Prediction of Oral Intake at Discharge with Early Assessment of Swallowing Function within 24 h after Admission: A Retrospective Cohort Study.

Dysphagia is one of the most common symptoms of stroke and can lead to other complications such as pneumonia, dehydration, and malnutrition. This retrospective cohort study evaluated the predictive value of a comprehensive swallowing assessment tool, the Mann Assessment of Swallowing Ability (MASA), in the acute phase of stroke for oral intake status at discharge. Among 1,133 consecutive patients with acute stroke, 512 patients whose swallowing function was assessed using the MASA within 24 h of admission were included. Data including demographic information, stroke severity, MASA, Oral Health Assessment Tool, body mass index, and serum albumin level were collected. Predictive factors for oral intake were analyzed using a multiple logistic regression model, and the receiver operating characteristic (ROC) curve analysis was used to determine the cutoff values of the MASA score for determining oral intake at discharge. Oral intake at discharge was established in 69.1% of the cohort (354/512). The multiple logistic regression analysis identified a higher MASA score, younger age, and higher serum albumin level as significant predictors of oral intake at discharge. The cutoff value of the MASA score for oral intake was 136.5 points, with an area under the ROC curve of 0.87. These findings suggest that the MASA is a valid tool for predicting oral intake in patients with dysphagia during the acute phase of stroke.

Detection of elusive DNA copy-number variations in hereditary disease and cancer through the use of noncoding and off-target sequencing reads.

Copy-number variants (CNVs) play a substantial role in the molecular pathogenesis of hereditary disease and cancer, as well as in normal human interindividual variation. However, they are still rather difficult to identify in mainstream sequencing projects, especially involving exome sequencing, because they often occur in DNA regions that are not targeted for analysis. To overcome this problem, we developed OFF-PEAK, a user-friendly CNV detection tool that builds on a denoising approach and the use of "off-target" DNA reads, which are usually discarded by sequencing pipelines. We benchmarked OFF-PEAK on data from targeted sequencing of 96 cancer samples, as well as 130 exomes of individuals with inherited retinal disease from three different populations. For both sets of data, OFF-PEAK demonstrated excellent performance (>95% sensitivity and >80% specificity vs. experimental validation) in detecting CNVs from in silico data alone, indicating its immediate applicability to molecular diagnosis and genetic research.

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.

Genetic and Clinical Features of ABCA4-Associated Retinopathy in a Japanese Nationwide Cohort.

PURPOSE: To clarify the genetic and clinical features of Japanese patients with ABCA4-associated retinopathy. DESIGN: Retrospective, multicenter cohort study. METHODS: Patients with retinal degeneration and biallelic ABCA4 variants were recruited from 13 different hospitals. Whole exome sequencing analysis was used for genetic testing. Comprehensive ophthalmic examinations were performed on matched patients. The primary outcome measure was identifying multimodal retinal imaging findings associated with disease progression. RESULTS: This study included 63 patients: 19 with missense/missense, 23 with missense/truncation, and 21 with truncation/truncation genotypes. In total, 62 variants were identified, including 29 novel variants. Six patients had a mild phenotype characterized by foveal-sparing or preserved foveal structure, including 4 with missense/missense and 2 with missense/truncation genotypes. The p.Arg212His variant was the most frequent in patients with mild phenotypes (4/12 alleles). Clinical findings showed a disease duration-dependent worsening of the phenotypic stage. Patients with the truncation/truncation genotype exhibited rapid retinal degeneration within a few years and definite fundus autofluorescence imaging patterns, including hyper autofluorescence at the macula and few or no flecks. CONCLUSIONS: Our results indicate that missense/missense or missense/truncation genotypes, including the p.Arg212His variant, are associated with a relatively mild phenotype. In contrast, the truncation/truncation genotype causes rapid and severe retinal degeneration in Japanese patients with ABCA4-associated retinopathy. These data are vital in predicting patient prognosis, guiding genetic counseling, and stratifying patients for future clinical trials.

Endosomal Toll-Like Receptors as Therapeutic Targets for Autoimmune Diseases.

