Searching across-cohort relatives in 54,092 GWAS samples via encrypted genotype regression.

Explicitly sharing individual level data in genomics studies has many merits comparing to sharing summary statistics, including more strict QCs, common statistical analyses, relative identification and improved statistical power in GWAS, but it is hampered by privacy or ethical constraints. In this study, we developed encG-reg, a regression approach that can detect relatives of various degrees based on encrypted genomic data, which is immune of ethical constraints. The encryption properties of encG-reg are based on the random matrix theory by masking the original genotypic matrix without sacrificing precision of individual-level genotype data. We established a connection between the dimension of a random matrix, which masked genotype matrices, and the required precision of a study for encrypted genotype data. encG-reg has false positive and false negative rates equivalent to sharing original individual level data, and is computationally efficient when searching relatives. We split the UK Biobank into their respective centers, and then encrypted the genotype data. We observed that the relatives estimated using encG-reg was equivalently accurate with the estimation by KING, which is a widely used software but requires original genotype data. In a more complex application, we launched a finely devised multi-center collaboration across 5 research institutes in China, covering 9 cohorts of 54,092 GWAS samples. encG-reg again identified true relatives existing across the cohorts with even different ethnic backgrounds and genotypic qualities. Our study clearly demonstrates that encrypted genomic data can be used for data sharing without loss of information or data sharing barrier.

High-level and -yield production of L-leucine in engineered Escherichia coli by multistep metabolic engineering.

L-leucine is an essential amino acid widely used in food and pharmaceutical industries. However, the relatively low production efficiency limits its large-scale application. In this study, we rationally developed an efficient L-leucine-producing Escherichia coli strain. Initially, the L-leucine synthesis pathway was enhanced by overexpressing feedback-resistant 2-isopropylmalate synthase and acetohydroxy acid synthase both derived from Corynebacterium glutamicum, along with two other native enzymes. Next, the pyruvate and acetyl-CoA pools were enriched by deleting competitive pathways, employing the nonoxidative glycolysis pathway, and dynamically modulating the citrate synthase activity, which significantly promoted the L-leucine production and yield to 40.69 g/L and 0.30 g/g glucose, respectively. Then, the redox flux was improved by substituting the native NADPH-dependent acetohydroxy acid isomeroreductase, branched chain amino acid transaminase, and glutamate dehydrogenase with their NADH-dependent equivalents. Finally, L-leucine efflux was accelerated by precise overexpression of the exporter and deletion of the transporter. Under fed-batch conditions, the final strain LXH-21 produced 63.29 g/L of L-leucine, with a yield and productivity of 0.37 g/g glucose and 2.64 g/(L h), respectively. To our knowledge, this study achieved the highest production efficiency of L-leucine to date. The strategies presented here will be useful for engineering E. coli strains for producing L-leucine and related products on an industrial scale.

N-chlorosuccinimide enhancing the antimicrobial effect of benzalkonium chloride on biofilm Pseudomonas aeruginosa and its interaction mechanisms.

This study investigated the influence of N-chlorosuccinimide (NCS) pretreatment on the antimicrobial effect of benzalkonium chloride (BZC, representative of QACs) against biofilm bacteria and its mechanisms. Results show that 0.04 - 0.07 mmol/L NCS pretreatment significantly increased the antimicrobial efficacy of 0.03 mmol/L BZC on biofilm cells by 30% - 70%. The main mechanisms involved membrane permeability, oxidative damage, and metabolic disorder. More precisely, NCS pretreatment increased the permeability of bacteria and reduced the activity of the electron transport system (ETS) and dehydrogenase (DHA). At the same time, the oxidative damage of both endogenous and exogenous ROS and the disorder of the antioxidant enzymes (superoxide dismutase and catalase) further improved their combined antibacterial ability. Moreover, NCS pretreatment greatly reduced the resistance of biofilm Pseudomonas aeruginosa to BZC. The findings of the study provide a new method to effectively enhance the antimicrobial efficiency of quaternary ammonium cationic surfactants (e.g., BZC) and reduce bacterial resistance, as well as a scientific guidance for the development of new antimicrobial products.

TonoVet versus Tonopen in a high intraocular pressure monkey model.

