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Contains fulltext : 292919.pdf (Publisher’s version ) (Open Access) BACKGROUND: High myopia (HM), defined as a spherical equivalent refractive error (SER) ≤ -6.00 diopters (D), is a leading cause of sight impairment, through myopic macular degeneration (MMD). We aimed to derive an improved polygenic score (PGS) for predicting children at risk of HM and to test if a PGS is predictive of MMD after accounting for SER. METHODS: The PGS was derived from genome-wide association studies in participants of UK Biobank, CREAM Consortium, and Genetic Epidemiology Research on Adult Health and Aging. MMD severity was quantified by a deep learning algorithm. Prediction of HM was quantified as the area under the receiver operating curve (AUROC). Prediction of severe MMD was assessed by logistic regression. FINDINGS: In independent samples of European, African, South Asian and East Asian ancestry, the PGS explained 19% (95% confidence interval 17-21%), 2% (1-3%), 8% (7-10%) and 6% (3-9%) of the variation in SER, respectively. The AUROC for HM in these samples was 0.78 (0.75-0.81), 0.58 (0.53-0.64), 0.71 (0.69-0.74) and 0.67 (0.62-0.72), respectively. The PGS was not associated with the risk of MMD after accounting for SER: OR = 1.07 (0.92-1.24). INTERPRETATION: Performance of the PGS approached the level required for clinical utility in Europeans but not in other ancestries. A PGS for refractive error was not predictive of MMD risk once SER was accounted for. FUNDING: Supported by the Welsh Government and Fight for Sight (24WG201).

Using latent variables in gene expression data can help correct unobserved confounders and increase statistical power for expression quantitative trait Loci (eQTL) detection. The probabilistic estimation of expression residuals (PEER) and principal component analysis (PCA) are widely used methods that can remove unwanted variation and improve eQTL discovery power in bulk RNA-seq analysis. However, their performance has not been evaluated extensively in single-cell eQTL analysis, especially for different cell types. Potential challenges arise due to the structure of single-cell RNA-seq data, including sparsity, skewness, and mean-variance relationship. Here, we show by a series of analyses that PEER and PCA require additional quality control and data transformation steps on the pseudo-bulk matrix to obtain valid latent variables; otherwise, it can result in highly correlated factors (Pearson's correlation r = 0.63 ~ 0.99). Incorporating valid PFs/PCs in the eQTL association model would identify 1.7 ~ 13.3% more eGenes. Sensitivity analysis showed that the pattern of change between the number of eGenes detected and fitted PFs/PCs varied significantly in different cell types. In addition, using highly variable genes to generate latent variables could achieve similar eGenes discovery power as using all genes but save considerable computational resources (~ 6.2-fold faster).

BackgroundConjunctival ultraviolet autofluorescence (CUVAF) is a method of detecting conjunctival damage related to ultraviolet radiation exposure. In cross-sectional studies, CUVAF area is positively associated with self-reported time spent outdoors and pterygium and negatively associated with myopia; however, longitudinal studies are scarce.AimsTo use a novel deep learning-based tool to assess 8-year change in CUVAF area in young adults, investigate factors associated with this change and identify the number of new onset pterygia.MethodsA deep learning-based CUVAF tool was developed to measure CUVAF area. CUVAF area and pterygium status were assessed at three study visits: baseline (participants were approximately 20 years old) and at 7-year and 8-year follow-ups. Participants self-reported sun protection behaviours and ocular history.ResultsCUVAF data were available for 1497 participants from at least one study visit; 633 (43%) participants had complete CUVAF data. Mean CUVAF areas at baseline and the 7-year and 8-year follow-ups were 48.4, 39.3 and 37.7 mm2, respectively. There was a decrease in mean CUVAF area over time (change in total CUVAF area=−0.96 mm2per year (95% CI: −1.07 to –0.86)). For participants who wore sunglasses ≥1/2 of the time, CUVAF area decreased by an additional −0.42 mm2per year (95% CI: −0.72 to –0.12) on average. Fourteen (1.5%) participants developed a pterygium.ConclusionsIn this young adult cohort, CUVAF area declined over an 8-year period. Wearing sunglasses was associated with a faster reduction in CUVAF area. Deep learning-based models can assist in accurate and efficient measurement of CUVAF area.

Purpose Cross-sectional studies have variably reported that poor sleep quality may be associated with myopia in children. Longitudinal data, collected over the ages when myopia develops and progresses, could provide new insights into the sleep-myopia paradigm. This study tested the hypothesis that 12-year trajectories of sleep behaviour from childhood to adolescence is associated with myopia during young adulthood. Methods At the 5-, 8-, 10-, 14- and 17-year follow-ups of the longitudinal Raine Study, which has been following a cohort since their birth in 1989-1992, participants' parents/guardians completed the Child Behaviour Checklist questionnaire (CBCL), which collected information on their child's sleep behaviour and quality. The CBCL includes six questions measuring sleep behaviour, which parents rated as 0 = not true, 1 = somewhat/sometimes true, or 2 = very/often true. Scores were summed at each follow-up to form a composite "sleep behaviour score". Latent Class Growth Analysis (LCGA) was used to classify participants according to their 12-year trajectory of sleep behaviour. At the 20-year follow-up, an eye examination was performed which included cycloplegic autorefraction and axial length measurement. Results The LCGA identified three clusters of participants based on their trajectory of sleep behaviour: those with minimal' (43.6% of the total Raine Study sample), 'declining' (48.9%), or 'persistent' (7.5%) sleep problems. A total of 1194 participants had ophthalmic data and longitudinal sleep data available for analysis (47.2% female, 85.6% Caucasian). No significant differences were observed in regards to age, sex, ethnicity or ocular parameters between trajectory groups. Unadjusted and fully adjusted analyses demonstrated that sleep problem behaviour was not significantly associated with changes in refractive error, axial length or corneal radius. Conclusions Our findings do not support the hypothesis that there is an association between sleep behaviour and myopia. Future longitudinal studies should explore sleep trajectory data pre- and post-myopia diagnosis to confirm our results.

