Disease-specific variant interpretation highlighted the genetic findings in 2325 Japanese patients with retinitis pigmentosa and allied diseases.

BACKGROUND: As gene-specific therapy for inherited retinal dystrophy (IRD) advances, unified variant interpretation across institutes is becoming increasingly important. This study aims to update the genetic findings of 86 retinitis pigmentosa (RP)-related genes in a large number of Japanese patients with RP by applying the standardised variant interpretation guidelines for Japanese patients with IRD (J-IRD-VI guidelines) built upon the American College of Medical Genetics and Genomics and the Association for Molecular Pathology rules, and assess the contribution of these genes in RP-allied diseases. METHODS: We assessed 2325 probands with RP (n=2155, including n=1204 sequenced previously with the same sequencing panel) and allied diseases (n=170, newly analysed), including Usher syndrome, Leber congenital amaurosis and cone-rod dystrophy (CRD). Target sequencing using a panel of 86 genes was performed. The variants were interpreted according to the J-IRD-VI guidelines. RESULTS: A total of 3564 variants were detected, of which 524 variants were interpreted as pathogenic or likely pathogenic. Among these 524 variants, 280 (53.4%) had been either undetected or interpreted as variants of unknown significance or benign variants in our earlier study of 1204 patients with RP. This led to a genetic diagnostic rate in 38.6% of patients with RP, with EYS accounting for 46.7% of the genetically solved patients, showing a 9% increase in diagnostic rate from our earlier study. The genetic diagnostic rate for patients with CRD was 28.2%, with RP-related genes significantly contributing over other allied diseases. CONCLUSION: A large-scale genetic analysis using the J-IRD-VI guidelines highlighted the population-specific genetic findings for Japanese patients with IRD; these findings serve as a foundation for the clinical application of gene-specific therapies.

Impact of hormesis to deepen our understanding of the mechanisms underlying the bioactivities of polyphenols.

Cells, organs, and the whole body are continuously exposed to various types of stressors, including oxidative stress, protein denaturation, hypoxia, energy starvation, and pathogen insults. Hormesis is an adaptive phenomenon in which a stressor induces cellular stress responses at low or moderate doses, while catastrophic damage is manifested at high doses. Polyphenols, as xenobiotic phytochemicals, exhibit stress responses in animal cells, as demonstrated in cellular and rodent models. In this review article, the author highlighted several molecular mechanisms underlying different types of stress adaptation and hormetic phenomena induced by bioactive polyphenols to substantially understand how and why those phytochemicals function in biological systems.

Retinal neurovascular alteration in type 2 diabetes with renal impairment in association with systemic arterial stiffness.

BACKGROUND: Diabetic retinopathy (DR) patients should be alert for subclinical macroangiopathy. We aimed to investigate the association between retinal neurovascular alteration and systemic arterial stiffness in type 2 diabetes mellitus (type 2 DM) patients with varying degrees of renal impairment. METHODS: The study included 170 patients with confirmed diagnosis of type 2 DM aged ≥18 years old. Renal function was assessed by estimated glomerular filtration rate (eGFR). Arterial stiffness was measured by brachial-ankle pulse wave velocity (baPWV) and ankle brachial index (ABI). Retinal neurovascular parameters were derived from Optical Coherence Tomography (OCT)/OCT-Angiography, represented by vessel density (VD Central, Inner, Outer, Full), foveal avascular zone (FAZ area and FAZ perimeter) of the superficial capillary plexus, the average of macular ganglion cell-inner plexiform layer thickness (ave mGC-IPLt) and the average of retinal nerve fiber layer thickness (aveRNFLt). The association between variables among the groups (according to renal function, diabetic retinopathy (DR) severity, and arterial stiffness categories) were analyzed by regression analysis with multiple hypothesis testing commands. RESULTS: Out of the 265 eyes, the mean DM duration and HbA1c were 6.21 ± 6.37 years and 8.44 ± 2.06% respectively. While the mean of eGFR, baPWV and ABI were 66.78 ± 32.80 ml/min/1.73m2, 15.49 ± 3.07 m/s, and 1.05 ± 0.12, respectively. Patients with more severe renal impairment demonstrated longer DM duration (p < 0.001), higher baPWV (p < 0.0001), and retinal vascular alteration. Proliverative DR group showed the lowest eGFR (p < 0.0001), highest baPWV (p < 0.0001), and retinal neurovascular changes. Significantly lower eGFR and retinal vascular alteration were found in the baPWV > 14 group. Some neurovascular parameters were significantly negatively correlated with baPWV; moreover, retinal neurovascular changes were also noted in the abnormal ABI group. CONCLUSIONS: The strong association between changes in the retinal neurovascular system, DR severity, renal impairment, and arterial stiffness in type 2 DM was confirmed. Patients with more severe renal impairment had higher levels of arterial stiffness, more severe DR and retinal neurovascular alteration. Retinal neurovascular changes seen in OCT/OCTA might mimic renal microvascular alteration and systemic arterial stiffness. Therefore, assessment of baPWV and OCT/OCTA should be integrated in DR screening to enhance cardiovascular risk stratification and prognosis as well as to provide clinically useful early identification of subclinical micro- and macrovascular alterations.

