YAP in development and disease: Navigating the regulatory landscape from retina to brain.

The distinctive role of Yes-associated protein (YAP) in the nervous system has attracted widespread attention. This comprehensive review strategically uses the retina as a vantage point, embarking on an extensive exploration of YAP's multifaceted impact from the retina to the brain in development and pathology. Initially, we explore the crucial roles of YAP in embryonic and cerebral development. Our focus then shifts to retinal development, examining in detail YAP's regulatory influence on the development of retinal pigment epithelium (RPE) and retinal progenitor cells (RPCs), and its significant effects on the hierarchical structure and functionality of the retina. We also investigate the essential contributions of YAP in maintaining retinal homeostasis, highlighting its precise regulation of retinal cell proliferation and survival. In terms of retinal-related diseases, we explore the epigenetic connections and pathophysiological regulation of YAP in diabetic retinopathy (DR), glaucoma, and proliferative vitreoretinopathy (PVR). Lastly, we broaden our exploration from the retina to the brain, emphasizing the research paradigm of "retina: a window to the brain." Special focus is given to the emerging studies on YAP in brain disorders such as Alzheimer's disease (AD) and Parkinson's disease (PD), underlining its potential therapeutic value in neurodegenerative disorders and neuroinflammation.

In vivo axial load-share ratio measurement using a novel hexapod system for safe external fixator removal.

BACKGROUND: External fixation is widely used in the treatment of traumatic fractures; however, orthopedic surgeons encounter challenges in deciding the optimal time for fixator removal. The axial load-share ratio (LS) of the fixator is a quantitative index to evaluate the stiffness of callus healing. This paper introduces an innovative method for measuring the LS and assesses the method's feasibility and efficacy. Based on a novel hexapod LS-measurement system, the proposed method is to improve the convenience and precision of measuring LS in vivo, hence facilitating the safe removal of external fixators. METHODS: A novel hexapod system is introduced, including its composition, theoretical model, and method for LS measurement. We conducted a retrospective study on 82 patients with tibial fractures treated by the Taylor Spatial Frame in our hospital from September 2018 to June 2020, of which 35 took LS measurements with our novel method (Group I), and 47 were with the traditional method (Group II). The external fixator was removed when the measurement outcome (LS < 10%) was consistent with the surgeon's diagnosis based on the clinical and radiological assessment (bone union achieved). RESULTS: No significant difference was found in the fracture healing time (mean 25.3 weeks vs. 24.9 weeks, P > 0.05), frame-wearing duration (mean 25.5 weeks vs. 25.8 weeks, P > 0.05), or LS measurement frequency (mean 1.1 times vs. 1.2 times, P > 0.05). The measurement system installation time in Group I was significantly shorter compared to Group II (mean 14.8 min vs. 81.3 min, P < 0.001). The LS value of the first measurement in Group I was lower than that of Group II (mean 5.1% vs. 6.9%, P = 0.011). In Group I, the refracture rate was 0, but in Group II it was 4.3% (2/47, P > 0.05). CONCLUSION: The novel hexapod LS-measurement system and involved method demonstrated enhanced convenience and precision in measuring the LS of the external fixator in vivo. The LS measurement indicates the callus stiffness of fracture healing, and is applicable to evaluate the safety of removing the fixator. Consequently, it is highly recommended for widespread adoption in clinical practice.

Trends in the Prevalence of Common Retinal and Optic Nerve Diseases in China: An Artificial Intelligence Based National Screening.

Purpose: Retinal and optic nerve diseases have become the primary cause of irreversible vision loss and blindness. However, there is still a lack of thorough evaluation regarding their prevalence in China. Methods: This artificial intelligence-based national screening study applied a previously developed deep learning algorithm, named the Retinal Artificial Intelligence Diagnosis System (RAIDS). De-identified personal medical records from January 2019 to December 2021 were extracted from 65 examination centers in 19 provinces of China. Crude prevalence and age-sex-adjusted prevalence were calculated by mapping to the standard population in the seventh national census. Results: In 2021, adjusted referral possible glaucoma (63.29, 95% confidence interval [CI] = 57.12-68.90 cases per 1000), epiretinal macular membrane (21.84, 95% CI = 15.64-29.22), age-related macular degeneration (13.93, 95% CI = 11.09-17.17), and diabetic retinopathy (11.33, 95% CI = 8.89-13.77) ranked the highest among 10 diseases. Female participants had significantly higher adjusted prevalence of pathologic myopia, yet a lower adjusted prevalence of diabetic retinopathy, referral possible glaucoma, and hypertensive retinopathy than male participants. From 2019 to 2021, the adjusted prevalence of retinal vein occlusion (0.99, 95% CI = 0.73-1.26 to 1.88, 95% CI = 1.42-2.44), macular hole (0.59, 95% CI = 0.41-0.82 to 1.12, 95% CI = 0.76-1.51), and hypertensive retinopathy (0.53, 95% CI = 0.40-0.67 to 0.77, 95% CI = 0.60-0.95) significantly increased. The prevalence of diabetic retinopathy in participants under 50 years old significant increased. Conclusions: Retinal and optic nerve diseases are an important public health concern in China. Further well-conceived epidemiological studies are required to validate the observed increased prevalence of diabetic retinopathy, hypertensive retinopathy, retinal vein occlusion, and macular hole nationwide. Translational Relevance: This artificial intelligence system can be a potential tool to monitor the prevalence of major retinal and optic nerve diseases over a wide geographic area.