In utero exposure to cigarette smoke has been suggested to result in thinner retinal nerve fibre layer (RNFL). However, the potential cofounding effects of in utero alcohol exposure and passive smo...

The prevalence of keratoconus (Belin/Ambrόsio Enhanced Ectasia Display Score ≥2.6 on Scheimpflug imaging) in a longitudinal, community cohort study from Western Australia was 3.4% (n=26/755). Keratoconus incidence over an 8-year period was 2.2% (n=15/669).

BACKGROUND The prevalence of myopia is increasing globally including in Europe and parts of Asia but Australian data are lacking. This study aim described the change in myopia prevalence in middle-aged Australian adults over approximately a 20-year period. METHODS Two contemporary Western Australian studies (conducted in mid-late 2010s): the coastal-regional Busselton Healthy Ageing Study (BHAS) and the urban Gen1 of the Raine Study (G1RS) were compared to two earlier studies (early-mid 1990s) in Australia: the urban Blue Mountains Eye Study (BMES) and urban/regional Melbourne Visual Impairment Project (MVIP). Refractive error was measured by autorefraction, vertometry, or subjective refraction. Participants (49-70 years) of European descent without self-reported/diagnosed cataract, corneal disease, or refractive or corneal surgery were included. RESULTS After exclusions, data were available from 2217, 1760, 700, 2987 and 756 participants from BMES, urban MVIP, regional MVIP, BHAS, and G1RS, respectively. The mean age ranged from 57.1 ± 4.6 years in the G1RS to 60.1 ± 6.0 years in the BMES; 44-48% of participants were male. When stratified by location, the contemporary urban G1RS cohort had a higher age-standardised myopia prevalence than the urban MVIP and BMES cohorts (29.2%, 16.4%, and 23.9%, p

Using latent variables in gene expression data can help correct spurious correlations due to unobserved confounders and increase statistical power for expression Quantitative Trait Loci (eQTL) detection. Probabilistic Estimation of Expression Residuals (PEER) is a widely used statistical method that has been developed to remove unwanted variation and improve eQTL discovery power in bulk RNA-seq analysis. However, its performance has not been largely evaluated in single-cell eQTL data analysis, where it is becoming a commonly used technique. Potential challenges arise due to the structure of single-cell data, including sparsity, skewness, and mean-variance relationship. Here, we show by a series of analyses that this method requires additional quality control and data transformation steps on the pseudo-bulk matrix to obtain valid PEER factors. By using a population-scale single-cell cohort (OneK1K, N = 982), we found that generating PEER factors without further QC or transformation on the pseudo-bulk matrix could result in inferred factors that are highly correlated (Pearson’s correlation r = 0.626∼0.997). Similar spurious correlations were also found in PEER factors inferred from an independent dataset (induced pluripotent stem cells, N = 31). Optimization of the strategy for generating PEER factors and incorporating the improved PEER factors in the eQTL association model can identify 9.0∼23.1% more eQTLs or 1.7%∼13.3% more eGenes. Sensitivity analysis showed that the pattern of change between the number of eGenes detected and PEER factors fitted varied significantly for different cell types. In addition, using highly variable genes (e.g., top 2000) to generate PEER factors could achieve similar eGenes discovery power as using all genes but save considerable computational resources (∼6.2-fold faster). We provide diagnostic guidelines to improve the robustness and avoid potential pitfalls when generating PEER factors for single-cell eQTL association analyses.

To explore relationships between patterns of fetal anthropometric growth, as reflective of fetal wellbeing, and global retinal nerve fiber layer (RNFL) thickness measured in young adulthood.Participants (n = 481) from within a Western Australian pregnancy cohort study underwent five serial ultrasound scans during gestation, with fetal biometry measured at each scan. Optic disc parameters were measured via spectral-domain optical coherence tomography imaging at a 20-year follow-up eye examination. Generalized estimating equations were used to evaluate differences in global RNFL thickness between groups of participants who had undergone similar growth trajectories based on fetal head circumference (FHC), abdominal circumference (FAC), femur length (FFL), and estimated fetal weight (EFW).Participants with consistently large FHCs throughout gestation had significantly thicker global RNFLs than those with any other pattern of FHC growth (P = 0.023), even after adjustment for potential confounders (P = 0.037). Based on model fit statistics, FHC growth trajectory was a better predictor of global RNFL thickness than birth weight or head circumference at birth. RNFL thickness did not vary significantly between groups of participants with different growth trajectories based on FAC, FFL, or EFW.FHC growth is associated with RNFL thickness in young adulthood and, moreover, is a better predictor than either birth weight or head circumference at birth.This research demonstrates an association between intrauterine growth and long-term optic nerve health, providing a basis for further exploring the extent of the influence of fetal wellbeing on clinical conditions linked to RNFL thinning.