Nucleic acid (NA)-sensing Toll-like receptors (TLRs) reside in the endosomal compartment of innate immune cells, such as macrophages and dendritic cells. NAs transported to the endosomal compartment are degraded by DNases and RNases. Degradation products, including single-stranded DNA, oligoRNA, and nucleosides, are recognized by TLR7, TLR8, and TLR9 to drive the defense responses against pathogens. NA degradation influences endosomal TLR responses by generating and degrading TLR ligands. TLR ligand accumulation because of impaired NA degradation causes constitutive TLR activation, leading to autoinflammatory and autoimmune diseases. Furthermore, some genes associated with these diseases promote endosomal TLR responses. Therefore, endosomal TLRs are promising therapeutic targets for TLR-mediated inflammatory diseases, and novel drugs targeting TLRs are being developed.

Association between corneal hysteresis and glaucoma in a Japanese population: the Hisayama Study.

AIMS: To investigate the association between corneal hysteresis and the presence of glaucoma and its subtypes in a general Japanese population. METHODS: We analysed the data of 2338 Japanese community-dwellers aged ≥40 years (1059 men, 1279 women) who underwent an eye examination in 2018 as part of the population-based, cross-sectional Hisayama Study. Participants were divided into quartile levels of corneal hysteresis, which had been measured with an ocular response analyzer. Glaucoma was defined based on the International Society of Geographical and Epidemiological Ophthalmology criteria. We conducted a logistic regression analysis to determine the ORs and their 95% CIs for the presence of outcomes according to the corneal hysteresis quartiles. RESULTS: Glaucoma was diagnosed in 154 participants: primary open-angle glaucoma (POAG), n=115; primary angle-closure glaucoma, n=17; exfoliation glaucoma, n=21 and secondary glaucoma without exfoliation glaucoma, n=1. After adjustment for confounders, the OR for prevalent glaucoma was significantly increased in the participants in the first corneal-hysteresis quartile compared with those in the fourth quartile (OR: 1.80; 95% CI: 1.03 to 3.17). Regarding glaucoma subtypes, the first-quartile participants had significantly greater likelihoods of the presence of POAG (OR: 1.63; 95% CI: 1.02 to 2.61) and exfoliation glaucoma (OR: 6.49; 95% CI: 1.44 to 29.30) compared with those in the third and fourth quartiles after adjustment for potential confounders. CONCLUSIONS: These results demonstrated a significant inverse association between corneal hysteresis and the likelihood of glaucoma, suggesting that the measurement of corneal hysteresis would provide useful information for elucidating the aetiology of glaucoma.

Genotypes and clinical features of RHO-associated retinitis pigmentosa in a Japanese population.

PURPOSE: To report the genotypes and clinical features of RHO-associated retinitis pigmentosa (RHO-RP) in the Kyushu region of Japan. STUDY DESIGN: Retrospective, single-center study. METHODS: Sixteen RP patients with pathogenic RHO variants seen at Kyushu University Hospital were investigated. Clinical data including age, best-corrected visual acuity (BCVA) in logarithm of the minimum angle of resolution (logMAR) units, visual field, fundus photography, and optical coherence tomography were retrospectively obtained. Visual outcomes were compared between classical and sector phenotypes and among genetic variants. RESULTS: The mean age at the first visit was 54.0 ± 15.7 years, with a mean follow-up of 7.6 ± 4.0 years. Fourteen patients (87.5%) showed the classical RP phenotype, of whom four were associated with p.[Pro23Leu] and two had p.[Pro347Leu] variants. In addition, two patients with the sector phenotype harbored p.[Ala164Val] variants. Among the classical RHO-RP patients, the mean BCVA decreased from 0.60 to 1.08 logMAR over the follow-up period (7.4 ± 4.1 years) whereas BCVA was preserved at 0.04 logMAR in sector RHO-RP patients (9.0 ± 3.0 years). Genotype-to-phenotype analysis demonstrated that p.[Pro347Leu] was associated with severe vision loss at an earlier age. Macular complications such as epiretinal membrane and cystoid macular edema were observed in 5 classical RHO-RP patients. CONCLUSION: p.[Pro23Leu], but not p.[Pro23His], was a frequent variant causing RHO-RP in the Kyushu region of Japan. As reported in previous studies, patients with the p.[Pro347Leu] variant showed a more severe phenotype, and variants causing sector RHO-RP were associated with a good prognosis.

Glucocorticoid-induced TNF receptor family-related protein functions as a costimulatory molecule for murine eosinophils.