Developments of inverse analysis by Kalman filters and Bayesian methods applied to geotechnical engineering.

The present paper reviews recent activities on inverse analysis strategies in geotechnical engineering using Kalman filters, nonlinear Kalman filters, and Markov chain Monte Carlo (MCMC)/Hamiltonian Monte Carlo (HMC) methods. Nonlinear Kalman filters with finite element method (FEM) broaden the choices of unknowns to be determined for not only parameters but also initial and/or boundary conditions, and the use of the posterior probability of the state variables can be widely applied to, for example, the decision making for design changes. The relevance of the unknowns and the observed values and the selection of the best sensor locations are some of the considerations made while using the Kalman filter FEM. This paper demonstrates several real-world geotechnical applications of the nonlinear Kalman filter and the MCMC with FEM. Future studies should focus on the following areas: attaining excellent performance for long-term forecasts using short-term observation and developing a viable method for selecting equations that describe physical phenomena and constitutive models.

A nerve-goblet cell association promotes allergic conjunctivitis through rapid antigen passage.

The penetration of allergens through the epithelial layer is the initial step in the development of allergic conjunctivitis. Although pollinosis patients manifest symptoms within minutes after pollen exposure, the mechanisms of the rapid transport of the allergens remain unclear. In the present study, we found that the instillation of pollen shells rapidly induces a large number of goblet cell-associated antigen passages (GAPs) in the conjunctiva. Antigen acquisition by stromal cells, including macrophages and CD11b+ dendritic cells, correlated with surface GAP formation. Furthermore, a substantial amount of antigen was transported to the stroma during the first 10 minutes of pollen exposure, which was sufficient for the full induction of an allergic conjunctivitis mouse model. This inducible, rapid GAP formation and antigen acquisition were suppressed by topical lidocaine or trigeminal nerve ablation, indicating that the sensory nervous system plays an essential role. Interestingly, pollen shell-stimulated GAP formation was not suppressed by topical atropine, suggesting that the conjunctival GAPs and intestinal GAPs are differentially regulated. These results identify pollen shell-induced GAP as a therapeutic target for allergic conjunctivitis.

Role of Extracellular Vesicles in Absorption and Functional Mechanisms of Quercetin.

