Background: Diabetic retinopathy (DR) urgently needs novel and effective therapeutic targets. Integrated analyses of plasma proteomic and genetic markers can clarify the causal relevance of proteins and discover novel targets for diseases, but no systematic screening for DR has been performed.
Methods: Summary statistics of plasma protein quantitative trait loci (pQTL) were derived from two extensive genome-wide analysis study (GWAS) datasets and one systematic review, with over 100 thousand participants covering thousands of plasma proteins. DR data were sourced from the largest FinnGen study, comprising 10,413 DR cases and 308,633 European controls. Genetic instrumental variables were identified using multiple filters. In the two-sample MR analysis, Wald ratio and inverse variance-weighted (IVW) MR were utilized to investigate thecausality of plasma proteins with DR. Bidirectional MR, Bayesian Co-localization, and phenotype scanning were employed to test for potential reverse causality and confounding factors in the main MR analyses. By systemically searching druggable gene lists, the ChEMBL database, DrugBank, and Gene Ontology database, the druggability and relevant functional pathways of the identified proteins were systematically evaluated.
Results: Genetically predicted levels of 24 proteins were significantly associated with DR risk at a false discovery rate <0.05 including 11 with positive associations and 13 with negative associations. For each standard deviation increase in plasm protein levels, the odds ratios (ORs) for DR varied from 0.51 (95% CI: 0.36-0.73; P=2.22×10-5) for tubulin polymerization-promoting protein family member 3 (TPPP3) to 2.02 (95% CI: 1.44-2.83; P=5.01×10-5) for olfactomedin like 3 (OLFML3). Bidirectional MR indicated there was no reverse causality that interfered with the results of the main MR analyses. Four proteins exhibited strong co-localization evidence (PH4 ≥0.8): cytoplasmic tRNA synthetase (WARS), acrosin binding protein(ACRBP), and intercellular adhesion molecule 1 (ICAM1) were negatively associated with DR risk, while neurogenic locus notch homolog protein 2 (NOTCH2) showed a positive association. No confounding factors were detected between pQTLs and DR according to the phenotypic scan. Drugability assessments highlighted 6 proteins already in drug development endeavor and 18 novel drug targets, with metalloproteinase inhibitor 3 (TIMP) currently in phase I clinical trials for DR. GO analysis identified 18 of 24 plasma proteins enriching 22 pathways related to cell differentiation and proliferation regulation.
Conclusions:Twenty-four promising drug targets for DR were identified, including four plasma proteins with particular co-localization evidence. These findings offer new insights into DR's etiology and therapeutic targeting, exemplifying the value of genomic and proteomic data in drug target discovery.
Background: Diabetic retinopathy (DR) urgently needs novel and effective therapeutic targets. Integrated analyses of plasma proteomic and genetic markers can clarify the causal relevance of proteins and discover novel targets for diseases, but no systematic screening for DR has been performed.
Methods: Summary statistics of plasma protein quantitative trait loci (pQTL) were derived from two extensive genome-wide analysis study (GWAS) datasets and one systematic review, with over 100 thousand participants covering thousands of plasma proteins. DR data were sourced from the largest FinnGen study, comprising 10,413 DR cases and 308,633 European controls. Genetic instrumental variables were identified using multiple filters. In the two-sample MR analysis, Wald ratio and inverse variance-weighted (IVW) MR were utilized to investigate thecausality of plasma proteins with DR. Bidirectional MR, Bayesian Co-localization, and phenotype scanning were employed to test for potential reverse causality and confounding factors in the main MR analyses. By systemically searching druggable gene lists, the ChEMBL database, DrugBank, and Gene Ontology database, the druggability and relevant functional pathways of the identified proteins were systematically evaluated.
Results: Genetically predicted levels of 24 proteins were significantly associated with DR risk at a false discovery rate <0.05 including 11 with positive associations and 13 with negative associations. For each standard deviation increase in plasm protein levels, the odds ratios (ORs) for DR varied from 0.51 (95% CI: 0.36-0.73; P=2.22×10-5) for tubulin polymerization-promoting protein family member 3 (TPPP3) to 2.02 (95% CI: 1.44-2.83; P=5.01×10-5) for olfactomedin like 3 (OLFML3). Bidirectional MR indicated there was no reverse causality that interfered with the results of the main MR analyses. Four proteins exhibited strong co-localization evidence (PH4 ≥0.8): cytoplasmic tRNA synthetase (WARS), acrosin binding protein(ACRBP), and intercellular adhesion molecule 1 (ICAM1) were negatively associated with DR risk, while neurogenic locus notch homolog protein 2 (NOTCH2) showed a positive association. No confounding factors were detected between pQTLs and DR according to the phenotypic scan. Drugability assessments highlighted 6 proteins already in drug development endeavor and 18 novel drug targets, with metalloproteinase inhibitor 3 (TIMP) currently in phase I clinical trials for DR. GO analysis identified 18 of 24 plasma proteins enriching 22 pathways related to cell differentiation and proliferation regulation.