Eosinophils are typical effector cells associated with type 2 immune responses and play key roles in the pathogenesis of allergic diseases. These cells are activated by various stimuli, such as cytokines, chemokines, and growth factors, but the regulatory mechanisms of eosinophil effector functions remain unclear. Glucocorticoid-induced tumor necrosis factor receptor family-related protein (GITR), a transmembrane protein belonging to the tumor necrosis factor (TNF) receptor superfamily, is a well-known regulatory molecule for T cell activation. Here, we show that GITR is also constitutively expressed on eosinophils and functions as a costimulatory molecule for these cells. Although degranulation was unaffected by GITR engagement of murine bone marrow-derived eosinophils, secretion of inflammatory cytokines such as interleukin (IL)-4, IL-6, and IL-13 from IL-33-activated bone marrow-derived eosinophils was augmented by anti-mouse GITR agonistic antibody (DTA-1). In conclusion, our results provide a new regulatory pathway of cytokine secretion from eosinophils in which GITR functions as a costimulatory molecule.

TLR7 promotes smoke-induced experimental lung damage through the activity of mast cell tryptase.

Toll-like receptor 7 (TLR7) is known for eliciting immunity against single-stranded RNA viruses, and is increased in both human and cigarette smoke (CS)-induced, experimental chronic obstructive pulmonary disease (COPD). Here we show that the severity of CS-induced emphysema and COPD is reduced in TLR7-deficient mice, while inhalation of imiquimod, a TLR7-agonist, induces emphysema without CS exposure. This imiquimod-induced emphysema is reduced in mice deficient in mast cell protease-6, or when wild-type mice are treated with the mast cell stabilizer, cromolyn. Furthermore, therapeutic treatment with anti-TLR7 monoclonal antibody suppresses CS-induced emphysema, experimental COPD and accumulation of pulmonary mast cells in mice. Lastly, TLR7 mRNA is increased in pre-existing datasets from patients with COPD, while TLR7+ mast cells are increased in COPD lungs and associated with severity of COPD. Our results thus support roles for TLR7 in mediating emphysema and COPD through mast cell activity, and may implicate TLR7 as a potential therapeutic target.

Imaging Features of Early Diffuse Idiopathic Skeletal Hyperostosis (pre-DISH): Analysis of Progression of Ligament Ossification over 5 Years by Computed Tomography.

Introduction: Some patients who have not been diagnosed with diffuse idiopathic skeletal hyperostosis (DISH) (patients in the preclinical stage of DISH [pre-DISH]) may develop DISH in the future. However, there are currently no clearly defined diagnostic criteria for pre-DISH. This study aims to define pre-DISH by analyzing the change in the ossification extent in each intervertebral space in the thoracic and lumbar spines over time using computed tomography (CT). Methods: Of the patients who underwent CT of the thoracic to pelvic region at least twice from 2009 to 2018, 188 who underwent CT at an interval of 5 years to 5 years and 2 months were enrolled. The prevalence of DISH during the first and second CT scans was investigated. The pre-DISH feature was defined, and the prevalence of pre-DISH on the first CT and the change after 5 years in patients with pre-DISH was investigated. Results: Of the 188 patients, 37 (19.7%) and 48 (25.5%) were diagnosed with DISH on the first and second CT scans, respectively. Pre-DISH was defined as the ossification characterized by the modified Mata score of three contiguous intervertebral spaces with a score of ≥2 points (222; 2 points, ligament ossification of half or more of the intervertebral disc height but incomplete fusion), and 52 patients were diagnosed with pre-DISH. Of the 52 patients with a score of ≥(222), 11 (21.2%) were diagnosed with DISH 5 years later. Conclusions: Patients who have three contiguous intervertebral spaces with a modified Mata score of 2 or 3 points should be considered pre-DISH.

Determinants of Activity Phenotype in Patients with Chronic Obstructive Pulmonary Disease.

Introduction: Physical activity (PA) and sedentary behavior (SB) have attracted attention in chronic obstructive pulmonary disease (COPD), and there have been efforts to evaluate PA and SB separately. The factors associated with the characteristics of the four activity phenotypes defined by the durations of PA and SB are largely unknown. The aim of this study was to clarify the factors that could differentiate each activity phenotype. Materials and Methods: Study subjects were outpatients with stable COPD who were ≥40 years of age. We investigated the influence of 26 different factors on the activity phenotypes of COPD and extracted the factors that showed significant differences among the four activity phenotypes. Results: Two hundred sixteen patients were included in the analysis. Exercise capacity and dyspnea were determinants that distinguished the low PA groups from the high PA groups. The pulmonary function and desaturation during exercise were factors that distinguished the high PA with low SB group from the low PA with high SB group. BMI, grip strength, upper arm circumference and HbA1c were higher in the low PA and low SB group than in the low PA and high SB group. Conclusion: These factors could be the determinants discriminating activity phenotypes of patients with COPD.