PRECIS Higher physical working capacity (PWC) at age 17 was associated with thicker peripapillary retinal nerve fiber layer (pRNFL) at age 20, suggesting a mechanistic link between cardiovascular fitness and neuroretinal integrity. PURPOSE Physical activity and cardiovascular fitness have been linked with lower odds of developing glaucoma. We tested the hypothesis that early beneficial effects of physical activity and cardiovascular fitness can be observed by measuring the pRNFL thickness in young healthy adults. METHODS The Raine Study is a longitudinal study that has followed a cohort since before their births in 1989-1992. Parent-reported physical activity was collected between 8 and 17 years, and latent class analysis was used to identify the participants' physical activity trajectories. At the 20-year follow-up (participants' mean age=20.1±0.4 y), participants' metabolic equivalent of task-minutes/week was determined using self-reported physical activity data. Participants' PWC was assessed at the 14- and 17-year follow-ups to estimate their level of cardiovascular fitness. An eye examination, which included spectral-domain optical coherence tomography imaging, was conducted at the 20-year follow-up for 1344 participants. RESULTS Parent-reported or participant-reported physical activity was not associated with pRNFL thickness. However, higher PWC at 17 years was associated with thicker pRNFL globally [by 0.3 µm; 95% confidence interval (CI)=0.2-0.6; P

PURPOSE: To describe the prevalence and systemic associations of keratoconus in young adults in Perth, Western Australia. DESIGN: Cross-sectional study. PARTICIPANTS: One thousand two hundred fifty-nine participants 20 years of age. METHODS: The Raine Study is a multigenerational, longitudinal cohort study based in Perth, Western Australia. This study represents a cross-sectional analysis of the birth cohort on returning for a 20-year follow-up. Participants underwent a detailed ophthalmic examination, including visual acuity assessment and Scheimpflug imaging using the Pentacam (Oculus, Wetzlar, Germany), and completed a health questionnaire. Keratoconus was defined as a Belin/Ambrόsio enhanced ectasia display score of 2.6 or more in either eye based on Pentacam imaging. MAIN OUTCOME MEASURES: Prevalence of keratoconus in this cohort. RESULTS: Of the 1259 participants, 50.8% were women and 85.7% were White. Fifteen participants had keratoconus in at least 1 eye, giving a prevalence of 1.2% (95% confidence interval, 0.7%-1.9%), or 1 in 84. A significant difference was found in best-corrected visual acuity (0.01 logarithm of the minimum angle of resolution vs. -0.05 logarithm of the minimum angle of resolution; P = 0.007), cylinder (1.25 diopters [D] vs. 0.25 D cylinder; P < 0.001) and spherical equivalent (-1.42 D vs. -0.50 D sphere; P = 0.02) on objective refraction, mean keratometry of the steep meridian (45.19 D vs. 43.76 D; P < 0.001), and mean corneal thickness at the thinnest point (475 μm vs. 536 μm; P < 0.001) between those with and without keratoconus. Keratoconus was associated with regular cigarette smoking (38.5% vs. 14.6%; P = 0.04), but showed no association with gender, race, body mass index, use of spectacles or contact lenses, history of allergic eye disease, or pregnancy. CONCLUSIONS: The prevalence of keratoconus in this Australian population-based study of 20-year-old adults was 1.2% (95% confidence interval, 0.7%-1.9%), or 1 in 84, which is one of the highest reported in the world. This has important implications for screening individuals at a younger age so that treatment can be initiated before disease progression.

Myopia (near-sightedness) is an important public health issue. Spending more time outdoors can prevent myopia but the long-term association between this exposure and myopia has not been well characterised. We investigated the relationship between time spent outdoors in childhood, adolescence and young adulthood and risk of myopia in young adulthood. The Kidskin Young Adult Myopia Study (KYAMS) was a follow-up of the Kidskin Study, a sun exposure-intervention study of 1776 children aged 6–12 years. Myopia status was assessed in 303 (17.6%) KYAMS participants (aged 25–30 years) and several subjective and objective measures of time spent outdoors were collected in childhood (8–12 years) and adulthood. Index measures of total, childhood and recent time spent outdoors were developed using confirmatory factor analysis. Logistic regression was used to assess the association between a 0.1-unit change in the time outdoor indices and risk of myopia after adjusting for sex, education, outdoor occupation, parental myopia, parental education, ancestry and Kidskin Study intervention group. Spending more time outdoors during childhood was associated with reduced risk of myopia in young adulthood (multivariable odds ratio [OR] 0.82, 95% confidence interval [CI] 0.69, 0.98). Spending more time outdoors in later adolescence and young adulthood was associated with reduced risk of late-onset myopia (≥ 15 years of age, multivariable OR 0.79, 95% CI 0.64, 0.98). Spending more time outdoors in both childhood and adolescence was associated with less myopia in young adulthood.

The purpose of this study was to explore the age-related change in choroidal thickness (ChT) and test the hypothesis that baseline ChT is predictive of refractive error change in healthy young adults.Participants underwent spectral-domain optical coherence tomography (SD-OCT) imaging and autorefraction at 20 (baseline) and 28 years old. The enhanced depth imaging mode on the SD-OCT was used to obtain images of the choroid. Scans were exported from the SD-OCT and analyzed with a custom software that automatically measures the central ChT. The longitudinal change in subfoveal ChT and association between baseline subfoveal ChT and 8-year change in refractive error (spherical equivalent) were determined using linear mixed models.In total, 395 eyes of 198 participants (44% men; 18-22 years at baseline) were included. Over 8 years, mean spherical equivalent decreased by 0.25 diopters (D) and axial length increased by 0.09 mm. Subfoveal choroid thickened by 1.3 µm/year (95% confidence interval [CI] = 0.6-2.0), but this was reduced by 0.9 µm/year (95% CI = 1.6-0.2) for every 1 mm increase in axial length. For every 10 µm increase in baseline ChT, average annual change in spherical equivalent and axial length reduced by 0.006 D/year and 0.003 mm/year, respectively.In a community-based cohort of young adults, the choroid continued to change during early adulthood. Choroidal thickening was less in eyes that were longer at baseline, and the choroid thinned in eyes that showed myopia progression. The association between baseline ChT and longitudinal changes in spherical equivalent and axial length supports the hypothesis that ChT may be predictive of refractive error development and/or myopia progression.