Purpose: The purpose of this study is to evaluate the consistency of and deviation in intraocular pressure (IOP) measurements obtained by the TonoVet rebound tonometer and the Tonopen applanation tonometer in a primate model. Methods: Twenty-four-hour IOPs (nine time points) were recorded in ten monkeys with normal IOP and eight monkeys with chronic high IOP (one eye was randomly selected for measurement in each animal) using a Tonopen and TonoVet device. Measurements obtained using both handheld devices were first compared in the healthy control group (90 readings). The monkeys with chronic ocular hypertension (COHT, 72 IOP readings) were divided into three subgroups according to the level of IOP. The consistency of and deviations in the measurements were analyzed using Bland-Altman plots, linear regression, and two-tailed Student t tests. Results: In monkeys with normal IOP, the two devices produced similar IOP readings (mean IOP deviation, 0.06 ± 2.08 mmHg, p = 0.761), with 56.67% of the deviation between -1 mmHg and 1 mmHg and 91.12% between -3 mmHg and 3 mmHg. However, in the animal model group (23-60 mmHg), the readings obtained by the TonoVet tonometer were higher than those obtained by the Tonopen tonometer (mean deviation, 13.76 ± 9.19 mmHg); furthermore, 75.68% of the TonoVet measurements deviated by ± 5 mmHg from the Tonopen measurements. Conclusions: In animals with normal IOP, the TonoVet and Tonopen tonometers produced consistent measurements. However, in a monkey model of chronic high IOP, the measurements obtained by these tonometers were inconsistent, with higher IOPs associated with larger measurement errors. Therefore, it is necessary to be aware that among different tonometers, there may be systemic errors and deviations in IOP measurements. These findings should facilitate efforts to obtain more accurate individualized diagnoses and prevent the utilization of misleading IOP values.

A Highly Selective "Turn-on" Fluorescent Probe for Detection of Fe3+ in Cells.

A new "turn-on" fluorescent probe Py based on rhodamine and piperonaldehyde was designed and synthesized for detecting Fe3+ in cells. The free probe Py was non-fluorescent. While only upon addition of Fe3+, the significant increase of the fluorescence and color were observed which could be visible directly by "naked-eye". The probe Py shows high selectivity and sensitivity for Fe3+ over other common metal ions in EtOH-H2O (3/2, v/v) mixed solution. The association constant and the detection limit were calculated to be 4.81 × 104 M-1 and 1.18 × 10-8 mol/L respectively. The introduction of piperonaldehyde unit could increase probe rigidity which could enhance its optical properties. Meanwhile, the binding mode between Py and Fe3+ was found to be a 1:1 complex formation. The density functional theory (DFT) calculations were performed which would further confirm the recognition mechanism between probe Py and Fe3+. In addition, the probe has been proved to be reversible for detecting Fe3+. Moreover, the probe Py was used to detect Fe3+ in cells successfully.

The Guangzhou Twin Eye Study: 2019 Update.

The primary aim of the Guangzhou Twin Eye Study (GTES) is to explore the impact that genes and environmental influences have on common eye diseases. Since 2006, approximately 1300 pairs of twins, aged 7-15 years, were enrolled at baseline. Progressive phenotypes, such as cycloplegic refraction, axial length, height and weight, have been collected annually. Nonprogressive phenotypes such as parental refraction, corneal thickness, fundus photo, intraocular pressure and DNA were collected once at baseline. We are collaborating with fellow international twin researchers and psychologists to further explore links with general medical conditions. In this article, we review the history, major findings and future research directions for the GTES.

Prediction of myopia development among Chinese school-aged children using refraction data from electronic medical records: A retrospective, multicentre machine learning study.