Conclusions:Twenty-four promising drug targets for DR were identified, including four plasma proteins with particular co-localization evidence. These findings offer new insights into DR's etiology and therapeutic targeting, exemplifying the value of genomic and proteomic data in drug target discovery.
Background: Research innovations inoculardisease screening, diagnosis, and management have been boosted by deep learning (DL) in the last decade. To assess historical research trends and current advances, we conducted an artifcial intelligence (AI)–human hybrid analysis of publications on DL in ophthalmology.
Methods: All DL-related articles in ophthalmology, which were published between 2012 and 2022 from Web of Science, were included. 500 high-impact articles annotated with key research information were used to fne-tune alarge language models (LLM) for reviewing medical literature and extracting information. After verifying the LLM's accuracy in extracting diseases and imaging modalities, we analyzed trend of DL in ophthalmology with 2 535 articles.
Results: Researchers using LLM for literature analysis were 70% (p= 0.000 1) faster than those who did not, while achieving comparable accuracy (97% versus 98%, p = 0.768 1). The field of DL in ophthalmology has grown 116% annually, paralleling trends of the broader DL domain. The publications focused mainly on diabetic retinopathy (p = 0.000 3), glaucoma (p = 0.001 1), and age-related macular diseases (p = 0.000 1) using retinal fundus photographs (FP, p = 0.001 5) and optical coherence tomography (OCT, p = 0.000 1). DL studies utilizing multimodal images have been growing, with FP and OCT combined being the most frequent. Among the 500 high-impact articles, laboratory studies constituted the majority at 65.3%. Notably, a discernible decline in model accuracy was observed when categorizing by study design, notwithstanding its statistical insignificance. Furthermore, 43 publicly available ocular image datasets were summarized.
Conclusion: This study has characterized the landscape of publications on DL in ophthalmology, by identifying the trends and breakthroughs among research topics and the fast-growing areas. This study provides an efcient framework for combined AI–human analysis to comprehensively assess the current status and future trends in the feld.
Background: Research innovations inoculardisease screening, diagnosis, and management have been boosted by deep learning (DL) in the last decade. To assess historical research trends and current advances, we conducted an artifcial intelligence (AI)–human hybrid analysis of publications on DL in ophthalmology.
Methods: All DL-related articles in ophthalmology, which were published between 2012 and 2022 from Web of Science, were included. 500 high-impact articles annotated with key research information were used to fne-tune alarge language models (LLM) for reviewing medical literature and extracting information. After verifying the LLM's accuracy in extracting diseases and imaging modalities, we analyzed trend of DL in ophthalmology with 2 535 articles.
Results: Researchers using LLM for literature analysis were 70% (p = 0.000 1) faster than those who did not, while achieving comparable accuracy (97% versus 98%, p = 0.768 1). The field of DL in ophthalmology has grown 116% annually, paralleling trends of the broader DL domain. The publications focused mainly on diabetic retinopathy (p = 0.000 3), glaucoma (p = 0.001 1), and age-related macular diseases (p = 0.000 1) using retinal fundus photographs (FP, p = 0.001 5) and optical coherence tomography (OCT, p = 0.000 1). DL studies utilizing multimodal images have been growing, with FP and OCT combined being the most frequent. Among the 500 high-impact articles, laboratory studies constituted the majority at 65.3%. Notably, a discernible decline in model accuracy was observed when categorizing by study design, notwithstanding its statistical insignificance. Furthermore, 43 publicly available ocular image datasets were summarized.
Conclusion: This study has characterized the landscape of publications on DL in ophthalmology, by identifying the trends and breakthroughs among research topics and the fast-growing areas. This study provides an efcient framework for combined AI–human analysis to comprehensively assess the current status and future trends in the feld.
