Abstract
Age is closely related to human health and disease risks. However, chronologically defined age often disagrees with biological age, primarily due to genetic and environmental variables. ...Identifying effective indicators for biological age in clinical practice and self-monitoring is important but currently lacking. The human lens accumulates age-related changes that are amenable to rapid and objective assessment. Here, using lens photographs from 20 to 96-year-olds, we develop LensAge to reflect lens aging via deep learning. LensAge is closely correlated with chronological age of relatively healthy individuals (R
2
> 0.80, mean absolute errors of 4.25 to 4.82 years). Among the general population, we calculate the LensAge index by contrasting LensAge and chronological age to reflect the aging rate relative to peers. The LensAge index effectively reveals the risks of age-related eye and systemic disease occurrence, as well as all-cause mortality. It outperforms chronological age in reflecting age-related disease risks (
p
< 0.001). More importantly, our models can conveniently work based on smartphone photographs, suggesting suitability for routine self-examination of aging status. Overall, our study demonstrates that the LensAge index may serve as an ideal quantitative indicator for clinically assessing and self-monitoring biological age in humans.
Tacrolimus has been widely applied to prevent organ rejection after transplantation. However, the conventional pharmaceutical formulation of tacrolimus limits its applications in ocular therapy due ...to its hydrophobicity and low corneal penetrability. We optimized tacrolimus-loaded methoxy poly (ethylene glycol-block-poly (d, l)-lactic-co-glycolic acid) nanoparticles (TAC-NPs) by simple and effective nanotechnology as a drug delivery system for corneal graft rejection to overcome these drawbacks. The prepared TAC-NPs were 82.9 ± 1.3 nm in size, and the drug loading and encapsulation efficiency were 8.01 ± 0.23% and 80.10 ± 2.33%. Furthermore, New Zealand rabbits were used to analyze the single-dose pharmacokinetics of the TAC-NPs using high-performance liquid chromatography tandem mass spectrometry (HPLC-MS/MS). In rats with allogenic penetrating keratoplasty, the administration of TAC-NPs dispersion drops improved the TAC concentrations in the aqueous humor and cornea, consistent with a significantly higher effective inhibition of IL-2, IL-17, and VEGF expression compared with conventional 0.1% tacrolimus drops. Meanwhile, we also compared two different topical administration methods (including eye drop and subconjunctival injection) of TAC-NPs to maximize the sustained release characteristic of NPs. In summary, the small-sized TAC-NPs enhanced transcorneal permeation and absorption of TAC and more effectively inhibited corneal allograft rejection, which indicated that biodegradable polymeric nanomaterials-based drug delivery system had great potential for improving the clinical therapy efficacy of hydrophobic drugs.
Abstract
Artificial intelligence (AI) based on deep learning has shown excellent diagnostic performance in detecting various diseases with good-quality clinical images. Recently, AI diagnostic ...systems developed from ultra-widefield fundus (UWF) images have become popular standard-of-care tools in screening for ocular fundus diseases. However, in real-world settings, these systems must base their diagnoses on images with uncontrolled quality (“passive feeding”), leading to uncertainty about their performance. Here, using 40,562 UWF images, we develop a deep learning–based image filtering system (DLIFS) for detecting and filtering out poor-quality images in an automated fashion such that only good-quality images are transferred to the subsequent AI diagnostic system (“selective eating”). In three independent datasets from different clinical institutions, the DLIFS performed well with sensitivities of 96.9%, 95.6% and 96.6%, and specificities of 96.6%, 97.9% and 98.8%, respectively. Furthermore, we show that the application of our DLIFS significantly improves the performance of established AI diagnostic systems in real-world settings. Our work demonstrates that “selective eating” of real-world data is necessary and needs to be considered in the development of image-based AI systems.