BACKGROUND: Electronic medical records provide large-scale real-world clinical data for use in developing clinical decision systems. However, sophisticated methodology and analytical skills are required to handle the large-scale datasets necessary for the optimisation of prediction accuracy. Myopia is a common cause of vision loss. Current approaches to control myopia progression are effective but have significant side effects. Therefore, identifying those at greatest risk who should undergo targeted therapy is of great clinical importance. The objective of this study was to apply big data and machine learning technology to develop an algorithm that can predict the onset of high myopia, at specific future time points, among Chinese school-aged children. METHODS AND FINDINGS: Real-world clinical refraction data were derived from electronic medical record systems in 8 ophthalmic centres from January 1, 2005, to December 30, 2015. The variables of age, spherical equivalent (SE), and annual progression rate were used to develop an algorithm to predict SE and onset of high myopia (SE ≤ -6.0 dioptres) up to 10 years in the future. Random forest machine learning was used for algorithm training and validation. Electronic medical records from the Zhongshan Ophthalmic Centre (a major tertiary ophthalmic centre in China) were used as the training set. Ten-fold cross-validation and out-of-bag (OOB) methods were applied for internal validation. The remaining 7 independent datasets were used for external validation. Two population-based datasets, which had no participant overlap with the ophthalmic-centre-based datasets, were used for multi-resource validation testing. The main outcomes and measures were the area under the curve (AUC) values for predicting the onset of high myopia over 10 years and the presence of high myopia at 18 years of age. In total, 687,063 multiple visit records (≥3 records) of 129,242 individuals in the ophthalmic-centre-based electronic medical record databases and 17,113 follow-up records of 3,215 participants in population-based cohorts were included in the analysis. Our algorithm accurately predicted the presence of high myopia in internal validation (the AUC ranged from 0.903 to 0.986 for 3 years, 0.875 to 0.901 for 5 years, and 0.852 to 0.888 for 8 years), external validation (the AUC ranged from 0.874 to 0.976 for 3 years, 0.847 to 0.921 for 5 years, and 0.802 to 0.886 for 8 years), and multi-resource testing (the AUC ranged from 0.752 to 0.869 for 4 years). With respect to the prediction of high myopia development by 18 years of age, as a surrogate of high myopia in adulthood, the algorithm provided clinically acceptable accuracy over 3 years (the AUC ranged from 0.940 to 0.985), 5 years (the AUC ranged from 0.856 to 0.901), and even 8 years (the AUC ranged from 0.801 to 0.837). Meanwhile, our algorithm achieved clinically acceptable prediction of the actual refraction values at future time points, which is supported by the regressive performance and calibration curves. Although the algorithm achieved balanced and robust performance, concerns about the compromised quality of real-world clinical data and over-fitting issues should be cautiously considered. CONCLUSIONS: To our knowledge, this study, for the first time, used large-scale data collected from electronic health records to demonstrate the contribution of big data and machine learning approaches to improved prediction of myopia prognosis in Chinese school-aged children. This work provides evidence for transforming clinical practice, health policy-making, and precise individualised interventions regarding the practical control of school-aged myopia.

Nature vs. nurture in human sociality: multi-level genomic analyses of social conformity.

Social conformity is fundamental to human societies and has been studied for more than six decades, but our understanding of its mechanisms remains limited. Individual differences in conformity have been attributed to social and cultural environmental influences, but not to genes. Here we demonstrate a genetic contribution to conformity after analyzing 1,140 twins and single-nucleotide polymorphism (SNP)-based studies of 2,130 young adults. A two-step genome-wide association study (GWAS) revealed replicable associations in 9 genomic loci, and a meta-analysis of three GWAS with a sample size of ~2,600 further confirmed one locus, corresponding to the NAV3 (Neuron Navigator 3) gene which encodes a protein important for axon outgrowth and guidance. Further multi-level (haplotype, gene, pathway) GWAS strongly associated genes including NAV3, PTPRD (protein tyrosine phosphatase receptor type D), ARL10 (ADP ribosylation factor-like GTPase 10), and CTNND2 (catenin delta 2), with conformity. Magnetic resonance imaging of 64 subjects shows correlation of activation or structural features of brain regions with the SNPs of these genes, supporting their functional significance. Our results suggest potential moderate genetic influence on conformity, implicate several specific genetic elements in conformity and will facilitate further research on cellular and molecular mechanisms underlying human conformity.

25-gauge lens-sparing vitrectomy with dissection of retrolental adhesions on the peripheral retina for familial exudative vitreoretinopathy in infants.