哺乳动物雷帕霉素靶蛋白(mammalian target of rapamycin,mTOR)是一种蛋白激酶，在体内主要参与营养水平、生长代谢的调节。mTOR是癌症、衰老和其他代谢相关病理性疾病的重要靶点，参与了增殖、转分化、自噬等多种生物学过程。眼被认为是具有免疫特权的区域，由于血管系统会影响视力，眼的血管系统位于中心光路以外。眼的许多区域都有将免疫细胞运输至发育不良、受损或衰老有关的病变部位的机制。尽管免疫应答主要是为了修复或保护自身，但是免疫细胞可能会分泌一些细胞因子，导致炎症或纤维化，进而损害视力。研究证实，mTOR与翼状胬肉、年龄相关性黄斑变性(age-related macular degeneration,AMD)、青光眼、白内障、糖尿病视网膜病变(diabetic retinopathy,DR)、眼部肿瘤等多种眼病密切相关。目前，mTOR抑制剂通常被用作免疫抑制剂，用于癌症的治疗，但mTOR抑制剂用于眼部疾病的报道尚少。因此，该文就mTOR信号通路在相关眼科疾病中的作用、调控机制、药物治疗等方面进行简要综述，为相关眼科疾病的病理机制与治疗提供思路，以便后续开展更深入的研究。
Mammalian target protein of rapamycin (mTOR) is a protein kinase that primarily involves in the regulation of nutrient levels andgrowth metabolism in vivo. mTOR serves as a crucial target for cancer, aging, and other metabolic related pathological diseases, participating in various biological processes such as proliferation, transdifferentiation, and autophagy. Te eye is considered an area with immune privilege, as the vascular system afects vision and is located outside the central light path. Many areas of the eye have mechanisms for transporting immune cells to the afected areas related to developmental, damaged, or aging. Although the immune response is primarily aimed at reparing or protecting itself, immune cells may secrete some cytokines, leading to infammation or fbrosis, which in turn can damage vision. Results from studies have confirmed that mTOR is closely related to pterygium, age-related macular degeneration (AMD), glaucoma, cataract, diabetic retinopathy (DR), eye tumors and other eye diseases. Currently, mTOR inhibitors are widely used as immunosuppressants and approved for cancer treatment; however, there are few reports on the use of mTOR inhibitors for eye diseases. Therefore, in the article it provides a brief overview of the role, regulatory mechanisms, and drug treatment of the mTOR signaling pathway in related ophthalmic diseases, providing ideas for the pathological mechanisms and treatment of related ophthalmic diseases, in order to carry out more in-depth research in the future.
The whole lacrimal passage intubation is widely used in lacrimal surgery. However, one of the most typical complications is the prolapse of the silicone tube from the medial canthus. In case, the bicanalicular silicone tube after whole lacrimal duct intubation has completely prolapsed from the medial canthus before extubation, then cannot be found in the opening of the nasolacrimal duct, and it would be a challenge to reposition or removal. A novel approach to employ a modified suture-probe and silk thread traction technique has been developed, and it is not only safe and effective, but also cost-effective.
The whole lacrimal passage intubation is widely used in lacrimal surgery. However, one of the most typical complications is the prolapse of the silicone tube from the medial canthus. In case, the bicanalicular silicone tube after whole lacrimal duct intubation has completely prolapsed from the medial canthus before extubation, then cannot be found in the opening of the nasolacrimal duct, and it would be a challenge to reposition or removal. A novel approach to employ a modified suture-probe and silk thread traction technique has been developed, and it is not only safe and effective, but also cost-effective.
精准的屈光规划——人工晶状体屈光力计算，是屈光性白内障手术的重要前提。人工晶状体计算公式使用患者术前的眼部生物学参数如眼轴长度、角膜曲率、前房深度、晶状体厚度等指标来预测患者在白内障术后的屈光状态。人工晶状体屈光力计算公式自1967年出现以来，不断发展革新，准确性得到了极大的提升。封面展示了几种基于不同原理而构建的计算公式：回归公式(以SRK公式为代表)、基于模型眼的会聚公式(以Holladay 1等为代表)、射线追踪公式(以Olsen为代表)与人工智能公式(以RBF为代表)。目前对于普通白内障患者，现有公式能够获得良好的预测准确性。然而，对于临床上很多特殊的患者(如眼球解剖参数异常、既往有其他眼病或眼部手术史)，如何准确预测术后的屈光状态仍存在较大的挑战。路途漫漫，学者们为提升人工晶状体屈光力计算准确性的努力却从未止步，力求为患者提供最佳的白内障手术效果。
