Comprehensive genetic analysis uncovers the mutational spectrum of MFRP and its genotype-phenotype correlation in a large cohort of Chinese microphthalmia patients.

PURPOSE: Microphthalmia is a severe congenital ocular disease featured by abnormal ocular development. The aim of this study was to detail the genetic and clinical characteristics of a large cohort of Chinese patients with microphthalmia related to MFRP variants, focusing on uncovering genotype-phenotype correlations. METHODS: Fifty microphthalmia patients from 44 unrelated Chinese families were recruited. Whole-exome sequencing (WES) was conducted to analyze the coding regions and adjacent intronic regions of MFRP. Axial lengths (AL) were measured for all probands and available family members. Protein structures of mutations with high frequency in our cohort were predicted. The genotype-phenotype correlations were explored by statistical analysis. RESULTS: Sixteen MFRP variants were detected in 17 families, accounting for 38.64 % of all microphthalmia families. There were 9 novel mutations (c.427+1G>C, c.428-2A>C, c.561_575del:p.A188_E192del, c.836G>A:p.C279Y, c.1010_1021del:p.H337_E340del:p.Y479*, c.1516_1517del:p.S506Pfs*66, c.1561T>G:p.C521G, c.1616G>A:p.R539H, and c.1735C>T:p.P579S) and six previously reported variants in MFRP, with p.E496K and p.H337_E340del being highly frequent, found in eight (47.06 %) and two families (11.76 %), respectively. Seven variants (43.75 %) were located in the C-terminal cysteine-rich frizzled-related domain (CRD) (7/16, 43.75 %). Protein prediction implicated p.E496K and p.H337_E340del mutations might lead to a destabilization of the MFRP protein. The average AL of all 42 eyes was 16.02 ± 1.05 mm, and 78.36 % of eyes with AL < 16 mm harbored p.E496K variant. Twenty-six eyes with variant variant had shorter AL than that of the other 16 eyes without this variant (p = 0.006), highlighting a novel genotype-phenotype correlation. CONCLUSIONS: In this largest cohort of Chinese patients with microphthalmia, the 9 novel variants, high frequency of p.E496W, and mutation hotspots in CRD reveals unique insights into the MFRP mutation spectrum among Chinese patients, indicating ethnic variability. A new genotype-phenotype correlation that p.E496K variant associated with a shorter AL is unveiled. Our findings enhance the current knowledge of MFRP-associated microphthalmia and provide valuable information for prenatal diagnosis as well as future therapy.

Cross-modal digit span and vocabulary proficiency in deaf or hard-of-hearing children.

This study aims to examine the relationship between vocabulary proficiency and short-term memory capacity in deaf or hard-of-hearing (DHH) children. We test the hypothesis that the relationship between vocabulary skills and digit span performance could be strengthened when the digit span task encompasses cross-modal integration processes. A group of DHH children performed two types of auditory digit span tasks. Furthermore, they participated in a standardized vocabulary proficiency test, comprising two subtests: Receptive Vocabulary and Expressive Vocabulary. The verbal digit span served as a significant predictor of Expressive Vocabulary among the DHH children. Simultaneously, the auditory-pointing digit span accounted for a substantial portion of performance variation in both Receptive and Expressive Vocabulary. After considering the impact of the duration of auditory-verbal intervention through regression models, likelihood ratio tests demonstrated that the auditory-pointing digit span persisted as a significant determinant of both receptive and expressive vocabulary skills. A positive influence of the intervention was also confirmed by the present results. This study provides evidence that memory span and the ability to integrate cross-modal information could serve as significant cognitive correlates of vocabulary proficiency in DHH children.

Clinical Characteristics of Microcystic Macular Edema in Chronic Primary Angle-Closure Glaucoma and Primary Open-Angle Glaucoma Patients.

INTRODUCTION: This study investigated the clinical characteristics of and risk factors for microcystic macular edema (MME) in patients with chronic primary angle-closure glaucoma (CPACG) and primary open-angle glaucoma (POAG). METHODS: This retrospective observational study included 1,588 eyes from 926 glaucoma inpatients and analyzed the patients' basic demographic information, visual field parameters, macular scans, and peripapillary retinal nerve fiber layer thickness. RESULTS: Our findings were that the incidence rate of MME was 3.97% (34/857) in CPACG and 5.88% (43/731) in POAG. MME was predominantly diagnosed at an advanced stage in CPACG (almost 100%) compared to POAG (93.02%). MME was most frequently involved in the inferior (83.12%) quadrant of the peri-macular region in both CPACG and POAG. Risk factors for MME occurrence in CPACG and POAG included lower visual field mean deviation (OR = 1.14, 95%: CI 1.05-1.24, p = 0.003; OR = 1.14, 95% CI: 1.06-1.21, p < 0.001) and younger age (OR = 0.92, 95% CI: 0.88-0.96, p < 0.001; OR = 0.96, 95% CI: 0.93-0.99, p = 0.003), while female sex (OR = 0.30, 95% CI: 0.11-0.84, p = 0.022) reduced the MME occurrence in POAG. CONCLUSION: MME could develop in both CPACG and POAG patients, occurring earlier in POAG. The inferior peri-macular region is commonly affected. Younger age and poorer visual field are risk factors for MME in glaucoma patients.