BACKGROUND: To evaluate the clinical outcome of 25-gauge lens-sparing vitrectomy with dissection of retrolental adhesions on the peripheral retina for familial exudative vitreoretinopathy in infants. METHODS: Fifty-one eyes of 39 infants with familial exudative vitreoretinopathy associated with retrolental adhesions on the peripheral retina, retinal fold with macular detachment, and partial lens opacity. A 25-gauge lens-sparing vitrectomy was performed, and retrolental adhesions between the peripheral retina and the posterior lens capsule were surgically dissected. Lens opacification, as assessed or graded by Lens Opacities Classification System III, and the retinal reattachment rate were observed and recorded monthly for up to 7 months postoperatively. RESULTS: After 7 months, the detached retina along the retinal fold was reattached in 42/51 (82.4%) eyes; the macula was reattached completely in 26/51 (51.0%) eyes and partially in 15/51 (29.4%) eyes. There was no statistically significant change in the lens opacity of the posterior capsule or cortex before or after surgery (P > 0.05, paired t test) or in postoperative progression of lens opacity (P > 0.05, modified McNemar's test) according to Lens Opacities Classification System III scores. CONCLUSIONS: A 25-gauge lens-sparing vitrectomy with dissection of peripheral retinal retrolental adhesions is helpful for preservation of the lens and reattachment of the macula in infants with FEVR.

Significant Axial Elongation with Minimal Change in Refraction in 3- to 6-Year-Old Chinese Preschoolers: The Shenzhen Kindergarten Eye Study.

PURPOSE: To document the distribution of ocular biometry and to evaluate its associations with refraction in a group of Chinese preschoolers. DESIGN: Population-based cross-sectional study. PARTICIPANTS: A total of 1133 preschoolers 3 to 6 years of age from 8 representative kindergartens. METHODS: Biometric measurements including axial length (AL), anterior chamber depth (ACD), and corneal radius of curvature (CR) were obtained from partial-coherence laser interferometry (IOL Master; Carl Zeiss Meditec, Oberkochen, Germany) before cycloplegia. Lens power (LP) and AL-to-CR ratio were calculated. Cycloplegic refraction (3 drops of 1% cyclopentolate) was measured using an autorefractor (KR8800; Topcon Corp., Tokyo, Japan), and spherical equivalent refraction (SER) was calculated. Biometric and refractive parameters were assessed as a function of age and gender. Multiple regression analysis was performed to explore the associations between refraction and ocular biometry. MAIN OUTCOME MEASURES: Ocular biometric distributions and their relationships to refraction. RESULTS: Among the 1127 children (99.5%) with successful cycloplegic refraction, mean SER was 1.37±0.63 diopters (D). Prevalence of myopia increased from 0% at 3 years of age to 3.7% (95% confidence interval, 1.0%-6.5%) at 6 years of age. Biometric parameters followed Gaussian distributions with means of 22.39±0.68 mm for AL, 7.79±0.25 mm for CR, and 24.61±1.42 D for calculated LP; and non-Gaussian distributions with means of 3.34±0.24 mm for ACD and 2.88±0.06 for AL-to-CR ratio. Axial length, ACD, and AL-to-CR ratio increased from 3 to 6 years of age, CR remained stable, whereas LP declined. Overall, SER declined slightly. For the SER variance, AL explained 18.6% and AL-to-CR ratio explained 39.8%, whereas AL, CR, and LP accounted for 80.0% after adjusting for age and gender. CONCLUSIONS: Young Chinese children are predominantly mildly hyperopic, with a low prevalence of myopia by the age of 6 years. An increase of 1 mm in AL was associated with only 0.45 D of myopic change. Decreases in LP reduce the myopic shifts that normally would be associated with increases in AL, and thus play a key role in refractive development in this age group.

Twin's Birth-Order Differences in Height and Body Mass Index From Birth to Old Age: A Pooled Study of 26 Twin Cohorts Participating in the CODATwins Project.

We analyzed birth order differences in means and variances of height and body mass index (BMI) in monozygotic (MZ) and dizygotic (DZ) twins from infancy to old age. The data were derived from the international CODATwins database. The total number of height and BMI measures from 0.5 to 79.5 years of age was 397,466. As expected, first-born twins had greater birth weight than second-born twins. With respect to height, first-born twins were slightly taller than second-born twins in childhood. After adjusting the results for birth weight, the birth order differences decreased and were no longer statistically significant. First-born twins had greater BMI than the second-born twins over childhood and adolescence. After adjusting the results for birth weight, birth order was still associated with BMI until 12 years of age. No interaction effect between birth order and zygosity was found. Only limited evidence was found that birth order influenced variances of height or BMI. The results were similar among boys and girls and also in MZ and DZ twins. Overall, the differences in height and BMI between first- and second-born twins were modest even in early childhood, while adjustment for birth weight reduced the birth order differences but did not remove them for BMI.

