represents the lowest intake of daily fruits and vegetables andhas the lowest healthy eating index scores of all age groups (Dietary Guidelines for Americans,2020-2025., December 2020.). Lutein cannot be produced by the body and must be obtainedfrom the daily diet or supplementation. The benefits of lutein in adults, pregnant moms, andinfants have been studied extensively and shown to be important for both visual andcognitive function. However, to date, no lutein intervention studies have been conducted inhealthy preteen and teenage children. Given the rapid developmental changes occurringduring the adolescent years, it is essential to understand the role of lutein in both eye andbrain development in preteen and teenage children.There are three key findings from the current study. First, it was demonstrated that6-months of supplementation with 5 mg lutein in a gummy format can increase macularpigment and thus retinal lutein levels in healthy preteen and teenage children. Second, it wasalso shown that 6-months lutein supplementation at a 5 mg dose can reduce digital eye strainin healthy teenagers and preteens that are exposed to digital devices for at least 4 hours perday. Finally, the results of the current study revealed that children’s health literacy is relatedto their own parent or guardian’s health literacy. Interestingly, parents’ health literacy butnot the children’s health literacy, was correlated with lutein levels in the eyes of the children,indicating an important role of the parent in children’s health, even during the preteen andteenage years.This was the first study to date to provide supplemental lutein to healthy teenage andpreteen children and assess outcome changes in eye and brain health. The results confirmthat even a daily dose as low as 5 mg can have a positive impact on a teenager’s macularpigment levels as well as meaningful reductions in digital eye strain. This finding isimportant for parents, schools and government organizations setting dietary guidelines forchildren. While 5 mg of lutein can be obtained from the diet, most children are not eating thenecessary fruits and vegetables to reach doses of even 1-2 mg lutein daily. To maximize eyeand brain development during the formative adolescent years, it may be helpful to considerways to increase fruit and vegetable intake in this age group. One method may be to increasehealthy literacy rates for parents, as the results of this study indicate that children of parentswith high health literacy also had higher lutein levels in their eyes.Having described the invention with reference to particular compositions, theories ofeffectiveness, and the like, it will be apparent to those of skill in the art that it is not intendedthat the invention be limited by such illustrative embodiments or mechanisms, and thatmodifications can be made without departing from the scope or spirit of the invention, asdefined by the appended claims. It is intended that all such obvious modifications andvariations be included within the scope of the present invention as defined in the appendedclaims. The claims are meant to cover the claimed components and steps in any sequencewhich is effective to meet the objectives there intended, unless the context specificallyindicates to the contrary.It should be further appreciated that minor dosage and formulation modifications ofthe composition and the ranges expressed herein may be made and still come within thescope and spirit of the present invention.The foregoing descriptions have been presented for the purposes of illustration anddescription. It is not intended to be an exhaustive list or limit the invention to the preciseforms disclosed. It is contemplated that other alternative processes and methods obvious tothose skilled in the art are considered included in the invention. The description is merelyexamples of embodiments. It is understood that any other modifications, substitutions,and / or additions may be made, which are within the intended spirit and scope of thedisclosure. From the foregoing, it can be seen that the exemplary aspects of the disclosureaccomplish at least all of the intended objectives.

Claims

1. CLAIMS1. A method of minimizing damage to a foveal architecture of an individual, comprising:administration of at least one ocular nutrient selected from the group consisting ofantioxidant vitamins, carotenoids, antioxidant minerals, and natural antioxidant extracts tothe individual, wherein the individual is at risk of damage to the foveal architecture due toexposure to digital screens, blue light, or near work.

2. The method of claim 1, wherein the at least one ocular nutrient is a carotenoid.

3. The method of claim 2, wherein the carotenoid is lutein and / or zeaxanthin.

4. The method of claim 2, wherein the foveal architecture has not been previouslydamaged.

5. The method of claim 2, wherein the individual has a condition from the groupconsisting of: damage to the retinal nerve layer, improper abnormal eyeball shape,irregular anatomical development of the fovea, and damage to the foveal architecture.

6. The method of claim 2, wherein the individual is a child, preteen, teen, or young adult.

7. A method of minimizing abnormal eyeball shape change in an individual, comprising:administration of at least one ocular nutrient selected from the group consisting ofantioxidant vitamins, carotenoids, antioxidant minerals, and natural antioxidantextracts to the individual, wherein the individual is at risk of abnormal eyeball shapedue to exposure to digital screens, blue light, or near work.

8. The method of claim 7, wherein the at least one ocular nutrient is a carotenoid.

9. The method of claim 8, wherein the carotenoid is lutein.

10. The method of claim 8, wherein the individual has a normal eyeball shape.

11. The method of claim 8, wherein individual has a condition from the group consistingof: damage to the retinal nerve layer, improper eyeball elongation, abnormal eyeballshape, irregular anatomical development of the fovea, and damage to the fovealarchitecture.

12. The method of claim 8, wherein the individual is a child, preteen, teen, or young adult.

13. A method of reducing eye conditions in an individual, comprising:administration of at least one carotenoid, wherein the individual is at risk fordeveloping at least one eye condition due to exposure to digital screens, blue light, ornear work.

14. The method of claim 13, wherein the at least one eye condition is selected from thegroup consisting of: vision, eye strain, accommodative fatigue, dry eye, strabismus,damage to foveal architecture, irregular development of fovea, eyeball shape change,improper eyeball elongation, screentime fatigue, biomechanical stress, and retinalnerve cell layer damage.

15. The method of claim 14, wherein the individual is already suffering from at least oneeye condition, wherein administration of the at least one carotenoid reduces an effectof the at least one eye condition.

16. The method of claim 14, wherein the individual is not yet suffering from at least oneeye condition, wherein administration of the at least one carotenoid prevents ordelays the at least one eye condition.

17. The method of claim 14, wherein the at least one carotenoid is administered at a levelsufficient to increase macular pigment levels.

18. The method of claim 16, wherein the carotenoid is administered between 0.0001 and2mg / kg body weight.

19. The method of claim 14, wherein the carotenoid is lutein and / or zeaxanthin.

20. The method of claim 14, wherein the individual is a child, preteen, teen, or youngadult.

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