The human immune system displays substantial variation between individuals, leading to differences in susceptibility to autoimmune disease. We present single-cell RNA sequencing (scRNA-seq) data from 1,267,758 peripheral blood mononuclear cells from 982 healthy human subjects. For 14 cell types, we identified 26,597 independent cis-expression quantitative trait loci (eQTLs) and 990 trans-eQTLs, with most showing cell type–specific effects on gene expression. We subsequently show how eQTLs have dynamic allelic effects in B cells that are transitioning from naïve to memory states and demonstrate how commonly segregating alleles lead to interindividual variation in immune function. Finally, using a Mendelian randomization approach, we identify the causal route by which 305 risk loci contribute to autoimmune disease at the cellular level. This work brings together genetic epidemiology with scRNA-seq to uncover drivers of interindividual variation in the immune system.

BACKGROUND: The Slip! Slop! Slap! Sunsmart safety campaign was an Australian initiative implemented in the 1980s. To assess this campaign's effect on pterygium, we examined the rate of pterygium surgery across Australia and described the prevalence and associations of pterygium in Perth, Australia's sunniest capital city. METHODS: The rate of pterygium surgery was examined using Australian Medicare data. A cross-sectional analysis of the Generation 1 (Gen1) cohort of the Raine Study was performed to investigate the prevalence of pterygium in Perth. We investigated the association between pterygium and conjunctival ultraviolet autofluorescence (CUVAF) area, an objective biomarker of sun exposure, and demographics and health variables derived from a detailed questionnaire. RESULTS: Between 1994 and 2017, the rate of Medicare funded pterygium surgery in Western Australia fell 11%, well below the national average decline of 47%. Of the 1049 Gen1 Raine Study participants, 994 (571 females; mean age 56.7 years, range = 40.9-81.7) were included in the analysis. The lifetime prevalence of pterygium was 8.4% (n = 83). A higher prevalence of pterygium was associated with outdoor occupation (p-trend = 0.007), male sex (p-trend 0.01) and increasing CUVAF area (p-value

To describe the choroidal thickness (ChT) in a large sample of young adults with the aim of establishing a normative ChT profile reference in this demographic cohort and explore its association with best-corrected visual acuity (BCVA).Cross-sectional study.From a single center, 741 young adults (19-30 years of age, 49% male) were recruited to undergo a comprehensive ophthalmic examination, including BCVA measurement, post-cycloplegic autorefraction, ocular biometry, tonometry, and spectral-domain optical coherence tomography (SD-OCT) imaging. The enhanced depth imaging mode on the SD-OCT was used. The main outcome measure was the central macular ChT (0.5-mm radius around the fovea). The ChTs at the inner (between 0.5-mm and 1.5-mm radius) and outer macular rings (between 1.5-mm and 2.5-mm radius) were also measured.The median central macular ChT was 370 μm (interquartile range 312-406 μm). The choroid was thickest at the superior-inner, inferior-inner, and central macular regions (370-373 μm) and thinnest nasally at the outer macular region (median 256 μm). Decreased central macular ChT was associated with younger age, female sex, nonwhite ethnicities, and myopia (P ≤ .013). There was a significant association between better BCVA and increased central macular ChT (P.001), after adjusting for age, sex, ethnicity, and ocular measures. His relationship was only apparent in eyes with central macular ChTs300 μm (P = .019) and absent in eyes with ChTs300 μm.The central ChT of young adults was 370 μm. There was a significant association between worse BCVA and thinner choroids below a threshold of 300 μm, raising the possibility that ChT could be predictive of visual function.

PRéCIS:: This study found an association between thinner superotemporal retinal nerve fiber layer (RNFL) and obstructive sleep apnea (OSA). However, the lack of association of sleep apnea with other disc measures does not support a link with glaucoma.Previous findings on the link between OSA and increased glaucoma risk have been inconsistent. In a community-based study of middle-aged and older adults, we explored for differences in optic disc measures that may resemble preclinical glaucomatous changes in relation to OSA status and severity.A total of 865 participants (46 to 67 y; 45% male) underwent an at-home sleep study during which their apnea-hypopnea index (AHI) and sleep oxygen saturation level were measured. Participants were determined to have no OSA (AHI5 events/h), mild (AHI 5 to 15), moderate (AHI 16 to 30), or severe OSA (AHI30). At a 6-year follow-up visit, the optic discs of both eyes were imaged using spectral domain optic coherence tomography to measure the Bruch membrane opening-minimum rim widths and RNFL thicknesses.On the basis of the AHI, 411 participants (48%) had OSA, of whom 92 (11% of total sample) and 26 (3%) had moderate and severe OSA, respectively. In the multivariate analysis, participants with severe OSA had thinner RNFL superotemporally than those without OSA or with mild OSA (P0.001 and 0.001, respectively). In addition, superotemporal RNFL was inversely associated with AHI (P=0.004) and sleep time with oxygen saturation level90% (P=0.005). There was no association between OSA measures and Bruch membrane opening-minimum rim widths.Our findings do not provide strong evidence of a link between measures of OSA and the optic disc. However, the association between increased OSA severity and thinner superotemporal RNFL has been reported consistently in previous studies and thus warrants further evaluation.

