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To assess the effect of a patient decision aid on the quality of decision-making for patients with age-related cataracts.773 patients with cataracts aged 50-80 years were randomly assigned to receive either the intervention decision aid (including standard information, quantitative information on the possible outcomes of cataract surgery and a value clarification exercise) or the control booklet (including standard information). The primary outcome was informed choice (defined as adequate knowledge and congruency between attitudes and surgical intentions), which was assessed at 2 weeks after intervention via a telephone interview.The decision aid increased the proportion of participants making an informed choice, from 5.68 % in the control group to 27.7 % in the intervention group (P0.001). Compared with controls, more participants in the intervention group had adequate overall knowledge about cataract surgery (36.8 % vs. 8.79 % in controls; P0.001), and fewer participants intended to undergo surgery (22.5 % vs. 34.1 % in controls; P0.001).Use of the patient decision aid may increase the proportion of patients making informed choices. Importantly, it might also reduce the acceptance of operations.Patient decision aids represent a simple and low-cost tool to facilitate informed choice among patients with cataracts.

Long nanopore reads are advantageous in de novo genome assembly. However, nanopore reads usually have broad error distribution and high-error-rate subsequences. Existing error correction tools cannot correct nanopore reads efficiently and effectively. Most methods trim high-error-rate subsequences during error correction, which reduces both the length of the reads and contiguity of the final assembly. Here, we develop an error correction, and de novo assembly tool designed to overcome complex errors in nanopore reads. We propose an adaptive read selection and two-step progressive method to quickly correct nanopore reads to high accuracy. We introduce a two-stage assembler to utilize the full length of nanopore reads. Our tool achieves superior performance in both error correction and de novo assembling nanopore reads. It requires only 8122 hours to assemble a 35X coverage human genome and achieves a 2.47-fold improvement in NG50. Furthermore, our assembly of the human WERI cell line shows an NG50 of 22 Mbp. The high-quality assembly of nanopore reads can significantly reduce false positives in structure variation detection., Nanopore reads have been advantageous for de novo genome assembly; however these reads have high error rates. Here, the authors develop an error correction and de novo assembly tool, NECAT, which produces efficient, high quality assemblies of nanopore reads.

Aims Acyl‐CoA synthetase long chain family member 4 (ACSL4) is closely related to tumor genesis and development in certain tissues. However, the function of ACSL4 in early brain injury (EBI) caused by subarachnoid hemorrhage (SAH) is unclear. In this study, we investigated the expression patterns and role of ACSL4 in SAH and post‐SAH EBI using a rat model of SAH. Methods The rat model of SAH was induced by autologous blood injection into the prechiasmatic cistern of rats. We also used two specific inhibitors of ferroptosis (Ferrostatin‐1 and Liproxstatin‐1) to investigate the role of ferroptosis in EBI. Results We found that ACSL4 levels in brain tissue increased significantly in post‐SAH EBI. Inhibiting the expression of ACSL4 using small interfering RNAs alleviated inflammation, blood‐brain barrier (BBB) impairment, oxidative stress, brain edema, and behavioral and cognitive deficits, and increased the number of surviving neurons, after SAH. Similar effects were obtained by suppressing ferroptosis. Conclusions ACSL4 exacerbated SAH‐induced EBI by mediating ferroptosis. These findings may provide a theoretical basis for potential therapy aimed at alleviating post‐SAH EBI., ACSL4 levels in brain tissue of rats increase significantly in EBI and brain damage after SAH could be reduced by down‐regulation of ACSL4. ACSL4 could trigger ferroptosis and aggravate brain damage via catalyzing lipid metabolism. It may provide a theoretical basis for potential therapy to alleviate EBI after SAH

PURPOSE: To compare the efficacy and safety of a fluid-jet technique with capsular polish in reducing residual lens fibers (RLFs) in phacoemulsification surgery. SETTING: Single center. DESIGN: Prospective nonrandomized comparative study. METHODS: Patients receiving phacoemulsification were included. Consecutive eligible patients alternately underwent either removal of RLFs on the posterior capsule using capsular polish after irrigation and aspiration, and before intraocular lens (IOL) implantation, or RLF removal using a fluid-jet technique after IOL implantation. Posterior capsular images were used to quantify RLFs. Visual parameters were evaluated at 1 day, 1 week, and 1 year postoperatively. The proportion of capsule occupied by posterior capsule opacification (PCO) (area %) and incidence of protocol-driven laser posterior capsulotomy were recorded at 1 year in masked fashion. RESULTS: Seven hundred forty eyes were allocated to polishing (n = 370) or fluid-jet technique (n = 370). Polishing required 70.4 ± 17.5 seconds and fluid-jet 32.2 ± 9.9 seconds (P ≤ 0.001). Compared with the polishing group, capsular area occupied by RLFs in the fluid-jet group was significantly smaller (3.5% vs 0.5%, P = .031) at the end of surgery. One day postoperatively, the fluid-jet group had more desirable corrected distance visual acuity, objective scattering index, and Strehl ratio (all P < .05). PCO area percentage did not differ between groups (6.5% vs 4.5%, P = .252) 1 year postoperatively, but incidence of posterior capsulotomy was lower in the fluid-jet group (3.2% vs 0.8%, P = .019). CONCLUSIONS: Fluid-jet removed RLFs effectively and had lower incidence of postoperative capsulotomy than capsular polishing.

Coronavirus disease 2019 (COVID-19), driven by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), was declared a global pandemic in March 2020. Pathogenic T cells and inflammatory monocytes are regarded as the central drivers of the cytokine storm associated with the severity of COVID-19. In this study, we explored the characteristic peripheral cellular profiles of patients with COVID-19 in both acute and convalescent phases by single-cell mass cytometry (CyTOF). Using a combination of algorithm-guided data analyses, we identified peripheral immune cell subsets in COVID-19 and revealed CD4+ T-cell depletion, T-cell differentiation, plasma cell expansion, and the reduced antigen presentation capacity of innate immunity. Notably, COVID-19 induces a dysregulation in the balance of monocyte populations by the expansion of the monocyte subsets. Collectively, our results represent a high-dimensional, single-cell profile of the peripheral immune response to SARS-CoV-2 infection.

Herpes simplex keratitis (HSK) is the most common cause of corneal blindness in developed nations, caused by primary or recurrent herpes simplex virus 1 (HSV-1) infection of the cornea. Latent infection of HSV-1, especially in the trigeminal ganglion (TG), causes recurrence of HSV-1 infection. As antiviral treatment is not effective on latent HSV-1, to test the possibility of inhibiting HSV-1 by SpCas9 (Streptococcus pyogenes Cas9) or SaCas9 (Staphylococcus aureus Cas9), ICP0 and ICP4, two important genes required for HSV-1 replication and reactivation, were chosen as targets. In Vero cells, SpCas9 and SaCas9 targeting ICP0 or ICP4 can effectively inhibit the proliferation of HSV-1 without affecting cell viability. No significant guide RNA (gRNA)-dependent off-targets were observed in the human genome by digenome sequencing and deep sequencing verification. Adeno-associated virus 1 (AAV1)-mediated delivery of SaCas9 inhibits HSV-1 replication by targeting ICP4 in mouse primary TG neuronal cells. SpCas9 and SaCas9 are able to inhibit HSV-1 infection in Vero cells and mouse TG neuronal cultures with high efficiency and good biosafety. AAV1-mediated delivery of SaCas9 shows great potential in treating HSK and inhibiting HSV-1 in TG neurons. Further investigations may be needed to test the inhibition of latent infections, which may result in the development of novel methods for treating viral diseases., Graphical Abstract, There is no effective treatment that can eliminate persistent HSV-1 within trigeminal ganglion (TG) neurons. Even though the meganucleases and CRISPR-SpCas9 system can interrupt the HSV-1 genome, they could not be packaged in an AAV system for in vivo therapy. In this study, the authors show the potential use of a single AAV1-mediated delivery system of ICP4-targeting SaCas9 to inhibit HSV-1 in TG neurons.

FGF-2 displays multifarious functions in regulation of angiogenesis and vascular remodeling. However, effective drugs for treating FGF-2+ tumors are unavailable. Here we show that FGF-2 modulates tumor vessels by recruiting NG2+ pricytes onto tumor microvessels through a PDGFRβ-dependent mechanism. FGF-2+ tumors are intrinsically resistant to clinically available drugs targeting VEGF and PDGF. Surprisingly, dual targeting the VEGF and PDGF signaling produces a superior antitumor effect in FGF-2+ breast cancer and fibrosarcoma models. Mechanistically, inhibition of PDGFRβ ablates FGF-2-recruited perivascular coverage, exposing anti-VEGF agents to inhibit vascular sprouting. These findings show that the off-target FGF-2 is a resistant biomarker for anti-VEGF and anti-PDGF monotherapy, but a highly beneficial marker for combination therapy. Our data shed light on mechanistic interactions between various angiogenic and remodeling factors in tumor neovascularization. Optimization of antiangiogenic drugs with different principles could produce therapeutic benefits for treating their resistant off-target cancers., Anti-VEGF therapy has many limitations that might be resolved by using combination treatment approaches. Here, the authors demonstrate that the dual-targeting of VEGF and PDGF is required for targeting resistant FGF2+ tumors which depend on the recruitment of pericytes on tumor microvessels.