SCOPE: Quercetin (QUE), a phytochemical found in various plant foods, has been shown to have a variety of physiological activities in vivo, though biological sites where it has activities and the mechanisms of transport have not been fully elucidated. METHODS AND RESULTS: In the present study, intracellular uptake of QUE into HT-29 human colon adenocarcinoma cells is found to result in spontaneous release of extracellular vesicles (EVs), which are subsequently embedded with QUE. In addition, QUE-embedded EVs are detected in serum of QUE-administered Sprague-Dawley rats. Interestingly, the rate of cellular uptake of QUE-encapsulated EVs (EV-QUE) into RAW264.7 macrophages is markedly higher than that of free QUE. Moreover, EV-QUE suppresses lipopolysaccharide (LPS)-induced nitric oxide at a lower concentration than free QUE. CONCLUSION: The present findings suggest that QUE may be embedded in EVs in the gastrointestinal tract, then become absorbed and enter the bloodstream to exhibit biological activities.

Using the AllerSearch Smartphone App to Assess the Association Between Dry Eye and Hay Fever: mHealth-Based Cross-Sectional Study.

BACKGROUND: Dry eye (DE) and hay fever (HF) show synergistic exacerbation of each other's pathology through inflammatory pathways. OBJECTIVE: This study aimed to investigate the association between DE and HF comorbidity and the related risk factors. METHODS: A cross-sectional observational study was conducted using crowdsourced multidimensional data from individuals who downloaded the AllerSearch smartphone app in Japan between February 2018 and May 2020. AllerSearch collected the demographics, medical history, lifestyle and residential information, HF status, DE symptoms, and HF-related quality of life. HF symptoms were evaluated using the nasal symptom score (0-15 points) and nonnasal symptom score (0-12 points). HF was defined by the participants' responses to the questionnaire as HF, non-HF, or unknown. Symptomatic DE was defined as an Ocular Surface Disease Index total score (0-100 points), with a threshold score of 13 points. HF-related quality of life was assessed using the Japanese Allergic Conjunctival Disease Standard Quality of Life Questionnaire (0-68 points). We conducted a multivariable linear regression analysis to examine the association between the severity of DE and HF symptoms. We subsequently conducted a multivariable logistic regression analysis to identify the factors associated with symptomatic DE (vs nonsymptomatic DE) among individuals with HF. Dimension reduction via Uniform Manifold Approximation and Projection stratified the comorbid DE and HF symptoms. The symptom profiles in each cluster were identified using hierarchical heat maps. RESULTS: This study included 11,284 participants, classified into experiencing HF (9041 participants), non-HF (720 participants), and unknown (1523 participants) groups. The prevalence of symptomatic DE among individuals with HF was 49.99% (4429/9041). Severe DE symptoms were significantly associated with severe HF symptoms: coefficient 1.33 (95% CI 1.10-1.57; P<.001) for mild DE, coefficient 2.16 (95% CI 1.84-2.48; P<.001) for moderate DE, and coefficient 3.80 (95% CI 3.50-4.11; P<.001) for severe DE. The risk factors for comorbid symptomatic DE among individuals with HF were identified as female sex; lower BMI; medicated hypertension; history of hematologic, collagen, heart, liver, respiratory, or atopic disease; tomato allergy; current and previous mental illness; pet ownership; living room and bedrooms furnished with materials other than hardwood, carpet, tatami, and vinyl; discontinuation of contact lens use during the HF season; current contact lens use; smoking habits; and sleep duration of <6 hours per day. Uniform Manifold Approximation and Projection stratified the heterogeneous comorbid DE and HF symptoms into 14 clusters. In the hierarchical heat map, cluster 9 was comorbid with the most severe HF and DE symptoms, and cluster 1 showed severe HF symptoms with minimal DE-related symptoms. CONCLUSIONS: This crowdsourced study suggested a significant association between severe DE and HF symptoms. Detecting DE among individuals with HF could allow effective prevention and interventions through concurrent treatment for ocular surface management along with HF treatment.

Clinical utility of maximum blink interval measured by smartphone application DryEyeRhythm to support dry eye disease diagnosis.