To examine the impact of sun exposure on human health, accurate measures of past sun exposure are required. We investigated how young adults’ recall of childhood sun-related behaviours compares with parent-reported measures collected during childhood. The Kidskin-Young Adult Myopia Study (KYAMS) is a follow-up of the Kidskin Study, a sun-protection intervention study conducted from 1995–2001. KYAMS participants, aged 25–30 years, reported time in sun, and use of hats and sunscreen, for each year from ages 5–26 years (n = 244). Using weighted kappa, we assessed agreement between these data and corresponding variables derived from the Kidskin Study parent questionnaires completed when KYAMS participants were aged 6–12 years. Ordinal logistic regression was used to test the association between self-reported sun-behaviours and corresponding parent-reported data. We found slight agreement between self-reported and parent-reported data for all sun-behaviour measures except hat use at 12 years. KYAMS recall of time in sun at 8–12 years was not associated with Kidskin Study parent-reported responses after adjustment for current time in sun. Recall of higher hat and sunscreen use was associated with higher parent-reported hat and sunscreen use (OR[hat] = 1.37, 95% CI: 1.16, 1.62; OR[sunscreen] = 1.23, 95% CI: 1.03, 1.48). However, KYAMS self-reported data were unable to predict corresponding parent-reported responses. Group data from retrospective recall of sun-related behaviours may be of limited value in studying the relationship between sun exposure and health outcomes; however, individual data are likely of little use.

Importance Myopia incidence and progression has been described extensively in children. However, few data exist regarding myopia incidence and progression in early adulthood.\ud\udObjective To describe the 8-year incidence of myopia and change in ocular biometry in young adults and their association with the known risk factors for childhood myopia.\ud\udDesign, Setting, and Participants The Raine Study is a prospective single-center cohort study. Baseline and follow-up eye assessments were conducted from January 2010 to August 2012 and from March 2018 to March 2020. The data were analyzed from June to July 2021. A total of 1328 participants attended the baseline assessment, and 813 participants attended the follow-up assessment. Refractive information from both visits was available for 701 participants. Participants with keratoconus, previous corneal surgery, or recent orthokeratology wear were excluded.\ud\udExposures Participants’ eyes were examined at ages 20 years (baseline) and 28 years.\ud\udMain Outcomes and Measures Incidence of myopia and high myopia; change in spherical equivalent (SE) and axial length (AL).\ud\udResults A total of 516 (261 male [50.6%]) and 698 (349 male [50.0%]) participants without myopia or high myopia at baseline, respectively, were included in the incidences analyses, while 691 participants (339 male [49%]) were included in the progression analysis. The 8-year myopia and high myopia incidence were 14.0% (95% CI, 11.5%-17.4%) and 0.7% (95% CI, 0.3%-1.2%), respectively. A myopic shift (of 0.50 diopters [D] or greater in at least 1 eye) occurred in 261 participants (37.8%). Statistical significance was found in longitudinal changes in SE (−0.04 D per year; P

SUMMARYChildren infected with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) develop less severe coronavirus disease 2019 (COVID-19) than adults. The mechanisms for the age-specific differences and the implications for infection-induced immunity are beginning to be uncovered. We show by longitudinal multimodal analysis that SARS-CoV-2 leaves a small footprint in the circulating T cell compartment in children with mild/asymptomatic COVID-19 compared to adult household contacts with the same disease severity who had more evidence of systemic T cell interferon activation, cytotoxicity and exhaustion. Children harbored diverse polyclonal SARS-CoV- 2-specific naïve T cells whereas adults harbored clonally expanded SARS-CoV-2-specific memory T cells. More naïve interferon-activated CD4+ T cells were recruited into the memory compartment and recovery was associated with the development of robust CD4+ memory T cell responses in adults but not children. These data suggest that rapid clearance of SARS-CoV-2 in children may compromise their cellular immunity and ability to resist reinfection.HIGHLIGHTSChildren have diverse polyclonal SARS-CoV-2-specific naïve T cellsAdults have clonally expanded exhausted SARS-CoV-2-specific memory T cellsInterferon-activated naïve T cells differentiate into memory T cells in adults but not childrenAdults but not children develop robust memory T cell responses to SARS-CoV-2

Children infected with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) develop less severe coronavirus disease 2019 (COVID-19) than adults. The mechanisms for the age-specific differences and the implications for infection-induced immunity are beginning to be uncovered. We show by longitudinal multimodal analysis that SARS-CoV-2 leaves a small footprint in the circulating T cell compartment in children with mild/asymptomatic COVID-19 compared to adult household contacts with the same disease severity who had more evidence of systemic T cell interferon activation, cytotoxicity and exhaustion. Children harbored diverse polyclonal SARS-CoV-2-specific naïve T cells whereas adults harbored clonally expanded SARS-CoV-2-specific memory T cells. A novel population of naïve interferon-activated T cells is expanded in acute COVID-19 and is recruited into the memory compartment during convalescence in adults but not children. This was associated with the development of robust CD4

Trait-associated genetic variants affect complex phenotypes primarily via regulatory mechanisms on the transcriptome. To investigate the genetics of gene expression, we performed cis- and trans-expression quantitative trait locus (eQTL) analyses using blood-derived expression from 31,684 individuals through the eQTLGen Consortium. We detected cis-eQTL for 88% of genes, and these were replicable in numerous tissues. Distal trans-eQTL (detected for 37% of 10,317 trait-associated variants tested) showed lower replication rates, partially due to low replication power and confounding by cell type composition. However, replication analyses in single-cell RNA-seq data prioritized intracellular trans-eQTL. Trans-eQTL exerted their effects via several mechanisms, primarily through regulation by transcription factors. Expression of 13% of the genes correlated with polygenic scores for 1,263 phenotypes, pinpointing potential drivers for those traits. In summary, this work represents a large eQTL resource, and its results serve as a starting point for in-depth interpretation of complex phenotypes.Analyses of expression profiles from whole blood of 31,684 individuals identify cis-expression quantitative trait loci (eQTL) effects for 88% of genes and trans-eQTL effects for 37% of trait-associated variants.