IMPORTANCE There is no clear consensus on which intraocular lens (IOL) power calculation formula provides the best refractive prediction in the paediatric population. BACKGROUND To evaluate the predictability of desired postoperative refractive outcomes by using six IOL formulas in paediatric cataract cases. DESIGN Retrospective case series. PARTICIPANTS A total of 377 eyes in 377 paediatric patients (

Accumulated oxidative damage may lead to irreversible retinal pigmented epithelium (RPE) cell death, which is considered to be the primary cause of dry age-related macular degeneration (AMD), leading to blindness in the elderly. However, an effective therapy for this disease is lacking. Here, we described a robust high-content screening procedure with a library of 814 protective compounds and found that D609 strongly protected RPE cells from sodium iodate (SI)-induced oxidative cell death and prolonged their healthy survival. D609 effectively attenuated excessive reactive oxygen species (ROS) and prevented severe mitochondrial loss due to oxidative stress in the RPE cells. Surprisingly, the potent antioxidative effects of D609 were not achieved through its own reducibility but were primarily dependent on its ability to increase the expression of metallothionein. The injection of this small water-soluble molecule also showed an explicit protective effect of the RPE layer in an SI-induced AMD mouse model. These findings suggested that D609 could serve as a novel antioxidative protector of RPE cells both in vitro and in vivo and unveiled a novel antioxidative mechanism of D609, which may ultimately have clinical applications for the treatment of AMD.

Aim To develop a novel approach called the Autoacuity Tester, and to evaluate its validity, especially the sensitivity and specificity for detecting amblyopia. Methods Children aged from 3 to 12y (n=552) were enrolled in the study. The validity of the Autoacuity Tester was evaluated by comparing it to the Tumbling E Early Treatment Diabetic Retinopathy Study (ETDRS) acuity chart for school age children, and Lea Symbols and Teller acuity card (TAC) for preschool children. The repeatability was assessed by coefficient of repeatability (COR). The sensitivity and specificity for detecting amblyopia were calculated. Results The mean difference (95% limits of agreement) between the Autoacuity Tester and the ETDRS tests were -0.03 (-0.24, 0.19) logMAR for the school age group. In preschool children, the mean difference was 0.04 (-0.14, 0.21) logMAR between the Autoacuity Tester and the TAC and 0.00 (-0.17, 0.18) logMAR between the Autoacuity Tester and the Lea Symbols. For the school age group, the COR was 0.20 logMAR for the Autoacuity Tester and 0.18 logMAR for the ETDRS. For the preschool group, the COR was 0.13 logMAR for the Autoacuity Tester and 0.21 logMAR for TAC. The Autoacuity Tester (88%) is more sensitive than TAC (72%) in detecting amblyopia (P=0.04), while had similar specificity (92% vs 90%, P=0.20). Conclusion The Autoacuity Tester provides a reliable alternative for assessing visual acuity, and offers advantage of higher testability and repeatability for preschool children.

PReCIS:: The overall incidence of postoperative suspected glaucoma and glaucoma after congenital cataract surgery is low; however, the identification of the associated risk factors helps to monitor susceptible individuals and to provide real-time surveillance and timely intervention. Purpose Pediatric patients who have undergone surgery for congenital or infantile cataracts have a risk of developing suspected glaucoma and glaucoma, but the current evidence does not address our understanding of the incidence and associated risk factors of suspected glaucoma/glaucoma for application in clinical standard care. Therefore, this study investigated the incidence of and risk factors for suspected glaucoma/glaucoma in patients who have undergone surgery for congenital/infantile cataracts. Methods This study used a prospective cohort of 241 eyes from 241 patients who were 10 years of age or younger and who had undergone congenital/infantile cataract surgeries and were recruited from January 2011 to December 2016 at the Zhongshan Ophthalmic Center. Pediatric patients who underwent cataract surgery were classified into 2 groups according to intraocular lens (IOL) implantation. The patients' baseline characteristics and the incidence and risk factors for suspected glaucoma/glaucoma were assessed. Results The incidence of suspected glaucoma after cataract surgery was 10.70% [26 of 241 eyes; 95% confidence interval (CI), 6.88%-14.70%]. The rate of suspected glaucoma developing into glaucoma was 26.92% (7 of 26 eyes; 95% CI, 9.87%-43.97%), and the incidence of glaucoma was 2.90% (7 of 241 eyes; 95% CI, 0.79%-5.03%). Our study revealed that the incidence of suspected glaucoma/glaucoma in patients who did not receive IOL implantation was 13.91% (21 of 151 eyes; 95% CI, 8.39%-19.42%), and the incidence in patients who received IOL implantation was 5.56% (5 of 90 eyes; 95% CI, 8.23%-10.28%). The preoperative central corneal thickness (hazard ratio, 1.003; 95% CI, 1.001 to 1.004; P=0.004) and a family history of congenital cataracts (hazard ratio, 2.314; 95% CI, 1.004-5.331; P=0.049) were significant risk factors in patients without IOL implantation. Patient age at the time of cataract surgery was not a statistically significant risk factor for the development of suspected glaucoma/glaucoma in patients without IOL implantation. Conclusions Identification of the incidence of and risk factors for suspected glaucoma/glaucoma may help clinicians monitor susceptible individuals and provide timely surveillance and interventions in a clinical setting. Age at the time of cataract surgery was not a risk factor for suspected glaucoma/glaucoma in patients without IOL implantation, and this may allow the timing window for pediatric cataract surgery to be expanded and support new insights into the optimal timing of surgery for standard care.

Aim To study the change in ocular refraction in patients with pediatric cataracts (PCs) after lens extraction. Methods A total of 1258 patients who were undergoing cataract extraction with/without intraocular lens (IOL) implantation were recruited during preoperative examinations between Jan 2010 and Oct 2013. Patient ages ranged from 1.5mo to 14y. Follow-ups were conducted at 1wk, 1, and 3mo postoperatively and every 3mo in the first year, then 6mo thereafter. Ocular refraction [evaluated as spherical equivalent (SE)] and yearly myopic shift (YMS) were recorded and statistically analyzed among patients with age at surgery, baseline ocular refraction, gender, postoperative time and laterality (bilateral vs unilateral). Results By Dec 31st 2015, 1172 participants had been followed for more than 2y. The median follow-up period was 3y. The critical factors affecting the ocular refraction of PC patients were baseline ocular refraction, postoperative time for both aphakic and pseudophakic eyes. YMS grew most rapidly in young childhood and early adolescence. Conclusion After lens surgeries, ocular refraction in PC patients shows an individual difference of change. Further concerns should be raising to monitor the rapid myopic shift at early adolescence of these patients.

The management of ophthalmic diseases in the virtual hospital can be implemented and is complementary to those of on-site F2F clinics. Virtual clinical service may be a useful model in the post-COVID-19 pandemic "new normal".

AIM: To investigate the mechanism of celastrol in inhibiting lens epithelial cells (LECs) fibrosis, which is the pathological basis of cataract. METHODS: Human LEC line SRA01/04 was treated with celastrol and transforming growth factor-β2 (TGF-β2). Wound-healing assay, proliferation assay, flow cytometry, real-time polymerase chain reaction (PCR), Western blot and immunocytochemical staining were used to detect the pathological changes of celastrol on LECs. Then, we cultured Sprague-Dawley rat lens in medium as a semi-in vivo model to find the function of celastrol further. RESULTS: We found that celastrol inhibited the migration of LECs, as well as proliferation (P

Epithelial-mesenchymal transition (EMT) is the main cause of fibrotic cataracts. Oxidative stress was recently shown to trigger epithelial-mesenchymal transition in human lens epithelial cells (hLECs). However, the underlying mechanism is not fully understood. Here we reported that exposure to low doses (100 μM) of H2O2 led to EMT in hLECs, as indicated by simultaneous down-regulated of E-cadherin and ZO-1, and up-regulated of alpha smooth muscle actin (α-SMA). H2O2-induced EMT was accompanied by accumulation of phosphorylated JNK1. In contrast, knockdown of JNK1 via siRNA reversed H2O2-induced EMT. Of interest, in human lens capsules of anterior subcapsule cataracts, the expressions of JNK1, as well as β-catenin and its downstream effectors cyclin D and c-Myc, were augmented compared to that in normal lens capsules. Mechanistically, activated JNK1 dislodged β-catenin from the cell membrane, which subsequently translocated to the nuclei and triggered transcription of its effectors. Nuclei β-catenin, cyclin D and c-Myc were accumulated in H2O2-induced EMT and JNK1 depletion abrogated these trend in hLECs. In conclusion, our data suggest that JNK1 is essential for H2O2-induced EMT in hLECs via mediating the translocation of β-catenin.