Serum proteomic identification and validation of two novel atherosclerotic aortic aneurysm biomarkers, profilin 1 and complement factor D.

BACKGROUND: Effective diagnostic biomarkers for aortic aneurysm (AA) that are detectable in blood tests are required because early detection and rupture risk assessment of AA can provide insights into medical therapy and preventive treatments. However, known biomarkers for AA lack specificity and reliability for clinical diagnosis. METHODS: We performed proteome analysis of serum samples from patients with atherosclerotic thoracic AA (TAA) and healthy control (HC) subjects to identify diagnostic biomarkers for AA. Serum samples were separated into low-density lipoprotein, high-density lipoprotein, and protein fractions, and the major proteins were depleted. From the proteins identified in the three fractions, we narrowed down biomarker candidates to proteins uniformly altered in all fractions between patients with TAA and HC subjects and evaluated their capability to discriminate patients with TAA and those with abdominal AA (AAA) from HC subjects using receiver operating characteristic (ROC) analysis. For the clinical validation, serum concentrations of biomarker candidates were measured in patients with TAA and AAA registered in the biobank of the same institute, and their capability for the diagnosis was evaluated. RESULTS: Profilin 1 (PFN1) and complement factor D (CFD) showed the most contrasting profiles in all three fractions between patients with TAA and HC subjects and were selected as biomarker candidates. The PFN1 concentration decreased, whereas the CFD concentration increased in the sera of patients with TAA and AAA when compared with those of HC subjects. The ROC analysis showed that these proteins could discriminate patients with TAA and AAA from HC subjects. In the validation study, these candidates showed significant concentration differences between patients with TAA or AAA and controls. PFN1 and CFD showed sufficient area under the curve (AUC) in the ROC analysis, and their combination further increased the AUC. The serum concentrations of PFN1 and CFD also showed significant differences between patients with aortic dissection and controls in the validation study. CONCLUSION: PFN1 and CFD are potential diagnostic biomarkers for TAA and AAA and measurable in blood samples; their diagnostic performance can be augmented by their combination. These biomarkers may facilitate the development of diagnostic systems to identify patients with AA.

Non-Invasive Myocardial Work Indices in Infants Born to Mothers With Diabetes in Pregnancy.

BACKGROUND: This study used echocardiography to investigate non-invasive myocardial work (MCW) indices in infants born to mothers with diabetes mellitus (DM) in pregnancy (gestational DM: GDM), including those diagnosed under novel classification criteria and those with pre-existing DM.Methods and Results: This single-centered, retrospective study included 25 infants born to mothers with GDM (termed "infant with GDM"), which was diagnosed by oral glucose tolerance test results during pregnancy or the presence of diabetes before the current pregnancy. We evaluated the relationship between the infant's MCW, such as global constructive work (GCW), global work index (GWI), global work efficiency (GWE), and global wasted work (GWW), and the mother's GDM maximal HbA1c during pregnancy. HbA1c level in GDM significantly negatively correlated with GWI* (r=-0.565) and GCW* (r=-0.641). In infants with GDM, GWI and GCW were significantly higher with <6.5% HbA1c than in those with >6.5% HbA1c GDM; however, the specific-layer global longitudinal strain analyses did not show any significant differences between the groups. The pressure-strain loop in infants with >6.5% HbA1c in GDM tended to be smaller than in those infants with <6.5% HbA1c GDM. CONCLUSIONS: The hyperglycemic environment of GDM leads to impaired MCW in the infants. MCW is useful for screening for cardiac illnesses among infants with GDM. Appropriate maternal blood glucose management while maintaining HbA1c <6.5% might be beneficial for the cardiac performance of infants with GDM.

Objective Measurement of Physical Activity and Sedentary Behavior in Patients with Chronic Obstructive Pulmonary Disease: Points to Keep in Mind during Evaluations.