The coronavirus disease (COVID-19) pandemic has emphasized the paucity of non-contact and non-invasive methods for the objective evaluation of dry eye disease (DED). However, robust evidence to support the implementation of mHealth- and app-based biometrics for clinical use is lacking. This study aimed to evaluate the reliability and validity of app-based maximum blink interval (MBI) measurements using DryEyeRhythm and equivalent traditional techniques in providing an accessible and convenient diagnosis. In this single-center, prospective, cross-sectional, observational study, 83 participants, including 57 with DED, had measurements recorded including slit-lamp-based, app-based, and visually confirmed MBI. Internal consistency and reliability were assessed using Cronbach's alpha and intraclass correlation coefficients. Discriminant and concurrent validity were assessed by comparing the MBIs from the DED and non-DED groups and Pearson's tests for each platform pair. Bland-Altman analysis was performed to assess the agreement between platforms. App-based MBI showed good Cronbach's alpha coefficient, intraclass correlation coefficient, and Pearson correlation coefficient values, compared with visually confirmed MBI. The DED group had significantly shorter app-based MBIs, compared with the non-DED group. Bland-Altman analysis revealed minimal biases between the app-based and visually confirmed MBIs. Our findings indicate that DryEyeRhythm is a reliable and valid tool that can be used for non-invasive and non-contact collection of MBI measurements, which can assist in accessible DED detection and management.

Smartphone App-Based and Paper-Based Patient-Reported Outcomes Using a Disease-Specific Questionnaire for Dry Eye Disease: Randomized Crossover Equivalence Study.

BACKGROUND: Using traditional patient-reported outcomes (PROs), such as paper-based questionnaires, is cumbersome in the era of web-based medical consultation and telemedicine. Electronic PROs may reduce the burden on patients if implemented widely. Considering promising reports of DryEyeRhythm, our in-house mHealth smartphone app for investigating dry eye disease (DED) and the electronic and paper-based Ocular Surface Disease Index (OSDI) should be evaluated and compared to determine their equivalency. OBJECTIVE: The purpose of this study is to assess the equivalence between smartphone app-based and paper-based questionnaires for DED. METHODS: This prospective, nonblinded, randomized crossover study enrolled 34 participants between April 2022 and June 2022 at a university hospital in Japan. The participants were allocated randomly into 2 groups in a 1:1 ratio. The paper-app group initially responded to the paper-based Japanese version of the OSDI (J-OSDI), followed by the app-based J-OSDI. The app-paper group responded to similar questionnaires but in reverse order. We performed an equivalence test based on minimal clinically important differences to assess the equivalence of the J-OSDI total scores between the 2 platforms (paper-based vs app-based). A 95% CI of the mean difference between the J-OSDI total scores within the ±7.0 range between the 2 platforms indicated equivalence. The internal consistency and agreement of the app-based J-OSDI were assessed with Cronbach α coefficients and intraclass correlation coefficient values. RESULTS: A total of 33 participants were included in this study. The total scores for the app- and paper-based J-OSDI indicated satisfactory equivalence per our study definition (mean difference 1.8, 95% CI -1.4 to 5.0). Moreover, the app-based J-OSDI total score demonstrated good internal consistency and agreement (Cronbach α=.958; intraclass correlation=0.919; 95% CI 0.842 to 0.959) and was significantly correlated with its paper-based counterpart (Pearson correlation=0.932, P<.001). CONCLUSIONS: This study demonstrated the equivalence of PROs between the app- and paper-based J-OSDI. Implementing the app-based J-OSDI in various scenarios, including telehealth, may have implications for the early diagnosis of DED and longitudinal monitoring of PROs.

Belly roll, a GPI-anchored Ly6 protein, regulates Drosophila melanogaster escape behaviors by modulating the excitability of nociceptive peptidergic interneurons.

Appropriate modulation of escape behaviors in response to potentially damaging stimuli is essential for survival. Although nociceptive circuitry has been studied, it is poorly understood how genetic contexts affect relevant escape responses. Using an unbiased genome-wide association analysis, we identified an Ly6/α-neurotoxin family protein, Belly roll (Bero), which negatively regulates Drosophila nociceptive escape behavior. We show that Bero is expressed in abdominal leucokinin-producing neurons (ABLK neurons) and bero knockdown in ABLK neurons resulted in enhanced escape behavior. Furthermore, we demonstrated that ABLK neurons responded to activation of nociceptors and initiated the behavior. Notably, bero knockdown reduced persistent neuronal activity and increased evoked nociceptive responses in ABLK neurons. Our findings reveal that Bero modulates an escape response by regulating distinct neuronal activities in ABLK neurons.