Effect of an artificial intelligence-assisted system on endoscopic diagnosis of superficial oesophageal squamous cell carcinoma and precancerous lesions: a multicentre, tandem, double-blind, randomised controlled trial.

BACKGROUND: Despite the usefulness of white light endoscopy (WLE) and non-magnified narrow-band imaging (NBI) for screening for superficial oesophageal squamous cell carcinoma and precancerous lesions, these lesions might be missed due to their subtle features and interpretation variations among endoscopists. Our team has developed an artificial intelligence (AI) system to detect superficial oesophageal squamous cell carcinoma and precancerous lesions using WLE and non-magnified NBI. We aimed to evaluate the auxiliary diagnostic performance of the AI system in a real clinical setting. METHODS: We did a multicentre, tandem, double-blind, randomised controlled trial at 12 hospitals in China. Eligible patients were aged 18 years or older and underwent sedated upper gastrointestinal endoscopy for screening, investigation of gastrointestinal symptoms, or surveillance. Patients were randomly assigned (1:1) to either the AI-first group or the routine-first group using a computerised random number generator. Patients, pathologists, and statistical analysts were masked to group assignment, whereas endoscopists and research assistants were not. The same endoscopist at each centre did tandem upper gastrointestinal endoscopy for each eligible patient on the same day. In the AI-first group, the endoscopist did the first examination with the assistance of the AI system and the second examination without it. In the routine-first group, the order of examinations was reversed. The primary outcome was the miss rate of superficial oesophageal squamous cell carcinoma and precancerous lesions, calculated on a per-lesion and per-patient basis. All analyses were done on a per-protocol basis. This trial is registered with the Chinese Clinical Trial Registry (ChiCTR2100052116) and is completed. FINDINGS: Between Oct 19, 2021, and June 8, 2022, 5934 patients were randomly assigned to the AI-first group and 5912 to the routine-first group, of whom 5865 and 5850 were eligible for analysis. Per-lesion miss rates were 1·7% (2/118; 95% CI 0·0-4·0) in the AI-first group versus 6·7% (6/90; 1·5-11·8) in the routine-first group (risk ratio 0·25, 95% CI 0·06-1·08; p=0·079). Per-patient miss rates were 1·9% (2/106; 0·0-4·5) in AI-first group versus 5·1% (4/79; 0·2-9·9) in the routine-first group (0·37, 0·08-1·71; p=0·40). Bleeding after biopsy of oesophageal lesions was observed in 13 (0·2%) patients in the AI-first group and 11 (0·2%) patients in the routine-first group. No serious adverse events were reported by patients in either group. INTERPRETATION: The observed effect of AI-assisted endoscopy on the per-lesion and per-patient miss rates of superficial oesophageal squamous cell carcinoma and precancerous lesions under WLE and non-magnified NBI was consistent with substantial benefit through to a neutral or small negative effect. The effectiveness and cost-benefit of this AI system in real-world clinical settings remain to be further assessed. FUNDING: National Natural Science Foundation of China, 1·3·5 project for disciplines of excellence, West China Hospital, Sichuan University, and Chengdu Science and Technology Project. TRANSLATION: For the Chinese translation of the abstract see Supplementary Materials section.

Anterior vitrectomy, phacoemulsification cataract extraction and irido-zonulo-hyaloid-vitrectomy in protracted acute angle closure crisis.