Myopia is an increasingly common condition that is associated with significant costs to individuals and society. Moreover, myopia is associated with increased risk of glaucoma, retinal detachment and myopic maculopathy, which in turn can lead to blindness. It is now well established that spending more time outdoors during childhood lowers the risk of developing myopia and may delay progression of myopia. There has been great interest in further exploring this relationship and exploiting it as a public health intervention aimed at preventing myopia in children. However, spending more time outdoors can have detrimental effects, such as increased risk of melanoma, cataract and pterygium. Understanding how spending more time outdoors prevents myopia could advance development of more targeted interventions for myopia. We reviewed the evidence for and against eight facets of spending time outdoors that may protect against myopia: brighter light, reduced peripheral defocus, higher vitamin D levels, differing chromatic spectrum of light, higher physical activity, entrained circadian rhythms, less near work and greater high spatial frequency (SF) energies. There is solid evidence that exposure to brighter light can reduce risk of myopia. Peripheral defocus is able to regulate eye growth but whether spending time outdoors substantially changes peripheral defocus patterns and how this could affect myopia risk is unclear. Spectrum of light, circadian rhythms and SF characteristics are plausible factors, but there is a lack of solid evidence from human studies. Vitamin D, physical activity and near work appear unlikely to mediate the relationship between time spent outdoors and myopia.

Obstructive sleep apnea (OSA) is linked to increased glaucoma risk in middle-aged and older adults. However, little is known about associations between OSA and glaucoma-related optic disc parameters in young adults. We explored associations between overnight polysomnography-derived measures of OSA and the optic disc in young adults.Cross-sectional cohort study.Eight hundred forty-eight adults 19 to 22 years of age.Participants underwent an ophthalmic examination that included OCT imaging of the optic disc and measurements of intraocular pressure, axial length, and refractive error. Participants then underwent an overnight polysomnography study that obtained measurements of apnea-hypopnea index (AHI), peripheral oxygen saturation level, and number of cortical arousals from sleep. Based on the AHI results, participants were grouped into no OSA (AHI5 events/hour), mild OSA (AHI ≥ 5 and15 events/hour), moderate OSA (AHI ≥ 15 and30 events/hour), or severe OSA (AHI ≥ 30 events/hour).Neuroretinal rim area, horizontal and vertical widths, and peripapillary retinal nerve fiber layer (RNFL) thickness.The median AHI result across the study cohort was 2.2 events per hour (interquartile range, 1.0-4.4 events/hour). Based on the AHI results, 178 participants (21.0%) demonstrated OSA: 150 with mild OSA, 26 with moderate OSA, and 2 with severe OSA. In the unadjusted analyses, participants with OSA on average showed thinner peripapillary RNFL at the inferotemporal (P = 0.026) and superotemporal (P = 0.008) segments compared with those without OSA. Additionally, higher AHI results were associated with thinner RNFL superotemporally (P = 0.007). These findings remained significant after adjusting for gender, body mass index, ethnicity, and potential ocular confounders. There were no significant differences in optic disc measures between groups of OSA severity.Obstructive sleep apnea may be associated with preclinical thinning of the peripapillary RNFL in young adults. This suggests that an increased glaucoma risk already may be present in individuals with OSA since young adulthood. Long-term follow-up of this cohort will allow further optic disc changes in relationship to polysomnography parameters to be documented and associations with future glaucoma diagnosis to be explored.

Changes in stratospheric ozone and climate over the past 40-plus years have altered the solar ultraviolet (UV) radiation conditions at the Earth’s surface. Ozone depletion has also contributed to climate change across the Southern Hemisphere. These changes are interacting in complex ways to affect human health, food and water security, and ecosystem services. Many adverse effects of high UV exposure have been avoided thanks to the Montreal Protocol with its Amendments and Adjustments, which have effectively controlled the production and use of ozone-depleting substances. This international treaty has also played an important role in mitigating climate change. Climate change is modifying UV exposure and affecting how people and ecosystems respond to UV; these effects will become more pronounced in the future. The interactions between stratospheric ozone, climate and UV radiation will therefore shift over time; however, the Montreal Protocol will continue to have far-reaching benefits for human well-being and environmental sustainability.

Inflammation and cigarette smoking predispose to macular diseases, and choroidal and retinal thinning. We explored the choroidal and retinal thicknesses in young adults against their 7-year C-reactive protein (CRP) level trajectory and pack-years smoked. Participants from the Raine study, a longitudinal cohort study, had serum CRP levels analysed at the 14-, 17-, and 20-year follow-ups. Group-based trajectory modelling was used to classify participants according to their 7-year CRP levels. At the 20-year follow-up (at 18–22 years old), participants completed questionnaires on their smoking history, and underwent optical coherence tomography imaging to obtain their choroidal and retinal thicknesses at the macula. Three CRP trajectories were identified: consistently low CRP levels (78% of sample), increasing (11%), or consistently high (11%). 340 and 1035 participants were included in the choroidal and retinal thickness analyses, respectively. Compared to those in the “Low” trajectory group, participants in the “Increasing” and “High” groups had 14–21 μm thinner choroids at most macular regions. Every additional pack-year smoked was linked with a 0.06–0.10 μm thinner retina at the inner and outer macular rings, suggesting a dose-dependent relationship between smoking and thinner retinas. These associations may suggest that an increased risk of future visual impairment or eye disease associated with these risk factors may be present since young adulthood.