Deep Learning Detection of Early Retinal Peripheral Degeneration From Ultra-Widefield Fundus Photographs of Asymptomatic Young Adult (17-19 Years) Candidates to Airforce Cadets.

Purpose: Artificial intelligence (AI)-assisted ultra-widefield (UWF) fundus photographic interpretation is beneficial to improve the screening of fundus abnormalities. Therefore we constructed an AI machine-learning approach and performed preliminary training and validation. Methods: We proposed a two-stage deep learning-based framework to detect early retinal peripheral degeneration using UWF images from the Chinese Air Force cadets' medical selection between February 2016 and June 2022. We developed a detection model for the localization of optic disc and macula, which are used to find the peripheral areas. Then we developed six classification models for the screening of various retinal cases. We also compared our proposed framework with two baseline models reported in the literature. The performance of the screening models was evaluated by area under the receiver operating curve (AUC) with 95% confidence interval. Results: A total of 3911 UWF fundus images were used to develop the deep learning model. The external validation included 760 UWF fundus images. The results of comparison study revealed that our proposed framework achieved competitive performance compared to existing baselines while also demonstrating significantly faster inference time. The developed classification models achieved an average AUC of 0.879 on six different retinal cases in the external validation dataset. Conclusions: Our two-stage deep learning-based framework improved the machine learning efficiency of the AI model for fundus images with high resolution and many interference factors by maximizing the retention of valid information and compressing the image file size. Translational Relevance: This machine learning model may become a new paradigm for developing UWF fundus photography AI-assisted diagnosis.

Vision rescue via unconstrained in vivo prime editing in degenerating neural retinas.

Retinitis pigmentosa (RP) is an inherited retinal dystrophy causing progressive and irreversible loss of retinal photoreceptors. Here, we developed a genome-editing tool characterized by the versatility of prime editors (PEs) and unconstrained PAM requirement of a SpCas9 variant (SpRY), referred to as PESpRY. The diseased retinas of Pde6b-associated RP mouse model were transduced via a dual AAV system packaging PESpRY for the in vivo genome editing through a non-NGG PAM (GTG). The progressing cell loss was reversed once the mutation was corrected, leading to substantial rescue of photoreceptors and production of functional PDE6ß. The treated mice exhibited significant responses in electroretinogram and displayed good performance in both passive and active avoidance tests. Moreover, they presented an apparent improvement in visual stimuli-driven optomotor responses and efficiently completed visually guided water-maze tasks. Together, our study provides convincing evidence for the prevention of vision loss caused by RP-associated gene mutations via unconstrained in vivo prime editing in the degenerating retinas.

Microglia: The breakthrough to treat neovascularization and repair blood-retinal barrier in retinopathy.

Microglia are the primary resident retinal macrophages that monitor neuronal activity in real-time and facilitate angiogenesis during retinal development. In certain retinal diseases, the activated microglia promote retinal angiogenesis in hypoxia stress through neurovascular coupling and guide neovascularization to avascular areas (e.g., the outer nuclear layer and macula lutea). Furthermore, continuously activated microglia secrete inflammatory factors and expedite the loss of the blood-retinal barrier which causes irreversible damage to the secondary death of neurons. In this review, we support microglia can be a potential cellular therapeutic target in retinopathy. We briefly describe the relevance of microglia to the retinal vasculature and blood-retinal barrier. Then we discuss the signaling pathway related to how microglia move to their destinations and regulate vascular regeneration. We summarize the properties of microglia in different retinal disease models and propose that reducing the number of pro-inflammatory microglial death and conversing microglial phenotypes from pro-inflammatory to anti-inflammatory are feasible for treating retinal neovascularization and the damaged blood-retinal barrier (BRB). Finally, we suppose that the unique properties of microglia may aid in the vascularization of retinal organoids.