To identify imaging characteristics of mouse persistent hyperplastic primary vitreous (PHPV) by Spectralis Optical Coherence Tomography (OCT), as well as to assess and compare the sensitivity and precision of OCT with color photography (CP) and Fundus Fluorescein Angiography (FFA) imaging in detecting mouse PHPV. Notch4-/- C57BL/6J mice (224 eyes) aged from 3 months to 7 months were examined in this study. CP, FFA and OCT imaging were utilized to examine vitreous cavity and retina of mouse eyes. Horizontal and radial OCT scan volume was centered on the optic nerve head. Hematoxylin and eosin (H&E) staining was performed to validate PHPV. For color photography and FFA imaging, retrolental irregular fibrovascular membrane-like tissues were found in 33 eyes with/without blood vessels in vitreous cavity. Among them, 31 eyes were visualized with lateral and oblique linear hyperreflective opacities in vitreous cavity using Spectralis OCT. Position of PHPV in posterior segment of eyes was also measured via OCT. Mouse PHPV was validated by H&E staining. Typical hyperreflective opacities in vitreous cavity were detected in PHPV mouse using Spectralis OCT. Spectralis OCT imaging can effectively detect mouse PHPV as color photography and FFA.

Ocular surface disease is one major type of eye diseases. Different etiologies trigger distinct pathological responses of the ocular surface. We previously reported that genetically engineered mice with ablation of Prickle 1 manifested precocious eyelid opening with ensuing cornea dysplasia. The current study aimed to characterize the molecular traits and the direct cause of ocular pathology associated with precocious eyelid opening in the Prickle 1 mutant mouse. Prickle 1 mutant mice exhibited a slew of ocular surface pathology including cell proliferation, cell fate transformation and inflammatory infiltration coinciding with the timing of the precocious eyelid opening. Forced eyelid opening in wild type mice did not induce cornea pathology comparable to that of the Prickle 1 mutants. Necrotic tissue debris was found associated with the lesioned cornea. RNAseq analysis of the mutant cornea revealed an expression profile shared by a range of dermatological diseases involving immune responses and cancer. Taken together, the data suggest that the necrotic eyelid debris plays an important role in ocular pathogenesis of the Prickle 1 mutant mouse, which may represent a type of non-infectious keratoconjunctivitis caused by damaged autologous tissues. Additionally, Prickle 1 mutant cornea pathogenesis may offer molecular insights into other types of epithelial pathogenesis.

Background The ideal surgical timings for cataract extraction (CE) and intraocular lens (IOL) implantation are vital for vision reconstruction in patients with childhood cataract (CC), yet they still remain controversial. We aimed to analyze the real-world practical pattern of surgical timings of CE and IOL implantations among a large number of Chinese CC patients. Materials and methods This cross-sectional, database study included CC inpatients from the *** over a 10-year period (from January 2005 to December 2014). Binary logistic regression and multiple linear regression analyses were performed to identify the factors affecting the timings of CE and IOL implantation. Results In the primary surgical stage, the mean ages of patients performed with CE (n = 839) and CE + IOL implantation (n = 1582) were 9.99 ± 18.21 months (5th-95th percentiles: 2–21) and 82.99 ± 52.99 months (5th-95th percentiles: 24–194), respectively. Surgical age, laterality, and axial length were identified as three factors (area under the curve [AUC]: 0.96, 95% CI: 0.94–0.97; Youden index: 0.86) affecting surgical procedure selection (CE or CE + IOL implantation) in the primary surgical stage. The time intervals between primary CE and secondary IOL implantation in bilateral (n = 311) and unilateral (n = 90) aphakia were 38.25 ± 16.84 months (5th-95th percentiles: 18–72) and 25.87 ± 10.56 months (5th-95th percentiles: 11–48), with significant difference (p Conclusions The timings of CE and IOL implantation mainly varied with the age and laterality. This study may provide data-based clinical experience for ophthalmologists regarding CE and IOL implantation of CC in China and other countries with similar socioeconomic conditions.

Purpose The tumor suppressor p53 is a master regulator of apoptosis and also plays a key role in cell cycle checking. In our previous studies, we demonstrated that p53 directly regulates Bak in mouse JB6 cells and that p53-Bak signaling axis plays an important role in mediating EGCG-induced apoptosis. Furthermore, we have recently demonstrated that the same p53-Bak apoptotic signaling axis executes an essential role in regulating lens cell differentiation. In addition, we have also shown that p53 controls both transcription factors, C-Maf and Prox-1 as well as lens crystallin genes, αA, β- and γ-crystallins. Here, we have examined whether p53 also regulates other known target genes during its modulation of lens differentiation. The human and mouse lens epithelial cells, FHL124 and αTN4-1 were cultured in Dulbecco's modified Eagle's medium (DMEM) containing 10% fetal bovine serum (FBS) and 1% Penicillin-Streptomycin. Methods Mice used in this study were handled in compliance with the "Protocol for the Care and Use of Laboratory Animals" (Sun Yat-sen University). Adult mice were used for the collection of lens cells. These samples were used for extraction of total proteins. A total of 32 embryonic mice {8 at 14.5 ED, 8 at 17.5 ED and 8 newborns for wild type} were used for immunohistochemistry, which were used for co-localization study. The mRNA levels were analysed with qRT-PCR. The protein levels were determined with western blot analysis and quantitated with Image J. Results Immunohistochemistry revealed that both the cell cycle checking genes, p21 and Gadd45α and the apoptotic genes, Bcl-2 and PUMA, display developmental changes associated with p53 during mouse lens development. Knockdown of p53 in the mouse lens epithelial cells caused inhibition of lens differentiation. Associated with this inhibition, the cell cycle genes displayed significant downreglation, the apoptotic genes was also attenuated but to a much less degree. In addition, we found that bFGF can induce dose-dependent upregulation of the upstream kinases, CHK1/2 and ERK1/2, both known to phosphorylate p53 and activate the later. Furthermore, We showed that in both developing lens and human lens epithelial cells, p53 can be co-localized with the catalytic subunit of the protein phoshphatase-1 (PP-1), suggesting that PP-1 regulates p53 phosphorylation status both in vivo and in vitro. Conclusion Taken together, our results suggest that during mouse lens development, p53 activity is regulated by ERK and CHK kinases-mediated activation, and by PP-1-mediated inactivation. p53 can regulate multiple groups of genes to mediate lens differentiation.

Purpose The purpose of this study was to investigate the change in axial length (AL) after cataract surgery measured by swept source optical coherence tomography (IOLMaster 700), and explore ways to eliminate this AL measurement error in pseudophakic eyes. Methods Patients with cataract who underwent unilateral phacoemulsification with four types of intraocular lens (IOLs) implantation (Asphina 509M, Tecnis PCB00, enVista MX60, and Acrysof SN60WF) were enrolled. Bilateral AL measurements were performed before and 1 month after cataract surgery utilizing IOLMaster 700. The postoperative AL of the operated eye was evaluated using three different modes (phakic, aphakic, and pseudophakic), and the fellow eye was measured by phakic mode. Associations among the AL change and cataract grade, lens thickness, preoperative AL, or refractive index of IOL were investigated using stepwise multivariate linear regression. Results A total of 305 patients with cataract with mean age of 65.97 ± 13.39 years were recruited. The mean postoperative AL was 0.10 mm and 0.21 mm shorter than the pre-operative AL utilizing pseudophakic and phakic modes, respectively (P < 0.001). No significant difference was observed between pre-operative and postoperative AL using aphakic mode (P = 0.264). There were no significant associations among AL change in pseudophakic eye and cataract grade, lens thickness, pre-operative AL, or refractive index of IOL (P > 0.05). Conclusions A correction factor of 0.10 mm is suggested to eliminate AL measurement error of IOLMaster 700 in pseudophakic eyes before further improvement of AL measurement accuracy. Translational Relevance Our study may help to eliminate the AL measurement error of IOLMaster 700 in pseudophakic eyes.