Purpose: To describe the thickness profiles of the full retinal and outer retinal layers (ORL) at the macula in healthy young adults, and associations with best-corrected visual acuity (BCVA). Methods: In total, 1604 participants (19-30 years) underwent an eye examination that included measurements of their BCVA, axial length, and autorefraction. The retinal thickness at the foveal pit and at the nine Early Treatment of Diabetic Retinopathy Study macular regions (0.5-mm radius around the fovea, and superior, inferior, temporal, and nasal quadrants of the inner and outer rings of the macula) were obtained using spectral-domain optical coherence tomography imaging. A custom program was used to correct for transverse magnification effects because of different axial lengths. Results: The median full retinal and ORL thicknesses at the central macula were 285 µm and 92 µm. The full retina was thinnest centrally and thickest at the inner macula ring, whereas the ORL was thickest centrally and gradually decreased in thickness with increasing eccentricity. There was no association between axial length and the full retinal or ORL thickness. Increased thicknesses of the full retina at the central macula was associated with better BCVA; however, the effect size was small and not clinically significant. Conclusions: This article mapped the full retinal and ORL thickness profile in a population-based sample of young healthy adults. Translational relevance: Thickness values presented in this article could be used as a normative reference for future studies on young adults and in clinical practice.

Since December 2019, a new form of severe acute respiratory syndrome (SARS) from a novel strain of coronavirus (SARS coronavirus 2 [SARS‐CoV‐2]) has been spreading worldwide. The disease caused by SARS‐CoV‐2 was named Covid‐19 and declared as a pandemic by the World Health Organization in March 2020. Clinical symptoms of Covid‐19 range from common cold to more severe disease defined as pneumonia, hypoxia, and severe respiratory distress. In the next stage, disease can become more critical with respiratory failure, sepsis, septic shock, and/or multiorgan failure. Outcomes of Covid‐19 indicate large gaps between the male–female and the young–elder groups. Several theories have been proposed to explain variations, such as gender, age, comorbidity, and genetic factors. It is likely that mixture of genetic and nongenetic factors interplays between virus and host genetics and determines the severity of disease outcome. In this review, we aimed to summarize current literature in terms of potential host genetic and epigenetic factors that associated with increased severity of Covid‐19. Several studies indicated that the genetic variants of the SARS‐CoV‐2 entry mechanism‐related (angiotensin‐converting enzymes, transmembrane serine protease‐2, furin) and host innate immune response‐related genes (interferons [IFNs], interleukins, toll‐like receptors), and human leukocyte antigen, ABO, 3p21.31, and 9q34.2 loci are critical host determinants related to Covid‐19 severity. Epigenetic mechanisms also affect Covid‐19 outcomes by regulating IFN signaling, angiotensin‐converting enzyme‐2, and immunity‐related genes that particularly escape from X chromosome inactivation. Enhanced understanding of host genetic and epigenetic factors and viral interactions of SARS‐CoV‐2 is critical for improved prognostic tools and innovative therapeutics.

Optical Coherence Tomography (OCT) enables non-invasive imaging of the retina and is used to diagnose and manage ophthalmic diseases including glaucoma. We present the first large-scale genome-wide association study of inner retinal morphology using phenotypes derived from OCT images of 31,434 UK Biobank participants. We identify 46 loci associated with thickness of the retinal nerve fibre layer or ganglion cell inner plexiform layer. Only one of these loci has been associated with glaucoma, and despite its clear role as a biomarker for the disease, Mendelian randomisation does not support inner retinal thickness being on the same genetic causal pathway as glaucoma. We extracted overall retinal thickness at the fovea, representative of foveal hypoplasia, with which three of the 46 SNPs were associated. We additionally associate these three loci with visual acuity. In contrast to the Mendelian causes of severe foveal hypoplasia, our results suggest a spectrum of foveal hypoplasia, in part genetically determined, with consequences on visual function., Author summary The thickness of the inner retinal layers is one of the biomarkers for glaucoma, the leading cause of irreversible blindness globally. Here we utilised the large-scale of the UK Biobank and the images of the retina it contains to look for genetic variants that effect the thickness of the inner retina. We find many variants associated with this variable, but surprisingly only one that also affects glaucoma. Further analysis shows that glaucoma and genetically determined inner retinal thickness are not on the same genetic pathway and it is rather the change of thickness over time that is indicative of the disease. This is important as it invites the potential for the discovered variants to be used as a representation of baseline thickness in the clinic in the future. We also show that foveal hypoplasia, the lack of the normal valley-like shape of the central retina, is present at a population level in a mild form and is affected by three variants that also affect visual acuity. This is an interesting discovery as foveal hypoplasia was previously thought of as an outcome of rare Mendelian disease.

Purpose: To evaluate the contribution of genetic and early life environmental factors, as reflected by fetal anthropometric growth trajectories, toward the development of myopia during childhood and adolescence. Methods: This analysis included 498 singleton Caucasian participants from the Raine Study, a pregnancy cohort study based in Western Australia. Serial fetal biometric measurements of these participants were collected via ultrasound scans performed at 18, 24, 28, 34, and 38 weeks’ gestation. At a 20-year follow-up, the participants underwent a comprehensive ophthalmic examination, including cycloplegic autorefraction and ocular biometry measurements. Using a group-based trajectory modeling approach, we identified groups of participants with similar growth trajectories based on measurements of fetal head circumference (HC), abdominal circumference, femur length (FL), and estimated fetal weight (EFW). Differences between trajectory groups with respect to prevalence of myopia, axial length (AL), and corneal radius of curvature measured at the 20-year follow-up were evaluated via logistic regression and analysis of variance. Results: Prevalence of myopia was highest among participants with consistently short or consistently long FLs (P = 0.04). There was also a trend toward increased prevalence with larger HC in late gestation, although not at a statistically significant level. Trajectory groups reflecting faster HC, FL, or EFW growth correlated with significantly flatter corneas (P = 0.03, P = 0.04, and P = 0.01, respectively) and a general, but not statistically significant, increase in AL. Conclusions: Environmental or genetic factors influencing intrauterine skeletal growth may concurrently affect ocular development, with effects persisting into adulthood.