Economic Impacts and Quality of Life for Caregivers of Patients with Retinitis Pigmentosa: A Cross-Sectional Japanese Study.

Retinitis pigmentosa (RP) is the second leading cause of visual impairment in Japan and causes progressive vision loss in affected patients. Caregiving for patients with RP is associated with socioeconomic impacts; however, data on the magnitude and scope of these impacts are lacking. This cross-sectional study surveyed informal caregivers of patients with RP in Japan. The questionnaire assessed the socioeconomic status of participants; work impacts through the Work Productivity and Activity Impairment Questionnaire adapted for caregivers; and quality of life impacts through the Japanese version of the Caregiver Reaction Assessment (CRA) and the 5-level EQ-5D version (EQ-5D-5L). Of the 37 participating caregivers, 28 (75.7%) were employed. Among those, the average annual income was 2,722,080 yen (n = 20) and the mean loss of work productivity was 6.6%. The mean EQ-5D-5L index score was 0.882, and the mean CRA total score was 2.1. A mild to very severe impact on family life, leisure and hobbies, social life, and mental health was experienced by 83.8%, 78.4%, 75.7%, and 70.3%, respectively. These results suggest that caregivers of patients with RP may be disadvantaged in terms of employment and income and may experience wide-ranging impacts on their quality of daily life.

Symptom-based stratification algorithm for heterogeneous symptoms of dry eye disease: a feasibility study.

BACKGROUND/OBJECTIVE: To test the feasibility of a dry eye disease (DED) symptom stratification algorithm previously established for the general population among patients visiting ophthalmologists. SUBJECT/METHODS: This retrospective cross-sectional study was conducted between December 2015 and October 2021 at a university hospital in Japan; participants who underwent a comprehensive DED examination and completed the Japanese version of the Ocular Surface Disease Index (J-OSDI) were included. Patients diagnosed with DED were stratified into seven clusters using a previously established symptom-based stratification algorithm for DED. Characteristics of the patients in stratified clusters were compared. RESULTS: In total, 426 participants were included (median age [interquartile range]; 63 [48-72] years; 357 (83.8%) women). Among them, 291 (68.3%) participants were diagnosed with DED and successfully stratified into seven clusters. The J-OSDI total score was highest in cluster 1 (61.4 [52.2-75.0]), followed by cluster 5 (44.1 [38.8-47.9]). The tear film breakup time was the shortest in cluster 1 (1.5 [1.1-2.1]), followed by cluster 3 (1.6 [1.0-2.5]). The J-OSDI total scores from the stratified clusters in this study and those from the clusters identified in the previous study showed a significant correlation (r = 0.991, P < 0.001). CONCLUSIONS: The patients with DED who visited ophthalmologists were successfully stratified by the previously established algorithm for the general population, uncovering patterns for their seemingly heterogeneous and variable clinical characteristics of DED. The results have important implications for promoting treatment interventions tailored to individual patients and implementing smartphone-based clinical data collection in the future.

Quality of Life and Economic Impacts of Retinitis Pigmentosa on Japanese Patients: A Non-interventional Cross-sectional Study.