Background The COVID-19 pandemic has led to worldwide school closures, with millions of children confined to online learning at home. As a result, children may be susceptible to anxiety and digital eye strain, highlighting a need for population interventions. Objective The objective of our study was to investigate whether a digital behavior change intervention aimed at promoting physical activity could reduce children’s anxiety and digital eye strain while undergoing prolonged homeschooling during the COVID-19 pandemic. Methods In this cluster randomized controlled trial, homeschooled grade 7 students at 12 middle schools in southern China were recruited through local schools and randomly assigned by the school to receive (1:1 allocation): (1) health education information promoting exercise and ocular relaxation, and access to a digital behavior change intervention, with live streaming and peer sharing of promoted activities (intervention), or (2) health education information only (control). The primary outcome was change in self-reported anxiety score. Secondary outcomes included change in self-reported eye strain and sleep quality. Results On March 16, 2020, 1009 children were evaluated, and 954 (94.5%) eligible children of consenting families were included in the intention-to-treat analysis. Children in the intervention (n=485, 6 schools) and control (n=469, 6 schools) groups were aged 13.5 (SD 0.5) years, and 52.3% (n=499) were male. The assigned interventions were completed by 896 children (intervention: n=467, 96.3%; control: n=429, 91.5%). The 2-week change in square-root–transformed self-reported anxiety scores was greater in the intervention (–0.23, 95% CI –0.27 to –0.20) vs control group (0.12, 95% CI 0.09-0.16; unadjusted difference –0.36, 95% CI –0.63 to –0.08; P=.02). There was a significant reduction in square-root–transformed eye strain in the intervention group (–0.08, 95% CI –0.10 to 0.06) compared to controls (0.07, 95% CI 0.05-0.09; difference –0.15, 95% CI –0.26 to –0.03; P=.02). Change in sleep quality was similar between the two groups. Conclusions This digital behavior change intervention reduced children’s anxiety and eye strain during COVID-19–associated online schooling. Trial Registration ClinicalTrials.gov NCT04309097; http://clinicaltrials.gov/ct2/show/NCT04309097

Purpose The purpose of this study was to investigate the characteristics and risk factors of intraocular lens (IOL) tilt and decentration of phacoemulsification after pars plana vitrectomy (PPV) using swept-source optical coherence tomography (SS-OCT). Methods One hundred four eyes with prior PPV and 104 eyes without PPV undergoing uneventful cataract surgery were enrolled in this study. IOL tilt and decentration were measured by SS-OCT (CASIA2) 3 months postoperatively. Results The mean IOL tilt and decentration were greater in the PPV group (5.36 ± 2.50 degrees and 0.27 ± 0.17 mm, respectively) than in the non-PPV group (4.54 ± 1.46 degrees, P = 0.005; 0.19 ± 0.12 mm, P < 0.001, respectively). Multiple logistic regression showed that silicone oil (SO) tamponade (odds ratio [OR] = 5.659, P = 0.021) and hydrophilic IOL (OR = 5.309, P = 0.022) were associated with IOL tilt over 7 degrees, and diabetes mellitus (DM; OR = 5.544, P = 0.033) was associated with IOL decentration over 0.4 mm. Duration of SO tamponade was positively correlated with IOL tilt (P = 0.014) and decentration (P < 0.001). The internal total higher-order aberration, coma, trefoil, and secondary astigmatism in the PPV group were higher than in the non-PPV group, and positively correlated with IOL tilt (P < 0.05). Conclusions Patients with prior vitrectomy had greater IOL tilt and decentration than the non-PPV group. Longer duration of SO tamponade, hydrophilic IOL, as well as DM were the risk factors of greater IOL tilt and decentration in patients with prior PPV. Translational Relevance Optically sophisticated designed IOLs should be used cautiously in vitrectomized eyes.

Background Genetic programs underlying preimplantation development and early lineage segregation are highly conserved across mammals. It has been suggested that nonhuman primates would be better model organisms for human embryogenesis, but a limited number of studies have investigated the monkey preimplantation development. In this study, we collect single cells from cynomolgus monkey preimplantation embryos for transcriptome profiling and compare with single-cell RNA-seq data derived from human and mouse embryos. Results By weighted gene-coexpression network analysis, we found that cynomolgus gene networks have greater conservation with human embryos including a greater number of conserved hub genes than that of mouse embryos. Consistently, we found that early ICM/TE lineage-segregating genes in monkeys exhibit greater similarity with human when compared to mouse, so are the genes in signaling pathways such as LRP1 and TCF7 involving in WNT pathway. Last, we tested the role of one conserved pre-EGA hub gene, SIN3A, using a morpholino knockdown of maternal RNA transcripts in monkey embryos followed by single-cell RNA-seq. We found that SIN3A knockdown disrupts the gene-silencing program during the embryonic genome activation transition and results in developmental delay of cynomolgus embryos. Conclusion Taken together, our study provided new insight into evolutionarily conserved and divergent transcriptome dynamics during mammalian preimplantation development.

Importance: Incision-related Descemet membrane detachment (DMD) is a common complication of cataract surgery. Most postoperative severe DMD that leads to corneal decompensation originates from intraoperative incision-related DMD. It is important to determine the incidence, extent, and associated risk factors of intraoperative DMD at each step of surgery to help in formulating precise and effective prevention strategies.Objectives: To investigate the intraoperative development of incision-site DMD associated with a 2.2-mm clear corneal incision during cataract surgery and to analyze its associated factors.Design, Setting, and Participants: In this case series, consecutive, prospectively enrolled 133 patients with cataract 50 to 90 years of age (133 eyes) undergoing coaxial 2.2-mm clear corneal microincision phacoemulsification with intraocular lens (IOL) implantation between January 1 and March 31, 2019, at Zhongshan Ophthalmic Center, Sun Yat-sen University, Guangzhou, China, were studied.Exposures: Coaxial 2.2-mm clear corneal microincision phacoemulsification with IOL implantation.Main Outcomes and Measures: Real-time incidence and extent of intraoperative incision-related DMD at each step of surgery.Results: Among 133 patients with cataracts (mean [SD] age, 72.3 [8.1] years; 77 [57.9%] female), DMD was encountered in 125 eyes (94.0%), occurring at the following steps: capsulorrhexis (2 [1.6%]), hydrodissection (7 [5.6%]), phacoemulsification (69 [55.2%]), irrigation-aspiration (44 [35.2%]), and IOL implantation (3 [2.4%]). The extent of DMD increased during the operation (mean [SD] difference between final and initial relative DMD length, 22.8% [1.4%]; 95% CI, 20.0-25.6; P Conclusions and Relevance: The results of this case series suggest that friction of surgical instruments has the greatest association with incisional DMD. Decreasing ultrasonic energy and phacoemulsification time may reduce the severity of incisional DMD.

Adult stem cell identity, plasticity, and homeostasis are precisely orchestrated by lineage-restricted epigenetic and transcriptional regulatory networks. Here, by integrating super-enhancer and chromatin accessibility landscapes, we delineate core transcription regulatory circuitries (CRCs) of limbal stem/progenitor cells (LSCs) and find that RUNX1 and SMAD3 are required for maintenance of corneal epithelial identity and homeostasis. RUNX1 or SMAD3 depletion inhibits PAX6 and induces LSCs to differentiate into epidermal-like epithelial cells. RUNX1, PAX6, and SMAD3 (RPS) interact with each other and synergistically establish a CRC to govern the lineage-specific cis-regulatory atlas. Moreover, RUNX1 shapes LSC chromatin architecture via modulating H3K27ac deposition. Disturbance of RPS cooperation results in cell identity switching and dysfunction of the corneal epithelium, which is strongly linked to various human corneal diseases. Our work highlights CRC TF cooperativity for establishment of stem cell identity and lineage commitment, and provides comprehensive regulatory principles for human stratified epithelial homeostasis and pathogenesis., Corneal epithelium shares similar molecular signatures to other stratified epithelia. Here, the authors map super-enhancers and accessible chromatin in corneal epithelium, identifying a transcription regulatory circuit, including RUNX1, PAX6, and SMAD3, required for corneal epithelial identity and homeostasis.

Mutations in the CRB1 gene reportedly cause early-onset autosomal recessive retinitis pigmentosa (RP), which can result in severe loss of vision at an early age. To investigate the mechanism of CRB1-knockout (CRB1-/-) induced RP, we generated a subline of H9 human embryonic stem cells harboring frame shift mutations in a homozygous state in exon 2 of the CRB1 gene. This subline expressed pluripotent stem cell markers, presented a normal karyotype, and preserved the ability to differentiate into endodermal, mesodermal, and ectodermal lineages.

Background Strategy establishment for improving the efficiency and sustainability of cataract surgical output is important for eye health program. The aim of this study is to assess the three-year output of a novel cataract screening model integrated into establishment of resident health record in a rural area of south China. Methods A novel cataract screening model which combined private hospital screening and annual health examinations for establishing resident health record from January 2015 to December 2017 was implemented in an eye hospital in Zhaoqing, Guangdong, China. Demographic information and cataract surgery rate were recorded. A subgroup of patients who underwent cataract surgery were surveyed by customized questionnaire to determine the accessibility to eye-care services and barriers to cataract surgery. Results A total of 172,814 people aged ≥50 years in Zhaoqing were screened and 56,292 (32.57%) people were diagnosed with age-related cataract, among whom 18,422 (10.66%) with a best corrected visual acuity (BCVA) less than 20/63 were recommended for cataract surgery. Surgery was performed on 11,105 (60.28%) recommended patients. After the introduction of this screening model, the cataract surgical rate (CSR) in this area dramatically increased to 2,739/million/y (by 1.8 folds) in 2015 and 3,678/million/y (by 2.4 folds) in 2017, compared with that in 2014 (1,520/million/y). Accessibility to eye-care service was improved, and the main reason for not receiving cataract surgery changed from misconception of cataract to having good vision in the fellow eye after 3 years of screening. Conclusions This study documented the benefit of a novel cataract screening model integrated into establishment of resident health record in rural China, which may serve as a cost-effective, practicable, and sustainable strategy to disseminate cataract knowledge and eliminate cataract blindness.