Congenital cataracts (CCs) have significant genotypic and phenotypic heterogeneity. The major intrinsic protein (MIP) gene, one of the causative genes of CCs, plays a vital role in maintaining the ...homeostasis and transparency of the lens. In this study, we identified a unique phenotype of anterior umbilication of the lens in a four-generation pedigree with CCs. All patients in the observed family had nystagmus, nuclear cataracts, and elongated axial lengths compared with their healthy counterparts except for patient I:2, whose axial length was unavailable, and patientII:4, who had total cataracts. We confirmed, using Sanger sequencing based on whole-exon sequencing (WES) data, that all patients carried a heterozygous variant NM_012064.4:c.97C > T (NP_036196.1:p.R33C) in their MIP gene. To our knowledge, 29 variants of the human MIP gene and the relative phenotypes associated with CCs have been identified. Nevertheless, this is the first report on the anterior umbilication of the lens with nuclear or total opacity caused by the c.97C > T (p.R33C) variant in the MIP gene. These results also provide evidence that the elongated axial length might be associated with this variant. This study further confirms the phenotypic heterogeneity of CCs.
A challenge of chronic diseases that remains to be solved is how to liberate patients and medical resources from the burdens of long-term monitoring and periodic visits. Precise management based on ...artificial intelligence (AI) holds great promise; however, a clinical application that fully integrates prediction and telehealth computing has not been achieved, and further efforts are required to validate its real-world benefits. Taking congenital cataract as a representative, we used Bayesian and deep-learning algorithms to create CC-Guardian, an AI agent that incorporates individualized prediction and scheduling, and intelligent telehealth follow-up computing. Our agent exhibits high sensitivity and specificity in both internal and multi-resource validation. We integrate our agent with a web-based smartphone app and prototype a prediction-telehealth cloud platform to support our intelligent follow-up system. We then conduct a retrospective self-controlled test validating that our system not only accurately detects and addresses complications at earlier stages, but also reduces the socioeconomic burdens compared to conventional methods. This study represents a pioneering step in applying AI to achieve real medical benefits and demonstrates a novel strategy for the effective management of chronic diseases.
Purpose:
To broaden the mutation and phenotype spectrum of the
GJA8
and
CHMP4B
genes and to reveal genotype-phenotype correlations in a cohort of Chinese patients with congenital cataracts (CCs).
...Methods:
Six Chinese Han families with CCs inherited in an autosomal dominant (AD) pattern were recruited for this study. All patients underwent full ocular examinations. Genomic DNA was extracted from the leukocytes of peripheral blood collected from all available patients and their unaffected family members. Whole-exome sequencing (WES) was performed on all probands and at least one of their parents. Candidate variants were further confirmed by Sanger sequencing. Bioinformatic analysis with several computational predictive programs was performed to assess the impacts of the candidate variants on the structure and function of the proteins.
Results:
Four heterozygous candidate variants in three different genes (
CRYBB2, GJA8
, and
CHMP4B
) were identified in affected individuals from the six families, including two novel missense variants (
GJA8
: c.64G > C/p. G22R, and
CHMP4B
: c.587C > G/p. S196C), one missense mutation (
CRYBB2
: c.562C > T/p. R188C), and one small deletion (
GJA8
: c.426_440delGCTGGAGGGGACCCT/p.143_147delLEGTL). The three missense mutations were predicted as deleterious in all four computational prediction programs. In the homologous model, the
GJA8
: p.143_147delLEGTL mutation showed a sequence deletion of five amino acids at the cytoplasmic loop of the Cx50 protein, close to the third transmembrane domain. Patients carrying mutations in the same gene showed similar cataract phenotypes at a young age, including total cataracts, Y-sutural with fetal nuclear cataracts, and subcapsular cataracts.
Conclusion:
This study further expands the mutation spectrum and genotype-phenotype correlation of
CRYBB2, GJA8
, and
CHMP4B
underlying CCs. This study sheds light on the importance of comparing congenital cataract phenotypes in patients at the same age stage. It offers clues for the pathogenesis of CCs and allows for an early prenatal diagnosis for families carrying these genetic variants.
Cryptophthalmos is characterized by congenital ocular dysplasia with eyelid malformation. The pathogenicity of mutations in genes encoding components of the FRAS1/FREM protein complex is well ...established, but the underlying pathomechanisms of this disease are still unclear. In the previous study, we generated mice carrying
compound heterozygous mutations using CRISPR/Cas9 and showed that these mice recapitulated the human cryptophthalmos phenotype.