INTRODUCTION: Retinitis pigmentosa (RP) is an inherited progressive disease, characterized by a loss of photoreceptors, and is the second leading cause of visual impairment in Japan. RP is currently incurable and can result in complete blindness, with affected patients typically experiencing a gradual loss of light sensitivity, visual field, and visual acuity. Identification of any unmet medical needs of patients with this condition requires an understanding of the impacts of RP; in this study, we surveyed Japanese patients with RP to investigate the quality of life and economic impacts of visual impairment. METHODS: This non-interventional, cross-sectional study surveyed Japanese patients with RP. Economic impact was measured using an original questionnaire that assessed out-of-pocket cost (e.g., vision aids and medical services), salary gap with the general public, and the cost of depression and anxiety. Worker productivity was assessed using the Work Productivity and Activity Impairment Questionnaire (WPAI). Quality of life was evaluated using the Health Utilities Index Mark 3 (HUI3), the National Eye Institute Visual Function Questionnaire-25 (VFQ-25), and the 5-level EQ-5D version (EQ-5D-5L). The primary outcome was direct and indirect costs of visual impairment or blindness during the lifetime of patients with RP. RESULTS: Among 122 surveyed patients with RP, the estimated annual cost per patient was 218,520 yen (2176 USD), and the estimated lifetime cost per patient was 18,523,909 yen (184,501 USD). Additional robustness testing increased the estimated annual cost and lifetime cost per patient to 783,176 yen (7801 USD) and 66,389,827 yen (661,253 USD), respectively. In working patients, work productivity loss was 26.2% per person and impairment of daily activities was 31.6% per person. The mean VFQ-25, HUI3, and EQ-5D-5L scores were 42.0, 0.393, and 0.833, respectively. CONCLUSION: RP imposed a heavy economic burden and negative quality of life impacts in Japanese patients.

The protective role of conjunctival goblet cell mucin sialylation.

Gel-forming mucins secreted by conjunctival goblet cells have been implicated in the clearance of allergens, pathogens, and debris. However, their roles remain incompletely understood. Here we show that human and mouse conjunctival goblet cell mucins have Alcian blue-detectable sialic acids, but not sulfates in the steady state. Interestingly, Balb/c mouse strain lacks this sialylation due to a point mutation in a sialyltransferase gene, St6galnac1, which is responsible for sialyl-Tn synthesis. Introduction of intact St6galnac1 to Balb/c restores the sialylation of conjunctival goblet cell mucus. Sialylated mucus efficiently captures and encapsulates the allergen particles in an impenetrable layer, leading to the protection of mice from the development of allergic conjunctivitis. Expression of ST6GALNAC1 and sialyl-Tn is upregulated in humans under conditions with chronic stimuli. These results indicate that the sialylated glycans on the ocular mucins play an essential role in maintaining the conjunctival mucosa by protecting from the incoming foreign bodies such as allergen particles.

Examining the potential influence of crosslinguistic lexical similarity on word-choice transfer in L2 English.

We examined whether and how L1-L2 crosslinguistic formal lexical similarity influences L2 word choice. Our sample included two learner subcorpora, containing 8,500 and 6,390 English texts, written in an educational setting, by speakers of diverse L1s in the A1-B2 CEFR range of L2 proficiency. We quantified similarity based on phonological overlap between L1 words and their L2 (English) translations. This similarity relates to psycholinguistic cognancy, which occurs when words and their translations share a high level of formal similarity, often due to historical cognancy from shared etymology or language contact. We then used mixed-effects statistical models to examine how this similarity influences the rate of use of the L2 words; essentially, we checked whether L2 words that are more similar to their L1 translations are used more often. We also controlled for potential confounds, including the baseline L1 frequency of the English words. The type of crosslinguistic similarity that we examined did not influence learners' choice of L2 words in their writing in the present sample, which represents a type of educational setting that many learners encounter. This suggests that the influence of such similarity is constrained, and that communicative needs can override transfer from learners' L1 to their L2, which raises questions regarding when and how else situational factors can influence transfer.

Individual multidisciplinary clinical phenotypes of nasal and ocular symptoms in hay fever: Crowdsourced cross-sectional study using AllerSearch.