Roles of Histone Acetyltransferases and Deacetylases in the Retinal Development and Diseases.

The critical role of epigenetic modification of histones in maintaining the normal function of the nervous system has attracted increasing attention. Among these modifications, the level of histone acetylation, modulated by histone acetyltransferases (HATs) and histone deacetylases (HDACs), is essential in regulating gene expression. In recent years, the research progress on the function of HDACs in retinal development and disease has advanced remarkably, while that regarding HATs remains to be investigated. Here, we overview the roles of HATs and HDACs in regulating the development of diverse retinal cells, including retinal progenitor cells, photoreceptor cells, bipolar cells, ganglion cells, and Müller glial cells. The effects of HATs and HDACs on the progression of various retinal diseases are also discussed with the highlight of the proof-of-concept research regarding the application of available HDAC inhibitors in treating retinal diseases.

Marker- three dimensional measurement versus traditional radiographic measurement in the treatment of tibial fracture using Taylor spatial frame.

BACKGROUND: The Taylor Spatial Frame (TSF) has been widely used for tibial fracture. However, traditional radiographic measurement method is complicated and the reduction accuracy is affected by various factors. The purpose of this study was to propose a new marker- three dimensional (3D) measurement method and determine the differences of reduction outcomes, if any, between marker-3D measurement method and traditional radiographic measurement in the TSF treatment. METHODS: Forty-one patients with tibial fracture treated by TSF in our institution were retrospectively analyzed from January 2016 to June 2019, including 21 patients in the marker-3D measurement group (experimental group) and 20 patients in the traditional radiographic measurement group (control group). In the experimental group, 3D reconstruction with 6 markers installed on the TSF was performed to determine the electronic prescription. In the control group, the anteroposterior (AP) and lateral radiographs were performed for the traditional parameter measurements. The effectiveness was evaluated by the residual displacement deformity (RDD) and residual angle deformity (RAD) in the coronal and sagittal plane, according to the AP and lateral X-rays after reduction. RESULTS: All patients achieved functional reduction. The residual RDD in AP view was 0.5 (0, 1.72) mm in experimental group and 1.74 (0.43, 3.67) mm in control group. The residual RAD in AP view was 0 (0, 1.25) ° in experimental group and 1.25 (0.62, 1.95) °in control group. As for the lateral view, the RDD was 0 (0, 1.22) mm in experimental group and 2.02 (0, 3.74) mm in control group, the RAD was 0 (0, 0) ° in experimental group and 1.42 (0, 1.93) ° in control group. Significant differences in all above comparisons were observed between the two groups (AP view RDD: P = 0.024, RAD: P = 0.020; Lateral view RDD: P = 0.016, RAD: P = 0.004). CONCLUSIONS: The present study introduced a marker-3D measurement method to complement the current TSF treatment. This method avoids the manual measurement error and improves the accuracy of fracture reduction, providing potential advantages of bone healing and function rehabilitation.

Intraoperative acute correction versus postoperative gradual correction for tibial shaft fractures with multiplanar posttraumatic deformities using the hexapod external fixator.

BACKGROUND: The purpose of this study was to determine the differences in clinical outcomes, if any, between intraoperative acute correction and postoperative gradual correction for tibial shaft fractures with multiplanar posttraumatic deformities using the hexapod external fixator. METHODS: We retrospectively analyzed 58 consecutive patients with tibial shaft fractures treated by the hexapod external fixator at our institution from January 2015 to April 2019. Twenty-three patients (Group I) underwent intraoperative acute correction, from January 2015 to October 2016. Starting in November 2016, the other 35 patients (Group II) all underwent postoperative gradual correction. The demographic data, operation duration, original residual deformities before correction, residual deformities after correction, and external fixation time were collected and analyzed. The clinical outcomes were evaluated by the Johner-Wruhs criteria at the last clinical visit. RESULTS: All patients achieved complete bone union with a mean time of 28.7 ± 4.6 weeks (range 21 to 37 weeks) in Group I and 27.9 ± 4.8 weeks (range 19 to 38 weeks) in Group II (P > 0.05). The operation duration in Group I (88.9 ± 7.7 min) was longer than that in Group II (61.9 ± 8.4 min), and there was a statistically significant difference (P < 0.05). There were no statistically significant differences between the two groups in original residual deformities before correction and residual deformities after correction (P > 0.05). The rate of postoperative complication was similar between the two groups. There was no statistical significance in demographic data and clinical outcomes between the two groups (P > 0.05). CONCLUSIONS: There is no difference in clinical outcomes between intraoperative acute correction and postoperative gradual correction for tibial shaft fractures with multiplanar posttraumatic deformities using the hexapod external fixator. Postoperative gradual correction may shorten the duration in the operation room and decrease the potential intraoperative risk.