Objectives Fibrotic cataract, including posterior capsule opacification (PCO) and anterior subcapsular cataract (ASC), renders millions of people visually impaired worldwide. However, the underlying mechanism remains poorly understood. Here, we report a miRNA‐based regulatory pathway that controls pathological fibrosis of lens epithelium. Materials and methods Expression of miR‐22‐3p and histone deacetylase 6 (HDAC6) in normal and PCO patient samples were measured by qPCR. Human lens epithelial explants were treated with TGF‐β2 in the presence or absence of miR‐22‐3p mimics or inhibitor. Cell proliferation was determined by MTS assay, and migration was tested by transwell assay. Expression of HDAC6 and EMT‐related molecules were analysed by Western blot, qPCR and immunocytochemical experiments. Results We identify miR‐22‐3p as a downregulated miRNA targeting HDAC6 in LECs during lens fibrosis and TGF‐β2 treatment. Mechanistically, gain‐ and loss‐of‐function experiments in human LECs and lens epithelial explants reveal that miR‐22‐3p prevents proliferation, migration and TGF‐β2 induced EMT of LECs via targeting HDAC6 and thereby promoting α‐tubulin acetylation. Moreover, pharmacological targeting of HDAC6 deacetylase with Tubacin prevents fibrotic opaque formation through increasing α‐tubulin acetylation under TGF‐β2 stimulated conditions in both human lens epithelial explants and the whole rat lenses. Conclusions These findings suggest that miR‐22‐3p prevents lens fibrotic progression by targeting HDAC6 thereby promoting α‐tubulin acetylation. The ‘miR‐22‐HDAC6‐α‐tubulin (de)acetylation’ signalling axis may be therapeutic targets for the treatment of fibrotic cataract., Schematic diagram depicting the role of ‘miR‐22‐HDAC6‐α‐tubulin (de)acetylation’ signalling axis in fibrotic cataract. miR‐22‐3p, which represses HDAC6 expression post‐transcriptionally and thereby promotes α‐tubulin acetylation, is downregulated during lens fibrosis. The ‘miR‐22‐HDAC6‐α‐tubulin (de)acetylation’ signalling axis regulates LECs proliferation, migration and EMT, the fundamental pathogenic processes trigging fibrotic cataract.

In humans, the lens is the organ with the ability to change morphology and refractive power, designated as accommodation, to focus light from various distances and obtain clear retinal image. The accommodative ability of the lens depends on its structure and biological parameters. The lens grows throughout the life, forming specific lens sutures and a unique gradient refractive index, and possesses regenerative ability under certain circumstances. Minimally invasive lens surgery that preserves endogenous lens epithelial stem/progenitor cells (LECs) can achieve functional lens regeneration in humans. The lens is the main source of intraocular aberration, especially intraocular higher-order aberrations (IHOAs) which is found to be binocularly symmetrical in phakic eyes. There is a compensation mechanism between corneal aberrations and lens aberrations. Therefore, the structure and the biological parameters of the lens, the binocular relationship of the lens and the correlation between the lens and cornea affect visual quality. This paper summarises the above findings and their current and potential applications in refractive surgeries, providing a comprehensive understanding of the lens as a strong determinant of visual quality in the optical system.

Background Acute glaucoma, characterized by a sudden elevation in intraocular pressure (IOP) and retinal ganglion cells (RGCs) death, is a major cause of irreversible blindness worldwide that lacks approved effective therapies, validated treatment targets and clear molecular mechanisms. We sought to explore the potential molecular mechanisms underlying the causal link between high IOP and glaucomatous RGCs death. Methods A murine retinal ischemia/ reperfusion (RIR) model and an in vitro oxygen and glucose deprivation/reoxygenation (OGDR) model were used to investigate the pathogenic mechanisms of acute glaucoma. Results Our findings reveal a novel mechanism of microglia-induced pyroptosis-mediated RGCs death associated with glaucomatous vision loss. Genetic deletion of gasdermin D (GSDMD), the effector of pyroptosis, markedly ameliorated the RGCs death and retinal tissue damage in acute glaucoma. Moreover, GSDMD cleavage of microglial cells was dependent on caspase-8 (CASP8)-hypoxia-inducible factor-1α (HIF-1α) signaling. Mechanistically, the newly identified nucleotide-binding leucine-rich repeat-containing receptor (NLR) family pyrin domain-containing 12 (NLRP12) collaborated with NLR family pyrin domain-containing 3 (NLRP3) and NLR family CARD domain-containing protein 4 (NLRC4) downstream of the CASP8-HIF-1α axis, to elicit pyroptotic processes and interleukin-1β (IL-1β) maturation through caspase-1 activation, facilitating pyroptosis and neuroinflammation in acute glaucoma. Interestingly, processing of IL-1β in turn magnified the CASP8-HIF-1α-NLRP12/NLRP3/NLRC4-pyroptosis circuit to accelerate inflammatory cascades. Conclusions These data not only indicate that the collaborative effects of NLRP12, NLRP3 and NLRC4 on pyroptosis are responsible for RGCs death, but also shed novel mechanistic insights into microglial pyroptosis, paving novel therapeutic avenues for the treatment of glaucoma-induced irreversible vision loss through simultaneously targeting of pyroptosis.

Purpose To compare the prediction accuracy of new intraocular lens (IOL) calculation formulas (Barrett Universal II [BUII], Emmetropia Verifying Optical [EVO], Kane and Ladas Super formula) and traditional formulas (Haigis, Hoffer Q, Holladay 1, and SRK/T) with Wang-Koch (WK) axial length (AL) adjustment in vitrectomized eyes. Design Retrospective consecutive case-series study. Methods One hundred eleven eyes of 111 patients underwent uneventful phacoemulsification and enVista MX60 implantation after vitrectomy were enrolled and divided into 4 groups according to whether the vitreous cavity was filled with silicone oil. The performance of each formula was evaluated with or without lens constant optimization. Results Before lens constants optimization, the mean prediction errors (MEs) of all formulas were statistically different from zero (0.14-0.46 diopters [D]) in vitrectomized eyes, except for the Kane formula. The BUII, EVO, Kane, and Haigis had relatively lower mean absolute error (MAE) and median absolute error (MedAE) with optimized constants. No significant systemic bias was found in new formulas for vitrectomized eyes with AL >26 mm (P > .05). The Hoffer Q and Holladay 1 displayed significantly hyperopic shift (0.39 and 0.51 D) for long eyes, which was corrected by the WK adjustment. There were no significant differences in the prediction accuracy of all formulas among 4 subgroups (P > .05). Conclusions The BUII, EVO, Kane, and Haigis displayed comparable performance in vitrectomized eyes with optimized constants. In vitrectomized highly myopic eyes, the new formulas and traditional formulas with WK adjustment exhibited satisfactory prediction accuracy. Silicone oil tamponade did not affect the prediction accuracy of formulas using IOLMaster 700.

Sumoylation is one of the key regulatory mechanisms in eukaryotes. Our previous studies reveal that sumoylation plays indispensable roles during lens differentiation (Yan et al. 2010. Proc Natl Acad Sci USA. 107:21034–21039; Gong et al. 2014. Proc Natl Acad Sci USA. 111:5574–5579). Whether sumoylation is implicated in cataractogenesis, a disease largely derived from aging, remains elusive. In the present study, we have examined the changing patterns of the sumoylation ligases and de‐sumoylation enzymes (SENPs) and their substrates including Pax6 and other proteins in cataractous lenses of different age groups from 50 to 90 years old. It is found that compared with normal lenses, sumoylation ligases 1 and 3, de‐sumoylation enzymes SENP3/7/8, and p46 Pax6 are clearly increased. In contrast, Ubc9 is significantly decreased. Among different cataract patients from 50s to 70s, male patients express more sumoylation enzymes and p46 Pax6. Ubc9 and SENP6 display age‐dependent increase. The p46 Pax6 displays age‐dependent decrease in normal lens, remains relatively stable in senile cataracts but becomes di‐sumoylated in complicated cataracts. In contrast, sumoylation of p32 Pax6 is observed in senile cataracts and increases its stability. Treatment of rat lenses with oxidative stress increases Pax6 expression without sumoylation but promotes apoptosis. Thus, our results show that the changing patterns in Ubc9, SENP6, and Pax6 levels can act as molecular markers for senile cataract and the di‐sumoylated p46 Pax6 for complicated cataract. Together, our results reveal the presence of molecular signature for both senile and complicated cataracts. Moreover, our study indicates that sumoylation is implicated in control of aging and cataractogenesis., The molecular signatures for both senile cataract and complicated cataract. Upregulation of sumoylation ligases Ubc9 and PIAS1, and de‐sumoylation enzyme SENP6, and SUMO1 conjugation of p32 Pax6 are molecular markers for senile cataract. Di‐sumoylation of p46 Pax6 is the molecular marker for complicated cataract.