BACKGROUND: Multidisciplinary efforts to prospectively collect and analyze symptoms of hay fever are limited. We aimed to identify the characteristics of nasal and ocular symptoms of hay fever, using the AllerSearch smartphone application. METHODS: This mobile health-based prospective observational study using the AllerSearch smartphone application was conducted between February 1, 2018, and May 1, 2020. Individuals who downloaded AllerSearch from Japan and provided comprehensive self-assessments (including 17 items related to quality of life [QoL]-related items) were included. The characteristics and risk factors for allergic rhinitis (AR) and allergic conjunctivitis (AC) were identified using hierarchical heat maps and multivariate logistic regression. RESULTS: Of the 9041 participants with hay fever, 58.8% had AR and AC, 22.2% had AR, and 5.7% had AC. The AR-AC comorbid cohort showed worse symptoms of hay fever and QoL scores than the other cohorts. Factors (odds ratio, 95% confidence interval) associated with AR-AC included a lower age (0.98, 0.97-0.98), female sex (1.31, 1.19-1.45), liver disease (1.58, 1.26-2.35), dry eye disease (1.45, 1.30-1.63), unknown dry eye disease status (1.46, 1.31-1.62), contact lens use discontinuation during the hay fever season (1.69, 1.28-2.23), and bedroom flooring material other than hardwood, carpet, tatami, or vinyl (1.91, 1.16-3.14). CONCLUSIONS: Analysis of medical big data for hay fever performed using a mobile health app helped identify risk factors and characteristics of AC, AR, and AR-AC. Phenotyping of highly variable symptoms of hay fever, such as nasal and ocular symptoms, can facilitate better-quality clinical care.

Transfer of quercetin ingested by maternal mice to neonatal mice via breast milk.

This is the first study that quantified quercetin (QUE) and its 16 metabolites in the breast milk of QUE-fed maternal mice, the plasma and urine of that, and neonatal mice. Interestingly, the QUE aglycone concentration in the milk was much higher than in the plasma of maternal mice, suggesting that QUE may exert biological activity in neonates.

Vision protection and robust axon regeneration in glaucoma models by membrane-associated Trk receptors.

Activation of neurotrophic factor signaling is a promising therapy for neurodegeneration. However, the transient nature of ligand-dependent activation limits its effectiveness. In this study, we solved this problem by inventing a system that forces membrane localization of the intracellular domain of tropomyosin receptor kinase B (iTrkB), which results in constitutive activation without ligands. Our system overcomes the small size limitation of the genome packaging in adeno-associated virus (AAV) and allows high expression of the transgene. Using AAV-mediated gene therapy in the eyes, we demonstrate that iTrkB expression enhances neuroprotection in mouse models of glaucoma and stimulates robust axon regeneration after optic nerve injury. In addition, iTrkB expression in the retina was also effective in an optic tract transection model, in which the injury site is near the superior colliculus. Regenerating axons successfully formed pathways to their brain targets, resulting in partial recovery of visual behavior. Our system may also be applicable to other trophic factor signaling pathways and lead to a significant advance in the field of gene therapy for neurotrauma and neurodegenerative disorders, including glaucoma.

Prevalence and characteristics of dry eye disease in Parkinson's disease: a systematic review and meta-analysis.

We investigated and characterized the prevalence of dry eye disease (DED) in Parkinson's disease (PD). PubMed and EMBASE databases were searched for relevant studies between January 1, 1979 and March 10, 2022. Quality was assessed using the Joanna Briggs Institute Critical Appraisal Checklist. Study-specific estimates were combined using the DerSimonian-Laird random-effects model. Prevalence of subjective DED symptoms in patients with PD and mean differences in blink rate, corneal thickness, tear film breakup time, and tear secretion volume on Schirmer test I were compared to those in controls. Of 383 studies, 13 (1519 patients with PD) and 12 were included in qualitative and quantitative syntheses, respectively. Meta-analysis revealed a 61.1% prevalence of subjective DED symptoms in PD and that, compared with controls, patients with PD had significantly lower blink rate, thinner corneal thickness, shorter tear film breakup time, and lower tear secretion volumes on Schirmer test I, without and with anesthesia.