Bony callus stiffness indirectly evaluated by the axial load-share ratio in vivo as a guide to removing a monolateral external fixator safely.

PURPOSE: As the monolateral external fixator is increasingly used in trauma-control and definitive management for high-energy long bone fractures, timing the fixator removal remains a challenge for surgeons. The purpose of this study was to determine the feasibility and effectiveness of the bony callus stiffness indirectly evaluated by the axial load-share ratio in vivo as a guide to removing a monolateral external fixator safely. METHODS: A total of 131 patients with tibial shaft fractures treated by the monolateral external fixator in our institution were collected from January 2013 to July 2019. In group I, the fixators were removed based on the clinical and radiological assessment only by the treating surgeon. As for group II, the axial load-share (LS) ratio test was accomplished by another medical team without the knowledge of the clinical results. The external fixator was removed when the mechanical test outcome (LS ratio < 10%) was consistent with the conclusion drawn from the clinical and radiological assessment (bone union achieved) by the treating surgeon. RESULTS: There was no statistical significance in demographic data between the two groups (P > 0.05). In group I, four patients suffered refracture (the refracture rate was 7.7%) after fixator removal and were successfully treated by an intramedullary nail. In group II, 71 patients underwent fixator removal after the first mechanical test, and another eight patients terminated the external fixation after the second test. None of the 79 patients in group II suffered refracture (the refracture rate was 0%). There was statistical significance in the refracture rate between the two groups (P < 0.05). CONCLUSION: The bony callus stiffness indirectly evaluated by the axial load-share ratio in vivo using the additional circular frame components is an effectively quantitative indicator to complement the clinical assessment of fracture healing in a monolateral external fixation treatment. Removal of the monolateral external fixator is safe when the axial load-share ratio dropped below 10%.

Correction outcomes of the postoperative malalignment salvaged by the temporary application of the hexapod external fixator in tibial diaphyseal fractures treated by monolateral external fixation.

BACKGROUND: Postoperative malalignment in fractures treated by monolateral external fixation is not uncommon in clinical practice. Accurate reduction without excessive tissue disruption caused by surgical intervention and sequentially manage the fractures using monolateral external fixation for definitive treatment is still a challenge for surgeons. The purpose of our study was to evaluate the feasibility and effectiveness of the temporary application of the hexapod external fixator (HEF) for the postoperative malalignment correction in tibial diaphyseal fractures treated by monolateral external fixation. METHODS: We carried out a retrospective analysis of 23 trauma patients with tibial diaphyseal fracture treated by the monolateral external fixation at our institution from January 2016 to May 2019. There were 21 males and 2 females with a mean age of 38 years (range 18-60 years). The hexapod external fixator was temporarily applied due to postoperative malalignment within two weeks and who unwilling to undergo a secondary surgical intervention. For patients with postoperative malalignment requiring correction, the HEF components were installed on the original existing half pins of the monolateral external fixator after removing the connecting rod. The standard anteroposterior and lateral X-rays of the injured limb combined with the temporary HEF were conducted to measure the hexapod external fixator parameters. Any residual deformities were corrected by gradual struts adjustment with the aid of computer-based software. When satisfactory alignment was achieved, the HEF was removed, and the monolateral external fixator was sequentially used as the definitive structure. RESULTS: All patients acquired functional reduction, which was evaluated by radiographs. The mean correction time was 4 days (range 2 to 8 days). The mean coronal plane translation (1.3±1.0 mm), coronal plane angulation (0.9±0.7°), sagittal plane translation (1.4±1.1 mm), and sagittal plane angulation (0.7±0.7°) after correction were all less than those (7.0±4.9 mm, 4.7±2.3°, 5.6±3.6 mm, 3.2±2.5°) before correction. CONCLUSIONS: The temporary application of the hexapod external fixator is an alternative and feasible method for the postoperative malalignment correction in tibial diaphyseal fractures treated by monolateral external fixation.