In terrestrial animals, the lacrimal drainage apparatus evolved to serve as conduits for tear flow; however, little is known about the ontogenesis of this system. Here, we defined the anatomy of the fully formed tear duct (TD) in mice, characterized crucial morphogenetic events for the development of tear duct components, and identified the site for primordial tear duct (PTD) initiation. We report that the PTD originates from the orbital lacrimal lamina (LL), a junction formed by the epithelia of the maxillary (mxp) and lateral nasal processes (lnp). We demonstrate that Prickle 1, a key component of planar cell polarity (PCP) signaling, is expressed in progenitors of the PTD and throughout tear duct morphogenesis. Disruption of Prickle 1 stalls tear duct elongation; in particular, the loss of basement membrane (BM) deposition and aberrant cytoplasmic accumulation of laminin are salient. Altered cell adhesion, cytoskeletal and vesicular transport systems, and cell axis orientation in Prickle 1 mutants support the role of Prickle 1 in PCP. Taken together, we highlight a crucial role of Prickle 1-mediated polarized BM secretion and deposition in PTD elongation.

Convolutional neural networks have shown their dominance in many computer vision tasks and been broadly used for medical image analysis. Unlike traditional image-based tasks, medical data is often in 3D form. 2D Networks designed for images shows poor performance and efficiency on these tasks. Although 3D networks work better, their computation and memory cost are rather high. To solve this problem, we decompose 3D convolution to decouple volumetric information, in the same way human experts treat volume data. Inspired by the concept of three medically-defined planes, we further propose a Multi-direction Fusion (MF) module, using three branches of this factorized 3D convolution in parallel to simultaneously extract features from three different directions and assemble them together. Moreover, we suggest introducing dilated convolution to preserve resolution and enlarge receptive field for segmentation. The network with proposed modules (MFNet) achieves competitive performance with other state-of-the-art methods on BraTS 2018 brain tumor segmentation task and is much more light-weight. We believe this is an effective and efficient way for volume-based medical segmentation.

Background To investigate the safety and effectiveness of Fuaile medical adhesive (FAL) with superselective catheterization in endovascular embolotherapy for the treatment of gastrointestinal hemorrhage (GIH) that was unresponsive to internal medicine treatment and gastroscopy management. Methods A total of 25 patients with GIH, confirmed using angiography but with failed results after internal medicine treatment or gastroscopy were retrospectively analyzed. A mixture of lipiodol and FAL (1:1) was used to embolize the bleeding vessels. In the follow-up, the operation time, FAL amount, technical success rate, clinical success rate, postoperative complications, and survival conditions were compared and analyzed. Results Among the 25 patients with GIH, FAL was applied alone in 23 patients and microcoil combined with FAL was applied in two patients. Hemostasis was successfully achieved in all patients. Two patients treated with embolotherapy experienced relapse of bleeding within 30 days but achieved successful hemostasis with FAL. Four patients died during follow-up: three patients died of advanced cancer and one patient died of severe infection induced by necrotizing pancreatitis. Three patients developed postoperative intestinal ischemic symptoms, which resolved spontaneously in two patients. In one patient, abdominal pain progressively aggravated. This patient underwent surgical resection, which confirmed the presence of colonic neoplasms. The intraoperative view revealed obvious ischemia of the local normal bowel near the tumor; however, the patient finally recovered and was discharged after surgery. The remaining patients exhibited good survival during the postoperative follow-up. Conclusion FAL embolotherapy has a high success rate for arterial GIH that was unresponsive to internal medicine treatment and gastroscopy management, with low postoperative rates of bleeding and complications; thus, this method has a high cost-efficacy.

Significance Oxidative stress-induced damage to retinal pigmented epithelial (RPE) cells is critically implicated in the pathogenesis of age-related macular degeneration (AMD), a leading cause of blindness in the elderly. Here we report that oxidative stress-induced heterochromatin formation is essential to promote RPE survival. Mechanistically, oxidative damage-induced formation of heterochromatin occurs at the 53 target promoters of apoptosis genes and is regulated by p53 sumoylation. Our study demonstrates mechanistic links among chromatin conformation, p53 sumoylation, and RPE cell death. We propose that targeting heterochromatin provides a novel strategy for AMD treatment., Oxidative stress (OS)-induced retinal pigment epithelium (RPE) cell apoptosis is critically implicated in the pathogenesis of age-related macular degeneration (AMD), a leading cause of blindness in the elderly. Heterochromatin, a compact and transcriptional inert chromatin structure, has been recently shown to be dynamically regulated in response to stress stimuli. The functional mechanism of heterochromatin on OS exposure is unclear, however. Here we show that OS increases heterochromatin formation both in vivo and in vitro, which is essential for protecting RPE cells from oxidative damage. Mechanistically, OS-induced heterochromatin selectively accumulates at p53-regulated proapoptotic target promoters and inhibits their transcription. Furthermore, OS-induced desumoylation of p53 promotes p53–heterochromatin interaction and regulates p53 promoter selection, resulting in the locus-specific recruitment of heterochromatin and transcription repression. Together, our findings demonstrate a protective function of OS-induced heterochromatin formation in which p53 desumoylation-guided promoter selection and subsequent heterochromatin recruitment play a critical role. We propose that targeting heterochromatin provides a plausible therapeutic strategy for the treatment of AMD.

Background Visual function and brain function decline concurrently with aging. Notably, cataract patients often present with accelerated age-related decreases in brain function, but the underlying mechanisms are still unclear. Optical structures of the anterior segment of the eyes, such as the lens and cornea, can be readily reconstructed to improve refraction and vision quality. However, the effects of visual restoration on human brain function and structure remain largely unexplored. Methods A prospective, controlled clinical trial was conducted. Twenty-six patients with bilateral age-related cataracts (ARCs) who underwent phacoemulsification and intraocular lens implantation and 26 healthy controls without ARC, matched for age, sex, and education, were recruited. Visual functions (including visual acuity, visual evoke potential, and contrast sensitivity), the Mini-Mental State Examination and functional magnetic resonance imaging (including the fractional amplitude of low-frequency fluctuations and grey matter volume variation) were assessed for all the participants and reexamined for ARC patients after cataract surgery. This trial was registered with ClinicalTrials.gov (NCT02644720). Findings Compared with the healthy controls, the ARC patients presented decreased brain functionality as well as structural alterations in visual and cognitive-related brain areas preoperatively. Three months postoperatively, significant functional improvements were observed in the visual and cognitive-related brain areas of the patients. Six months postoperatively, the patients' grey matter volumes in these areas were significantly increased. Notably, both the function and structure in the visual and cognitive-related brain areas of the patients improved significantly and became comparable to those of the healthy controls 6 months postoperatively. Interpretation We demonstrated that ocular reconstruction can functionally and structurally reverse cataract-induced brain changes. The integrity of the eye is essential for maintaining the structure and function of the brain within and beyond the primary visual pathway., Highlights • Cataract patients with reduced visual function presented a simultaneous decrease in brain function and grey matter volume. • Cataract surgery can reverse cerebral changes in both visual and cognitive-related regions associated with visual decline. • The integrity of the eye is essential for maintaining the structure and function of the brain. The eyes and brain are anatomically and functionally connected. Age related cataract (ARC) is associated with structural and functional impairments of the brain. However, whether these changes are reversible after cataract surgery is largely unknown. We assessed the patients based on subjective cognitive evaluations and objective functional magnetic resonance imaging before and after surgery. Significant improvements in brain function and increases in the grey matter volumes of the visual, cognitive-related, and somatosensory brain areas were observed, demonstrating that the impaired brain function and structure of ARC patients can be reversed after restoration of visual acuity.