精准的屈光规划——人工晶状体屈光力计算，是屈光性白内障手术的重要前提。人工晶状体计算公式使用患者术前的眼部生物学参数如眼轴长度、角膜曲率、前房深度、晶状体厚度等指标来预测患者在白内障术后的屈光状态。人工晶状体屈光力计算公式自1967年出现以来，不断发展革新，准确性得到了极大的提升。封面展示了几种基于不同原理而构建的计算公式：回归公式(以SRK公式为代表)、基于模型眼的会聚公式(以Holladay 1等为代表)、射线追踪公式(以Olsen为代表)与人工智能公式(以RBF为代表)。目前对于普通白内障患者，现有公式能够获得良好的预测准确性。然而，对于临床上很多特殊的患者(如眼球解剖参数异常、既往有其他眼病或眼部手术史)，如何准确预测术后的屈光状态仍存在较大的挑战。路途漫漫，学者们为提升人工晶状体屈光力计算准确性的努力却从未止步，力求为患者提供最佳的白内障手术效果。
该文报道一例30岁的男性患者因“双眼自幼视力不佳，强光下视物模糊加重4年余”就诊，经过眼部检查评估，诊断为双眼瞳孔残膜、双眼屈光不正。患者接受一期双眼瞳孔残膜切除、二期双眼行有晶状体眼后房型环曲面人工晶状体(toric implantable collamer lens,TICL)植入手术，术后视力恢复良好。文章回顾了该例患者的诊治过程，为临床屈光不正同时伴有瞳孔残膜患者的诊治提供参考。
A 30-year-old male patient presented at our institution with a history of poor vision in both eyes since childhood, exacerbated by blurriness under bright light for over four years. Following a comprehensive ophthalmic examination, the patient was diagnosed with bilateral pupillary membrane remnants and refractive errors. The patient underwent a two-stage surgical intervention, starting with the removal of the pupillary membrane remnants, followed by the implantation of toric implantable collamer lenses (TICL) in the posterior chamber of the lensless eyes. Postoperative outcomes were favorable, with significant improvement in visual acuity. This article reviews the therapeutic journey of the patient, offering insights into the diagnosis and management of individuals with concurrent refractive anomalies and pupillary membrane remnants, thereby contributing to the clinical discourse on the subject.
随着角膜疾病治疗技术的不断进步，前弹力层移植技术(包括Inlay和Onlay技术)已成为晚期圆锥角膜治疗的重要手段，能有效改善患者的角膜地形图和视力结果，稳定角膜扩张，提高患者的生活质量。该文综述了前弹力层移植技术的理论基础、移植物的来源与制备技术、手术技术、临床疗效以及相关并发症，为晚期圆锥角膜的治疗提供了新的视角。研究表明，这种先进的移植技术相较于传统方法，在减少手术风险、简化手术流程以及加快术后恢复方面具有明显优势，特别是在降低异体移植物排斥反应及手术并发症的风险上，前弹力层移植表现出色。Onlay技术作为一种近期开发的新方法，其独特优势是无需剖离角膜，更好地保护角膜结构。此外这种技术的高度适应性和可逆性，为患者提供了更多的治疗选择和更好的视觉恢复。尽管如此，技术细节如移植物的尺寸和形状定制、手术深度的最优化等方面仍需进一步研究和优化，以提高整体治疗效果。
With the continuous advancement of corneal disease treatment technology, Bowman layer transplantation (including Inlay and Onlay technology) has become an important means for the treatment of advanced progressive keratoconus, which can effectively improve the corneal topography and visual acuity of patients, stabilize corneal dilation, and improve the quality of life of patients. Tis article reviews the theoretical basis of Bowman layer transplantation, the source and preparation of grafs, surgical techniques, clinical efcacy, and related complications, which provides a new perspective for the treatment of advanced keratoconus. It is stated in the research that this advanced transplantation technique has significant advantages over traditional methods in reducing surgical risks, simplifying the surgical procedures, and improving postoperative recovery. Especially in reducing the risk of allograft rejection and surgical complications, the bowman layer transplantation performs excellently. As a novel developed method, Onlay technology has the unique advantage of eliminating the need to dissect the cornea, which beter protects the corneal structure. In addition, due to the highly adaptable and reversible nature of this technique, it provides patients with more treatment options and beter visual recovery. However, in terms of technical details such as customizing the size and shape of the transplant, optimizing the surgical depth, etc., it is needed to conduct further research and optimization to improve the overall treatment efect.