In this study, we tracked changes in the metabolic profile of embryos and expression of metabolism-related genes in
mutant mice on E13.5 compared with wild-type mice. RNA sequencing (RNA-seq) was utilized to decipher the differentiated expression of genes associated with metabolism. Untargeted metabolomics and targeted metabolomics analyses were performed to detect and verify the shifts in the composition of the embryonic metabolome.
Differentially expressed genes participating in amino acid metabolism and energy metabolism were observed by RNA-seq. Transcriptomic analysis suggests that 821 (39.89%) up-regulated genes and 320 (32.99%) down-regulated genes were involved in the metabolic process in the enriched GO terms. A total of 92 significantly different metabolites were identified including creatine, guanosine 5'-monophosphate, cytosine, cytidine 5'-monophosphate, adenine, and L-serine. Interestingly, major shifts related to ATP binding cassette transporters (ABC transporters) and the biosynthesis of amino acids in the composition of the embryonic metabolome were observed by KEGG metabolic analysis, indicating that these pathways could also be involved in the pathogenesis of cryptophthalmos.
We demonstrate that
mutant fetal mice have increased susceptibility to the disruption of eye morphogenesis in association with distinct transcriptomic and metabolomic signatures. Our findings suggest that the metabolomic signature established before birth may play a role in mediating cryptophthalmos in
mutant mice, which may have important implications for the pathogenesis of cryptophthalmos.
Background/AimsTo develop a deep learning system for automated glaucomatous optic neuropathy (GON) detection using ultra-widefield fundus (UWF) images.MethodsWe trained, validated and externally ...evaluated a deep learning system for GON detection based on 22 972 UWF images from 10 590 subjects that were collected at 4 different institutions in China and Japan. The InceptionResNetV2 neural network architecture was used to develop the system. The area under the receiver operating characteristic curve (AUC), sensitivity and specificity were used to assess the performance of detecting GON by the system. The data set from the Zhongshan Ophthalmic Center (ZOC) was selected to compare the performance of the system to that of ophthalmologists who mainly conducted UWF image analysis in clinics.ResultsThe system for GON detection achieved AUCs of 0.983–0.999 with sensitivities of 97.5–98.2% and specificities of 94.3–98.4% in four independent data sets. The most common reasons for false-negative results were confounding optic disc characteristics caused by high myopia or pathological myopia (n=39 (53%)). The leading cause for false-positive results was having other fundus lesions (n=401 (96%)). The performance of the system in the ZOC data set was comparable to that of an experienced ophthalmologist (p>0.05).ConclusionOur deep learning system can accurately detect GON from UWF images in an automated fashion. It may be used as a screening tool to improve the accessibility of screening and promote the early diagnosis and management of glaucoma.
Posterior capsule opacification (PCO), resulting from residual lens epithelial cell (LEC) epithelial–mesenchymal transition (EMT), abnormal proliferation, and migration, is the most common ...complication of cataract surgery. A recent study determined that extracellular vesicles (EVs) and reactive oxygen species (ROS) regulate the EMT process during cutaneous wound healing and tumour metastasis. However, their underlying mechanism in PCO is unclear. In this study, we examined the secreted EVs from a scratch model in vitro. We found that the production of ROS was increased after mechanical injury, especially at the wound edge, and there was an increased viability of LECs, which can be blocked by diphenyleneiodonium, an NADPH oxidase inhibitor. Cell viability and migration were increased upon treatment with 1 μM H2O2, but significantly reduced when the concentration of H2O2 increased to 100 μM. Transwell assay showed that both post-surgery LECs and LECs treated with 1 μM H2O2 significantly induced the migration of normal LECs by EV secretion. Extraction and quantification of EVs derived from injured and H2O2-treated LECs showed a similar increase in production. Co-incubation of EVs from both injured and H2O2-treated LECs with normal LECs and organ-cultured mouse lenses activated EMT, which was attenuated by a ROS inhibitor. These results suggest that EVs participate in ROS-induced lens EMT, making EVs a potential target for treating PCO.
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