Glutamate excitotoxicity has been implicated in intracerebral hemorrhage (ICH)-induced secondary brain injury (SBI). Synaptosome associated protein 23 (SNAP23) and SNAP25 are respectively participate in presynaptic glutamate release and postsynaptic glutamate receptor (NMDA receptor) trafficking, both of which are essential for glutamate-mediated excitatory toxicity. SNAP23 and SNAP25 exhibit high homology and SNAP23 has been shown to interact with Annexin A7 (ANXA7). This study was to examine the role of ANXA7 in ICH-induced neuronal damage. A collagenase ICH model was performed in adult male Sprague Dawley rats. First, a possible relationship between ANXA7 and ICH pathology was confirmed by an increase in the protein and mRNA level of ANXA7 in the brain tissue around hematoma of ICH rats and the rescue effects of ANXA7 knockdown in vivo on neuronal death, blood-brain barrier damage, brain edema, neurobehavioral deficient, and inflammatory response. In addition, the rescue effect of ANXA7 knockdown on neurobehavioral deficient was also verified in rat autologous blood injection ICH model. Second, we found that ICH significantly increased the phosphorylation ratio of ANXA7 at the threonine residues mainly in neurons. Finally, based on site-specific mutagenesis, we identified that ANXA7 phosphorylation at threonine 286 is required for its interaction with SNAP25 at presynaptic axon terminal and SNAP23 at postsynaptic axon terminal. Collectively, our findings suggest that ANXA7 contributed to SBI at least partially through regulating glutamate toxicity after ICH. Selective inhibition of ANXA7 phosphorylation may be a novel approach to ameliorate ICH-induced SBI.

Importance Allergic conjunctivitis (AC) is one of the most common allergic diseases and is especially problematic in children and adolescents. The course of AC is generally prolonged and often recurs. Understanding the health-related quality of life (QOL) of both children with AC and their parents would be useful. Objective To evaluate the association between AC and health-related QOL in children and their parents. Design, Setting, and Participants A prospective case-control study was conducted at Zhongshan Ophthalmic Center, a single tertiary referral center, from November 16, 2019, through January 20, 2020. Participants comprised 92 children aged 5 to 18 years with AC and their parents and 96 healthy, age-matched children who served as controls and their parents. The 92 children in the AC group were subdivided into cohorts with vernal keratoconjunctivitis (VKC) (23 [25.0%]) or atopic keratoconjunctivitis (AKC) (7 [7.6%]) and seasonal allergic conjunctivitis (SAC) (26 [28.3%]) or perennial allergic conjunctivitis (PAC) (36 [39.1%]). Exposures Allergic conjunctivitis. Main Outcomes and Measures Pediatric Quality of Life Inventory, version 4.0 (PedsQL), scores for children and their parents. Scores range from 0 to 100, with higher scores indicating better health-related QOL and fewer negative aspects. Results In the AC group, 77 of 92 (83.7%) participants were boys, and 67 (72.8%) of the parents were women. Of the individuals in the control group, 55 of 96 (57.3%) of the children were girls and 76 (79.2%) of the parents were women. Median total PedsQL scores were reduced in both children with AC (69.6 [interquartile range [IQR], 66.3-72.8 vs 96.7; IQR, 92.7-98.9; P

To evaluate the efficacy and safety of hybrid revascularization by carotid endarterectomy and endovascular intervention in the treatment of chronic internal carotid artery occlusion (ICAO).We performed a retrospective analysis of patients who received hybrid treatment for symptomatic chronic ICAO between December 2016 and December 2018. Fifty-six patients with long-segment ICAO were enrolled and divided into the short duration (1-3 months) and long ICAO duration (3 months) groups, and their clinical and angiographic data were analyzed.The mean duration was 106.8 ± 36.1 days from the date of ICAO diagnosis to revascularization. Totally, 10 patients (17.8%, n = 56) in the short duration group while no patients in the long duration group failed recanalization (n = 7). Perioperative complications included intraoperative thromboembolism in 1 (1.8%) patient and subarachnoid hemorrhage in 2 (3.6%) patients. Early phase postoperative hypertension was noted in 11 (19.6%) patients and cervical hemorrhage in 1 (1.8%) patient. No severe neurological deficits occurred. Overall, the 6-month modified Rankin score, Mini-mental State Examination (MMSE) and Montreal Cognitive Assessment (MoCA) scores in patients with successful recanalization significantly improved versus the baseline (P 0.05). After successful recanalization, the long duration group demonstrated more stents for revascularization compared with the short duration group (P 0.05). Five (10.8%) patients had recurrent transient ischemic attack, and 1 (2.2%) patient developed stroke in the successful revascularization group during 6 months of follow-up. ICA restenosis occurred in 5 (8.9%) patients and re-occlusion was noted in 1 (1.8%) patient.Hybrid operation may be feasible and effective for patients with symptomatic chronic complete ICAO according to our limited data. The original occlusion site from the carotid bifurcation and the duration of ICAO should be considered as independent indicators for successful recanalization as well as perioperative outcomes.

Fibrosis is a chronic process involving development and progression of multiple diseases in various organs and is responsible for almost half of all known deaths. Epithelial–mesenchymal transition (EMT) is the vital process in organ fibrosis. Lens is an elegant biological tool to investigate the fibrosis process because of its unique biological properties. Using gain- and loss-of-function assays, and different lens fibrosis models, here we demonstrated that microRNA (miR)-26a and miR-26b, members of the miR-26 family have key roles in EMT and fibrosis. They can significantly inhibit proliferation, migration, EMT of lens epithelial cells and lens fibrosis in vitro and in vivo. Interestingly, we revealed that the mechanisms of anti-EMT effects of miR-26a and -26b are via directly targeting Jagged-1 and suppressing Jagged-1/Notch signaling. Furthermore, we provided in vitro and in vivo evidence that Jagged-1/Notch signaling is activated in TGFβ2-stimulated EMT, and blockade of Notch signaling can reverse lens epithelial cells (LECs) EMT and lens fibrosis. Given the general involvement of EMT in most fibrotic diseases, cancer metastasis and recurrence, miR-26 family and Notch pathway may have therapeutic uses in treating fibrotic diseases and cancers.

The concept of innate immunity has been expanded to recognize environmental pathogens other than microbial components. However, whether and how the innate immunity is initiated by epithelium in response to environmental physical challenges such as low humidity and high osmolarity in an autoimmune disease, dry eye, is still largely unknown. Using two experimental dry eye models, primary human corneal epithelial cultures exposed to hyperosmolarity and mouse ocular surface facing desiccating stress, we uncovered novel innate immunity pathway by ocular surface epithelium, where oxidized mitochondrial DNA induces imbalanced activation of NLRP3/NLRP6 inflammasomes via stimulation of caspase-8 and BRCC36 in response to environmental stress. Activated NLRP3 with suppressed NLRP6 stimulates caspase-1 activation that leads to IL-1β and IL-18 maturation and secretion. NLRP3-independent caspase-8 noncanonically activates caspase-1 via reciprocal regulation of NLRP3/NLRP6-mediated inflammasomes. Reactive oxygen species-induced mitochondrial DNA oxidative damage and BRCC36 deubiquitinating activity provide a missing link and mechanism by which innate immunity responds to environmental stress via caspase-8-involved NLRP3/NLRP6 inflammasomes.

Gene therapy is one of the most promising potential therapeutic strategies for many types of cancer. Cell apoptosis is an active, programmed physiological process of the body, and its disruption has been closely associated with the occurrence of tumor development. Apoptin is known to induce tumor cell apoptosis. In the present study, the MCF-7 breast cancer cell line was transfected with a human serum albumin (HSA) and apoptin expressing plasmid [HSA-polyethylenimine (PEI)-pcDNA-Apoptin]. Reverse transcription-quantitative polymerase chain reaction and western blotting were performed to detect the expression of apoptin in the transfected MCF-7 cells, while MTT assays and flow cytometry were conducted to detect cell viability and apoptosis. Furthermore, hematoxylin and eosin staining was used to observe the morphology of xenografts from mice injected with MCF-7 cells. It was demonstrated that the HSA-PEI-pcDNA-Apoptin expression plasmid resulted in the upregulation of apoptin in MCF-7 cells, and efficiently suppressed breast tumor growth in vivo. These findings indicated that the use of HSA as an apoptin expression vector has potential therapeutic benefits for cancer and confirms the requirement for the further evaluation of apoptin in clinical trials.

Purpose Lens fibrosis involves aberrant growth, migration, and transforming growth factorβ (TGFβ)-induced epithelial-mesenchymal transition (EMT) of lens epithelial cells (LECs). In this study, we investigated the role of the bromo- and extra-terminal domain (BET) inhibitor in lens fibrotic disorder to identify drug-based therapies. Methods Rat lens explants, rabbit primary lens epithelial cells (rLECs), human lens explants and human SRA01/04 cells were treated with TGFβ2 in the presence or absence of the BET bromodomain inhibitor JQ1 or the MYC inhibitor 10058-F4. Proliferation was determined by MTS assay. Cell migration was measured by wound healing and transwell assays. The expression levels of fibronectin (FN), α-smooth muscle actin (α-SMA), E-cadherin, and phosphorylated downstream Smads were analyzed by Western blot, qRT-PCR, and immunocytochemical experiments. Transcriptome analysis was conducted to explore the molecular mechanism. Results Blockage of BET bromodomains with JQ1 significantly suppressed rLECs proliferation by inducing G1 cell cycle arrest. Furthermore, JQ1 attenuated TGFβ2-dependent upregulation of mesenchymal gene expression and phosphorylation of Smad2/3 during the progression of EMT, whereas E-cadherin expression was preserved. JQ1 repressed MYC expression, which was dose- and time-dependently upregulated by TGFβ2. Inhibiting MYC with either the small-molecule inhibitor 10058-F4 or genetic knockdown phenocopied the effects of JQ1 treatment. MYC overexpression partially reversed the JQ1-regulated EMT-related alteration of gene expression. Both JQ1 and 10058-F4 blocked the expression of TGFβ receptor II and integrin αv in rLECs and abolished TGFβ2-induced opacification and subcapsular plaque formation in rat lens explants. Conclusions Our results demonstrate the antifibrotic role of JQ1 in maintaining the epithelial characteristics of LECs and blocking TGFβ2-induced EMT, possibly by downregulating MYC, thereby providing new avenues for treating lens fibrosis.