PURPOSE: To describe a modified surgical approach with anterior vitrectomy, phacoemulsification (phaco) cataract extraction and irido-zonulo-hyaloid-vitrectomy (IZHV) in protracted acute angle closure crisis (AACC). PATIENTS AND METHODS: Non-comparative, retrospective case series including 21 eyes in 19 consecutive cases of protracted AACC, which persists for at least 7 days despite maximal medical and laser therapies, were included in this study. All patients underwent a modified surgical procedure with anterior vitrectomy, phaco cataract extraction, IOL implantation, goniosynechialysis (GSL) and IZHV, using modest phaco dynamic parameters with intraocular pressure (IOP) set at 30 mmHg through the procedure using Centurion® Vision System equipped with active fluidics while the anterior vitrectomy was set at 4000 or 5000 rpm. IOP and anterior chamber space were maintained through the procedure using ophthalmic viscosurgical device (OVD) injected through paracentesis whenever the Phaco or I/A probe was withdrawn from within the anterior chamber. Medical history, visual acuity (VA), IOP and anterior and posterior segment findings were recorded and compared before and after surgical treatment. RESULTS: The average age of all patients was 60.05 years old, while the average period of persistent AACC was 20.05 days. Preoperatively, the average IOP of all included eyes was 44.40 ± 8.42 mmHg despite maximal topical and systemic anti-glaucoma medications and/or laser surgeries, while the average VA was 1.46 ± 0.88 (log MAR). Postoperatively, IOP was well controlled in all patients with an average IOP at 12.06 ± 3.07 mmHg without any anti-glaucoma medications at follow-ups, which was decreased significantly from that in preoperative measurements (P < 0.001). Visual acuity was improved significantly at final follow-up with an average postoperative VA at 0.74 ± 0.77 (log MAR, P < 0.001). Anterior segment inflammation was surprisingly mild with no or minimal inflammatory cells or exudates. Anterior segment configuration was resolved in all the cases. There was no recurrent IOP spike, anterior chamber shallowing or severe complications during an average follow-up of 5.38 months (ranging from 3 to 6 months). CONCLUSIONS: Protracted AACC is a complex situation while a modified surgical strategy of anterior vitrectomy, phaco cataract extraction and IZHV provides a safe and efficient solution.

Nanophthalmos-Associated MYRF Gene Mutation Causes Ciliary Zonule Defects in Mice.

Purpose: Patients with nanophthalmos who undergo intraocular surgery often present with abnormal ciliary zonules. In a previous study, we reported mutation in MYRF that is implicated in the pathogenesis of nanophthalmos. The aim of this study was to model the mutation in mice to explore the role of MYRF on zonule structure and its major molecular composition, including FBN1 and FBN2. Methods: Human MYRF nanophthalmos frameshift mutation was generated in mouse using the CRISPR-Cas9 system. PCR and Sanger sequencing were used for genotype analysis of the mice model. Anterior chamber depth (ACD) was measured using hematoxylin and eosin-stained histology samples. Morphologic analysis of ciliary zonules was carried out using silver staining and immunofluorescence. Transcript and protein expression levels of MYRF, FBN1, and FBN2 in ciliary bodies were quantified using quantitative real-time PCR (qRT-PCR) and Western blot. Results: A nanophthalmos frameshift mutation (c.789delC, p.N264fs) of MYRF in mice showed ocular phenotypes similar to those reported in patients with nanophthalmos. ACD was reduced in MYRF mutant mice (MYRFmut/+) compared with that in littermate control mice (MYRF+/+). In addition, the morphology of ciliary zonules showed reduced zonular fiber density and detectable structural dehiscence of zonular fibers. Furthermore, qRT-PCR analysis and Western blot showed a significant decrease in mRNA expression levels of MYRF, FBN1, and FBN2 in MYRFmut/+ mice. Conclusions: Changes in the structure and major molecular composition of ciliary zonules accompanied with shallowing anterior chamber were detected in MYRFmut/+ mice. Therefore, MYRF mutant mice strain is a useful model for exploring pathogenesis of zonulopathy, which is almost elusive for basic researches due to lack of appropriate animal models.

Auditory memory span in Mandarin-speaking preschoolers with congenital hearing loss: Impact of task structure.

Objective: The current research was conducted to test the prediction that children who have hearing loss and are developing spoken language can perform at the same level as hearing children in an auditory memory span task if actual production of speech is excluded from task requirement.Method: A listen-and-point digit span task and two sub-tests of Wechsler Intelligence Scale for Children-IV (Verbal Digit Span and Matrix Reasoning) were administered to thirty hearing children and thirty-three children with hearing loss. A language assessment instrument for Mandarin-speaking preschool children was also administered to the participants with hearing loss.Results: The listen-and-point task not only correlated with the Verbal Digit Span sub-test, but also correlated with the comprehension sub-test of the language assessment instrument. The size of auditory memory span was similar in both groups of participants in the listen-and-point task. Moreover, the memory span estimated in the listen-and-point task was smaller than that estimated in the Verbal Digit Span task. The correlation coefficients between chronological age and the listen-and-point task were also similar in both groups of children.Conclusions: When speech processes are not required in an auditory working memory task, demand for the phonological loop is reduced and the children with hearing loss are able to perform as well as the hearing children. Moreover, the auditory memory span develops at the same rate for the children with hearing loss as for the hearing children.