Evaluation of the reliability and validity of Functional Assessment Of Chronic Illness Therapy-Spiritual Well-Being-Expanded in elderly patients with chronic orthopaedic diseases.

BACKGROUND: The Functional Assessment Of Chronic Illness Therapy-Spiritual Well-Being-Expanded (FACIT-Sp-Ex) scale can simultaneously evaluate the quality of life and spiritual health level of patients with chronic orthopaedic diseases. We performed the FACIT-Sp-Ex scale in Chinese, and tested its reliability and validity in patients with chronic orthopaedic diseases. METHODS: There were 249 patients with chronic orthopaedic diseases who were selected for the questionnaire survey. AMOS 23.0 and SPSS 25.0 were used for statistical analysis to calculate the reliability and validity of the Chinese version of the scale. RESULTS: The Chinese version of FACIT-Sp-Ex scale showed that root mean square error of approximation (RMSEA) was 0.06. Cronbach's alpha coefficient was 0.83, the subscale was 0.72 ~ 0.82. The meaning, peace, relational subscales and total scale of the FACIT-Sp-Ex were negatively correlated with hospital anxiety and depression scale (HADS) and positively correlated with health-related quality of life (HRQOL). All four subdomains were inversely associated with HADS anxiety symptoms, the peace and relational subscales were inversely associated with HADS depressive symptoms. Elderly female patients score higher than male patients in faith subscale. The highest-scoring disease in FACIT-Sp-Ex faith scale was osteoarthritis, which in FACIT-Sp-Ex total scale are piriformis syndrome and osteoarthritis. CONCLUSION: The Chinese version of FACIT-Sp-Ex scale has good reliability and validity, which can be used as an evaluation tool for the spiritual status and quality of life of Chinese elderly chronic orthopaedic patients.

[Soft and hard tissue changes and vertical correlation of early skeletal Class â ¢ malocclusion treated with Sander â ¢ appliance].

PURPOSE: To explore the correlation between the soft and hard tissue changes and the vertical direction of early skeletal Class Ⅲ malocclusion treated with Sander Ⅲ appliance. METHODS: Thirty-two patients with skeletal Class Ⅲ malocclusion who underwent Sander Ⅲ appliance correction were enrolled. The changes of soft and hard tissues were observed before and after treatment for 12 months. The correlation between soft tissue and vertical direction was analyzed. SPSS 25.0 software package was used for statistical analysis. RESULTS: After 12 months of treatment, SNB decreased (P<0.05), ANB, A-PTV, Go-Me increased (P<0.05), soft tissue index LL-LI increased (P<0.05), LL-EP decreased (P<0.05). L1/MP was reduced after treatment (P<0.05), and U1E-PTV was increased (P<0.05). Correlation analysis showed that UL-UI was positively correlated with tilt angle, U1E-PP and U6E-PP(P<0.05); LL-LI was negatively correlated with tilt angle, U1E-PP and U6E-PP (P<0.05). Sn -UL/FH and U6E-PP were positively correlated (P<0.05). CONCLUSIONS: Sander Ⅲ appliance can effectively correct the soft and hard tissue deformity of patients with early skeletal Class Ⅲ malocclusion. The shape of the lip tends to be coordinated with the improvement of hard tissue. The soft tissue index is closely related to the vertical direction of the hard tissue.

Recurrent GNAQ mutation encoding T96S in natural killer/T cell lymphoma.

Natural killer/T cell lymphoma (NKTCL) is a rare and aggressive malignancy with a higher prevalence in Asia and South America. However, the molecular genetic mechanisms underlying NKTCL remain unclear. Here, we identify somatic mutations of GNAQ (encoding the T96S alteration of Gαq protein) in 8.7% (11/127) of NKTCL patients, through whole-exome/targeted deep sequencing. Using conditional knockout mice (Ncr1-Cre-Gnaqfl/fl), we demonstrate that Gαq deficiency leads to enhanced NK cell survival. We also find that Gαq suppresses tumor growth of NKTCL via inhibition of the AKT and MAPK signaling pathways. Moreover, the Gαq T96S mutant may act in a dominant negative manner to promote tumor growth in NKTCL. Clinically, patients with GNAQ T96S mutations have inferior survival. Taken together, we identify recurrent somatic GNAQ T96S mutations that may contribute to the pathogenesis of NKTCL. Our work thus has implications for refining our understanding of the genetic mechanisms of NKTCL and for the development of therapies.