The Onset and Progression of Myopia Slows in Chinese 15-Year-Old Adolescents Following Vocational Rather Than Academic School Pathways.

Purpose: The purpose of this study was to investigate the changes in spherical equivalent (SE) and axial length (AL) and cumulative incidence of myopia and high myopia in Chinese 15-year-old adolescents entering a non-academic stream of senior high school education. Methods: A total of 880 first-born twins with a baseline age range of 7 to 15 years were enrolled and followed annually until 18 years of age. Cycloplegic refractions and AL were examined. Educational exposure was divided into academic high school (AHS) and vocational high school (VHS) streams. A piecewise linear mixed-effects model was used to estimate the effect of education exposures on SE development, the slope before the age of 15 years (ß2), and the slope change at the age of 15 years (ß3) was compared between the 2 groups. Results: The curves of refractive development in a myopic direction changed in parallel in the AHS and VHS group before 15 years. For nonmyopic children, ß2 was -0.19 and -0.20 diopters (D)/year (P = 0.270), and ß3 was 0.16 and 0.14 D/year (P = 0.270), in the AHS and VHS groups, respectively. Among patients with myopia, ß2 was -0.52 and -0.54 D/year (P = 0.500), and ß3 was 0.37 and 0.32 D/year (P = 0.004), in the AHS and VHS groups, respectively. The trends in AL were similar. The 3-year cumulative incidence of myopia was 35.3% (AHS) versus 14.7% (VHS; P < 0.001), and that of high myopia was 5.7% and 3.3% (P = 0.129). Conclusions: Students undertaking a VHS rather than an AHS education have slower myopic shifts in refraction and less incident myopia after the age of 15 years.

Clinical spectrum and possible pathogenesis of progressive outer retinal necrosis.

OBJECTIVE: Progressive outer retinal necrosis (PORN) is an alphaherpesvirus-caused panuveitis with devastating consequences for the eye. Our study aims to describe new findings in the clinical spectrum and propose a mechanism for the pathogenesis of PORN. METHODS: Observational, consecutive case series. Seven eyes from five patients diagnosed with PORN were enrolled. Detailed case histories, ocular examination findings and multimodal images of retina were collected. Optic nerve and brain imaging were obtained by MRI. RESULTS: All eyes were confirmed human alphaherpesviruses positive in ocular fluid by qPCR. Optic nerve oedema was observed on MRI in all eyes. A relative afferent pupillary defect was recorded in the affected eye for the unilateral cases. Two patients with unilateral involvement had a history of viral encephalitis and focal encephalomalacia found in the temporal lobe on brain MRI. The affected eyes were characterised by sensory retinal necrosis sparing retinal pigment epithelium, starting at the end of the retinal nerve fibre (horizontal raphe or peripheral area of the retina) and progressing rapidly along the nerve fibre. The wall of the retinal artery and vein was destroyed, resulting in blood flow interruption on fluorescein angiography and retinal haemorrhages along the large vessels. CONCLUSIONS: Combination the neurotropic characteristics of alphaherpesviruses and the signs of PORN, we hypothesised that the reactivated PORN virus originated from the lateral geniculate nucleus, then propagated along the optic nerve and was released at the terminals, causing necrosis of the entire sensory retina rather than just affecting the outer segment.

Green Space Morphology and School Myopia in China.