PURPOSE To investigate the relationship between time spent outdoors, at particular ages in childhood and adolescence, and myopia status in young adulthood using serum 25-hydroxyvitamin D [25(OH)D] concentration as a biomarker of time spent outdoors. METHODS Participants of the Raine Study Generation 2 cohort had 25(OH)D concentrations measured at the 6-, 14-, 17- and 20-year follow-ups. Participants underwent cycloplegic autorefraction at age 20 years, and myopia was defined as a mean spherical equivalent -0.50 dioptres or more myopic. Logistic regression was used to analyse the association between risk of myopia at age 20 years and age-specific 25(OH)D concentrations. Linear mixed-effects models were used to analyse trajectory of 25(OH)D concentrations from 6 to 20 years. RESULTS After adjusting for sex, race, parental myopia, body mass index and studying status, myopia at 20 years was associated with lower 25(OH)D concentration at 20 years (per 10 nmol/L decrease, odds ratio (aOR)=1.10, 95% CI: 1.02, 1.18) and a low vitamin D status [25(OH)D

SIX1/SIX6 polymorphism has been shown to be associated with glaucoma. Studies have also found that, in older adults, retinal nerve fibre layer (RNFL) thickness is significantly thinned with each copy of the risk allele in SIX1/SIX6. However, it is not known whether these genetic variants exert their effects in younger individuals. Comparing a healthy young adult with an older adult cohort (mean age 20 vs 63 years), both of Northern European descent, we found that there was no significant RNFL thinning in each copy of the risk alleles in SIX1/SIX6 in the eyes of younger individuals. The older cohort showed an unexpectedly thicker RNFL in the nasal sector with each copy of the risk allele for both the SIX1 (rs10483727) and SIX6 (rs33912345) variants. In the temporal sector, thinner RNFL was found with each copy of the risk allele in rs33912345 with a decrease trend observed in rs10483727. Our results suggest that SIX1/SIX6 gene variants exert their influence later in adult life.

Optical Coherence Tomography (OCT) enables non-invasive imaging of the retina and is often used to diagnose and manage multiple ophthalmic diseases including glaucoma. We present the first large-scale quantitative genome-wide association study of inner retinal morphology using phenotypes derived from OCT images of 31,434 UK Biobank participants. We identify 46 loci associated with thickness of the retinal nerve fibre layer or ganglion cell inner plexiform layer. Only one of these loci has previously been associated with glaucoma, and Mendelian randomisation confirms that inner retinal thickness, despite being a valid biomarker for the disease, is not on the same genetic causal pathway as glaucoma. Image analysis methods were used to extract overall retinal thickness at the fovea, representative of hypoplasia, with which three out of the 46 SNPs were associated. These SNPs have been previously linked with pigmentation, confirmed by their association with hair colour in the UK Biobank dataset. We additionally associate these three loci with visual acuity. In contrast to the already known Mendelian causes of severe foveal hypoplasia, our results suggest a previously unknown spectrum of foveal hypoplasia in the population, in part genetically determined, that has consequences on visual function.

To describe the prevalence and systemic associations of keratoconus in young adults in Perth, Western Australia.Cross-sectional study.One thousand two hundred fifty-nine participants 20 years of age.The Raine Study is a multigenerational, longitudinal cohort study based in Perth, Western Australia. This study represents a cross-sectional analysis of the birth cohort on returning for a 20-year follow-up. Participants underwent a detailed ophthalmic examination, including visual acuity assessment and Scheimpflug imaging using the Pentacam (Oculus, Wetzlar, Germany), and completed a health questionnaire. Keratoconus was defined as a Belin/Ambrόsio enhanced ectasia display score of 2.6 or more in either eye based on Pentacam imaging.Prevalence of keratoconus in this cohort.Of the 1259 participants, 50.8% were women and 85.7% were White. Fifteen participants had keratoconus in at least 1 eye, giving a prevalence of 1.2% (95% confidence interval, 0.7%-1.9%), or 1 in 84. A significant difference was found in best-corrected visual acuity (0.01 logarithm of the minimum angle of resolution vs. -0.05 logarithm of the minimum angle of resolution; P = 0.007), cylinder (1.25 diopters [D] vs. 0.25 D cylinder; P0.001) and spherical equivalent (-1.42 D vs. -0.50 D sphere; P = 0.02) on objective refraction, mean keratometry of the steep meridian (45.19 D vs. 43.76 D; P0.001), and mean corneal thickness at the thinnest point (475 μm vs. 536 μm; P0.001) between those with and without keratoconus. Keratoconus was associated with regular cigarette smoking (38.5% vs. 14.6%; P = 0.04), but showed no association with gender, race, body mass index, use of spectacles or contact lenses, history of allergic eye disease, or pregnancy.The prevalence of keratoconus in this Australian population-based study of 20-year-old adults was 1.2% (95% confidence interval, 0.7%-1.9%), or 1 in 84, which is one of the highest reported in the world. This has important implications for screening individuals at a younger age so that treatment can be initiated before disease progression.