Class 2 CRISPR–Cas proteins have been widely developed as genome editing and transcriptional regulating tools. Class 1 type I CRISPR–Cas constitutes ~60% of all the CRISPR–Cas systems. However, only type I–B and I–E systems have been used to control mammalian gene expression and for genome editing. Here we demonstrate the feasibility of using type I–F system to regulate human gene expression. By fusing transcription activation domain to Pseudomonas aeruginosa type I–F Cas proteins, we activate gene transcription in human cells. In most cases, type I–F system is more efficient than other CRISPR-based systems. Transcription activation is enhanced by elongating the crRNA. In addition, we achieve multiplexed gene activation with a crRNA array. Furthermore, type I–F system activates target genes specifically without off-target transcription activation. These data demonstrate the robustness and programmability of type I–F CRISPR–Cas in human cells. Class 1 type I CRISPR–Cas systems have not been as extensively developed for genome engineering as Class 2 systems. Here the authors modify the Type I–F CRISPR–Cas system for transcriptional activation of gene expression.

Age-related macular degeneration (AMD) is a leading cause of irreversible blindness worldwide. Oxidative stress (OS), inflammation and genetics are considered the key pathogenic factors contributing to AMD development. Recent evidence shows the pro-inflammatory interleukin 17 (IL17) signaling is activated in AMD patients and promotes disease pathogenesis. However, the interplay between OS and IL17 signaling, and the regulatory mechanism of IL17 pathway are largely unknown. OS-induced retinal pigment epithelial cell (RPE) damage causes both the initial pathogenesis of AMD and secondary degeneration of rods and cones. Healthy RPE is essential for ocular immune privilege, however, damaged RPE cells can activate inflammatory response. In the present study, we identified IL17RA, the principle receptor of IL17 signaling, is one of the most upregulated inflammatory genes in human RPE cells upon OS exposure. The prominent increase of IL17RA was also observed in RPE and retina of an AMD-like mouse model. Knockdown of IL17RA in RPE cells prevented OS-induced RPE cell apoptosis and reduced the inflammatory response in both RPE and macrophages. Furthermore, we found that transcription factor KLF4 directly activates IL17RA expression, therefore, promotes the production of IL1β and IL8 in an IL17RA-dependent manner. In addition, the mRNA level of KLF4 isoform 2 was positively correlated with that of IL17RA in AMD patients. Together, our study demonstrates an unrevealed relationship between IL17RA and OS, and a new regulatory mechanism of IL17RA by KLF4 in RPE cells. These findings suggest that inhibition of IL17RA as a new potential therapeutic target for AMD through RPE protection and inflammatory suppression upon OS exposure.

Shared decision making and meaningful patient involvement are key in improving cataract treatment outcomes, but no decision aid has been formally developed and validated for this purpose. Our aims were to develop a patient decision aid to guide patients’ decision about when to undergo cataract surgery, and to determine patient’s comprehension and booklet’s acceptability. The patient decision aid was developed and included evidence-based information about general cataract, its benefits, risks of treatment options, and value clarification exercise. A total of 30 patients with age-related cataract aged between 50 and 80 years were interviewed after using either the patient decision aid (n = 15) or the traditional education booklet (n = 15). The patients who received the decision aid agreed that the information was new (n = 15, 100%), the length of the aid was “just about right” (n = 13, 87%), the information was clear and easy to understand (n = 13, 87%), the decision aid was helpful in making decision (n = 13, 87%) and would like to recommend this decision aid to others (n = 14, 93%). The decision aid was assessed positively by patients with age-related cataract. There is a need for its further verification in the context of primary eye care setting.

Background: We investigated whether specific appointments for quality-assured care could increase referral uptake, often low in China, in children's vision screening. Methods: We randomized children aged 4-7 years in Yudu, Jiangxi, China, by school to Control (free school-based eye screening, parents of children failing screening recommended for further examination [usual practice]) or Intervention (identical examinations, with parents additionally provided with specific appointments for further examinations by quality-assured doctors at a designated local hospital). Both groups could select any hospital for referral exams, which were not free. Six months after screening, parents were interviewed on referral compliance and potential determinants. Findings: Among 9936 children at 63 schools randomized to Intervention (32 schools, 5053 [50·9%] children) or Control (31 schools, 4883 [49·1%] children), 1114 children (11·2%) failed screening. Among 513 referred Intervention children (46·1%, 32 schools, mean age 5·36 years, 53·0% boys) and 601 referred Control children (53·9%, 31 schools, mean age 5·30 years, 57·7 % boys), 104 (20·3%) and 135 (22·5%) were lost to follow-up respectively. Under Intention to Treat analysis, assuming children lost to follow-up were non-compliant, Intervention children had significantly higher compliance than Controls (308/513=60·0 % vs. 225/601=37·4%, P

Purpose Dry eye disease (DED) is a common and multifactor-induced autoimmune ocular surface disease. Environmental factors, such as desiccating stress (DS) and hyperosmolarity, affect the corneal epithelium to induce ocular surface inflammation in DED. We aimed to explore the potential mechanisms by which innate immunity and pyroptosis are initiated in the mucosal epithelium in response to environmental stress. Methods Experimental dry eye was established in C57BL/6 J mice and genetic mice on the background of C57BL/6 J mice by subcutaneous injection of scopolamine and exposure to a desiccating environment. SDHCEC cell line was subjected to hyperosmolarity stress (450 mOsM). The phenol red thread tear test and corneal epithelial defects evaluation were used as assessments of severity of DED. RNA-sequencing, quantitative real-time PCR, western blotting and immunofluorescence staining were performed in this study. Results Loss-of-function studies indicated that genetic deletion of GSDMD alleviates DS-induced corneal epithelium defects, and GSDMD is needed for IL-33 processing. We further found that NLRP12 collaborates with NLRC4 inflammasome to initiate GSDMD-dependent pyroptosis, which requires TLR4-induced caspase-8 (CASP8) activation in the mucosal corneal epithelium in response to DS. Conclusions These findings provide compelling evidence that GSDMD-dependent pyroptosis plays a pivotal role in DED. A novel mechanism involving NLRP12 and NLRC4 inflammasomes-induced GSDMD-dependent pyroptosis, accompanied by IL-33 processing is responsible for ocular surface epithelial defects in response to environmental stress. GSDMD is required for IL-33 processing and the subsequent amplification of inflammatory cascades. These findings reveal novel therapeutic targets for treating DED.

Background: Approximately 1 in 33 newborns is affected by congenital anomalies worldwide. We aimed to develop a practical model for identifying infants with a high risk of congenital cataracts (CCs), which is the leading cause of avoidable childhood blindness. Methods: This case-control study was performed in the Zhongshan Ophthalmic Center and involved 2005 subjects, including 1274 children with CCs and 731 healthy controls. The CC identification models were established based on birth conditions, family medical history, and family environmental factors using the random forest (RF) and adaptive boosting methods (trained by 1129 CC cases and 609 healthy controls), which were tested by internal 4-fold cross-validation and external validation (145 CC cases and 122 healthy controls). The models were also tested using 4 datasets with gradually reduced proportions of CC patients (bilateral cases) to validate their performance in an approximate simulation of a clinical environment with a relatively low disease prevalence. Findings: The CC identification models showed high discrimination in both the 4-fold cross validation (area under the curve (AUC)=0.91 [95% confidence interval: 0.88–0.94] in bilateral cases; 0.82 [0.77–0.89] in unilateral cases) and external validation (AUC=0.93±0.05 in bilateral cases; 0.86±0.01 in unilateral cases), and achieved stable performance in the clinical tests (AUC=0.94–0.96 in the four subgroups by RF). Furthermore, family history of CC, low parental education level, and comorbidity were identified as the top three most relevant factors to both bilateral and unilateral CC diagnosis. Interpretation: Our CC identification models can accurately discriminate CC patients from healthy children and have the potential to serve as a complementary screening procedure, especially in undeveloped and remote areas. Keywords: Congenital anomaly, Congenital cataract, Identification model, Machine learning