Importance: China has experienced both rapid urbanization and major increases in myopia prevalence. Previous studies suggest that green space exposure reduces the risk of myopia, but the association between myopia risk and specific geometry and distribution characteristics of green space has yet to be explored. These must be understood to craft effective interventions to reduce myopia. Objective: To evaluate the associations between myopia and specific green space morphology using novel quantitative data from high-resolution satellite imaging. Design, Setting, and Participants: This prospective cohort study included students grades 1 to 4 (aged 6 to 9 years) in Shenzhen, China. Baseline data were collected in 2016-2017, and students were followed up in 2018-2019. Data were analyzed from September 2020 to January 2022. Exposures: Eight landscape metrics were calculated using land cover data from high-resolution Gaofen-2 satellite images to measure area, aggregation, and shape of green space. Main Outcome and Measures: The 2-year cumulative change in myopia prevalence at each school and incidence of myopia at the student level after 2 years were calculated as main outcomes. The associations between landscape metrics and school myopia were assessed, controlling for geographical, demographic, and socioeconomic factors. Principal component analyses were performed to further assess the joint effect of landscape metrics at the school and individual level. Results: A total of 138 735 students were assessed at baseline. Higher proportion, aggregation, and better connectivity of green space were correlated with slower increases in myopia prevalence. In the principal component regression, a 1-unit increase in the myopia-related green space morphology index (the first principal component) was negatively associated with a 1.7% (95% CI, -2.7 to -0.6) decrease in myopia prevalence change at the school level (P = .002). At the individual level, a 1-unit increase in myopia-related green space morphology index was associated with a 9.8% (95% CI, 4.1 to 15.1) reduction in the risk of incident myopia (P < .001), and the association remained after further adjustment for outdoor time, screen time, reading time, and parental myopia (adjusted odds ratio, 0.88; 95% CI, 0.80 to 0.97; P = .009). Conclusions and Relevance: Structure of green space was associated with a decreased relative risk of myopia, which may provide guidance for construction and renovation of schools. Since risk estimates only indicate correlations rather than causation, further interventional studies are needed to assess the effect on school myopia of urban planning and environmental designs, especially size and aggregation metrics of green space, on school myopia.

A deep learning system for myopia onset prediction and intervention effectiveness evaluation in children.

The increasing prevalence of myopia worldwide presents a significant public health challenge. A key strategy to combat myopia is with early detection and prediction in children as such examination allows for effective intervention using readily accessible imaging technique. To this end, we introduced DeepMyopia, an artificial intelligence (AI)-enabled decision support system to detect and predict myopia onset and facilitate targeted interventions for children at risk using routine retinal fundus images. Based on deep learning architecture, DeepMyopia had been trained and internally validated on a large cohort of retinal fundus images (n = 1,638,315) and then externally tested on datasets from seven sites in China (n = 22,060). Our results demonstrated robustness of DeepMyopia, with AUCs of 0.908, 0.813, and 0.810 for 1-, 2-, and 3-year myopia onset prediction with the internal test set, and AUCs of 0.796, 0.808, and 0.767 with the external test set. DeepMyopia also effectively stratified children into low- and high-risk groups (p < 0.001) in both test sets. In an emulated randomized controlled trial (eRCT) on the Shanghai outdoor cohort (n = 3303) where DeepMyopia showed effectiveness in myopia prevention compared to NonCyc-based model, with an adjusted relative reduction (ARR) of -17.8%, 95% CI: -29.4%, -6.4%. DeepMyopia-assisted interventions attained quality-adjusted life years (QALYs) of 0.75 (95% CI: 0.53, 1.04) per person and avoided blindness years of 13.54 (95% CI: 9.57, 18.83) per 1 million persons compared to natural lifestyle with no active intervention. Our findings demonstrated DeepMyopia as a reliable and efficient AI-based decision support system for intervention guidance for children.

The Guangzhou Twin Project: an update.

The Guangzhou Twin Registry is a population-based registry of twins residing in Guangzhou City. The initial registry database included 9,700 pairs of young twins recruited from the Official Household Registry of Guangzhou City. The registry is designed to provide a resource to identify the genetic and environmental causes of common diseases with an initial focus on eye diseases. From 2006 onward, phenotype and DNA collection have been completed for more than 1,200 twin pairs and their parents or siblings. Most of the young twins have come back for an annual examination of the progressive traits, such as refraction, ocular biometry, weight, and height. Genome-wide association scans have been completed recently. This article gives an update of the study design, cohort profile, previous findings, and future directions. Results from the Guangzhou Twin Project may contribute to the understanding of gene-environmental interplay for complex diseases in both adults and children.