因不同的眼部和神经性疾病，导致视觉功能严重受损，为低视力患者日常活动(如阅读及驾驶)及生活质量、心理健康带来严重的影响。人们对外界信息的感知主要来源于视觉，除威胁生命的重大疾病外，对人感官影响最大的损害当属视觉损伤。且随着人口日益老龄化，该问题日趋加重，低视力已成为目前全球范围内一个严重的公共卫生问题。目前，低视力康复发展面临着临床和科研的巨大挑战，要研发出一种能有效改善视觉功能，同时能兼顾多种功能的视障辅助技术，这需要医学、生物学、工程学、微电子学、计算机学等多学科的共同发展和相互合作。低视力康复通过为患者提供适宜的视障辅助技术，最大化利用患者的残余视力及视觉功能，改善与低视力相关的功能限制，有效改善其独立性和整体生活质量，使其独立生活、工作并融入社会成为可能。该文对经典的助视器、人工视觉(视觉假体/视觉感官替代设备)、经颅刺激及视觉生物反馈训练等视障辅助技术在低视力康复中的应用进展进行综述。
Patients with low vision are severely impaired in visual function due to different ocular and neurological disorders,which have a serious impact on their daily activities (such as reading and driving), quality of life and mental health.People's perception of external information mainly comes from vision. Expect for the life-threatening major diseases,visual damage has the greatest impact on people's senses. With the ageing of the population, the problem is getting worse, and low vision has become a serious public health problem in the world. Currently the development of low vision rehabilitation is facing a huge challenge in clinical and scientific research, to develop a visual impairment assistance technology that can effectively improve visual function while balancing multiple functions. It requires the joint development and cooperation of multiple disciplines such as medicine, biology, engineering, microelectronics, and computer science. Low vision rehabilitation provides patients with appropriate visual impairment assistance technology,maximizing the use of residual vision and visual function of patients, improving the functional limitations associated with low vision, effectively improving their independence and overall quality of life, and makes it possible for them to live, work and integrate into the society independently. This article reviews the progress in the application on visual impaired assistive technologies such as classic visual aids, artificial vision (visual prostheses/visual sensory replacement devices), transcranial stimulation and visual biofeedback training in low vision rehabilitation.
目的：探究T盒转录因子2(T-box transcription factor 2,TBX2)在葡萄膜黑色素瘤(uveal melanoma,UVM)中的表达水平、生存预后、免疫浸润相关性。方法：首先通过TIMER2.0数据库分析正常组织和肿瘤组织中TBX2表达和临床特征，从UCSC Xena数据库下载泛癌的生存数据，使用Cox比例风险模型和Kaplan-Meier曲线分析评估TBX2对预后的预测价值。然后使用cBioPortal数据库分析人源TBX2突变前后生存改变，通过BloodSpot和TIMER2.0数据库探究TBX2与癌症免疫浸润之间的相关性。癌症单细胞状态图谱和基因集变异分析(gene set variation analysis,GSVA)探究其表达与分子机制的相关性。结果： 15种肿瘤类型的TBX2 mRNA表达水平显著改变，TBX2是肾上腺皮质癌(adrenocortical carcinoma,ACC)、肾乳头状细胞癌(kidney renal papillary cell carcinoma,KIRP)、UVM典型的生存预后标志物。其突变与生存状态无明显相关性，在UVM中T淋巴细胞浸润水平提高导致不良预后风险升高。此外，在UVM中TBX2通路富集至ATP结合盒(ATP-binding cassette transporter,ABC)转运蛋白、DNA修复和损伤。结论：TBX2在UVM的生存和免疫浸润中起着关键作用，将来可能作为一种UVM预后及免疫治疗效果的预测因子。
Objective: To investigate the expression level of T-box transcription factor 2(TBX2) in uveal melanoma (UVM), the correlation between survival prognosis and immune infiltration. Methods: The expression and clinical features of TBX2in normal and tumorwere analyzed by TIMER2.0 database. The survival data of pancarcinoma were downloaded from UCSC Xena database, and the prognotic value of TBX2 was evaluated using Cox proportional risk model and Kaplan-Meier curve analysis. Then cBioPortal database was used to analyze the changes before and after TBX2 mutation survivalin human, and BloodSpot and TIMER2.0 databases were used to explore the correlation between TBX2 and cancer immune infiltration. Cancer single cell status mapping and gene set variation analysis (GSVA) were used to explore the correlation between its expression and molecular mechanisms. Results: The mRNA expression levels of TBX2 were significantly changed in 15 tumor types. TBX2 is adrenocortical carcinoma (ACC) and kidney renal papillary cell carcinoma (Kidney renal papillary cell carcinoma). KIRP and UVM are typical prognostic markers of survival. The mutation had no significant correlation with survival status, and increased T cell infiltration level in UVM led to increased risk of poor prognosis. In addition, the TBX2 pathway is enriched to the ATP-binding cassette transporter (ABC) transporters, DNA repair, and damage in UVM. Conclusion: TBX2 plays a key role in survival and immune invasion of uveal melanoma.and may be used as a predictor of UVM prognosis and immunotherapy effect in thefuture.