Objective measurement methods using accelerometers have become the mainstream approach for evaluating physical activity (PA) and sedentary behavior (SB). However, several problems face the objective evaluation of PA and SB in patients with chronic obstructive pulmonary disease (COPD). For example, indicators of PA differ depending on whether the accelerometer detects the kind of activity on the one hand, or its intensity on the other. Measured data are also strongly influenced by environmental factors (weather, season, employment status, etc.) and methodological factors (days with uncommon activities, non-wearing time, minimum required wearing time per day, minimum number of valid days required, etc.). Therefore, adjusting for these factors is required when evaluating PA or SB, especially when evaluating the effects of intervention. The exclusion of sleeping time, unification of total measurement time, and minimization of the required wearing time per day might be more important for the evaluation of ST than for evaluating PA. The lying-down-time-to-sitting-time ratio was shown to be larger in COPD patients than in healthy subjects. In this review, we clarified the problems encountered during objective evaluations of PA and SB in patients with COPD and encouraged investigators to recognize the presence of these problems and the importance of adjusting for them.

Rhodopsin-positive cell production by intravitreal injection of small molecule compounds in mouse models of retinal degeneration.

We aimed to verify whether the intravitreal injection of small molecule compounds alone can create photoreceptor cells in mouse models of retinal degeneration. Primary cultured mouse Müller cells were stimulated in vitro with combinations of candidate compounds and the rhodopsin expression was measured on day 7 using polymerase chain reaction and immunostaining. We used 6-week-old N-methyl-N-nitrosourea-treated and 4-week-old rd10 mice as representative in vivo models of retinal degeneration. The optimal combination of compounds selected via in vitro screening was injected into the vitreous and the changes in rhodopsin expression were investigated on day 7 using polymerase chain reaction and immunostaining. The origin of rhodopsin-positive cells was also analyzed via lineage tracing and the recovery of retinal function was assessed using electroretinography. The in vitro mRNA expression of rhodopsin in Müller cells increased 30-fold, and 25% of the Müller cells expressed rhodopsin protein 7 days after stimulation with a combination of 4 compounds: transforming growth factor-ß inhibitor, bone morphogenetic protein inhibitor, glycogen synthase kinase 3 inhibitor, and γ-secretase inhibitor. The in vivo rhodopsin mRNA expression and the number of rhodopsin-positive cells in the outer retina were significantly increased on day 7 after the intravitreal injection of these 4 compounds in both N-methyl-N-nitrosourea-treated and rd10 mice. Lineage tracing in td-Tomato mice treated with N-methyl-N-nitrosourea suggested that the rhodopsin-positive cells originated from endogenous Müller cells, accompanied with the recovery of the rhodopsin-derived scotopic function. It was suggested that rhodopsin-positive cells generated by compound stimulation contributes to the recovery of retinal function impaired by degeneration.

A Scoring System for Anterior Longitudinal Ligament Ossification of the Lumbar Spine in Diffuse Idiopathic Skeletal Hyperostosis: Relationship Between the Extent of Ligament Ossification and the Range of Motion.

STUDY DESIGN: Retrospective observational study. OBJECTIVE: To investigate the relationship between the extent of ligament ossification and the range of motion (ROM) of the lumbar spine and develop a new scoring system. METHODS: Forty-three patients (30 men and 13 women) with lumbar spinal canal stenosis who underwent decompression from January to December 2018. Ligament ossification at L1/2 to L5/S was assessed on plain X-ray (Xp) and computed tomography (CT) using a modified Mata scoring system (0 point: no ossification, 1 point: ossification of less than half of the intervertebral disc height, 2 points: ossification of half or more of the intervertebral disc height, 3 points: complete bridging), and the intra-rater and inter-rater reliability of the scoring was assessed. The relationship of the scores with postoperative lumbar ROM was investigated. RESULT: Intra-rater reliability was high (Cronbach's α was 0.74 for L5/S on Xp but 0.8 or above for other sections), as was inter-rater reliability (Cronbach's α was 0.8 or above for all the segments). ROM significantly decreased as the score increased (scores 1 to 2, and 2 to 3). A significant moderate negative correlation was found between the sum of the scores at L1/2-L5/S and the ROM at L1-S (ρ = - 0.4493, P = 0.025). CONCLUSION: Our scoring system reflects lumbar mobility and is reproducible. It is effective for assessing DISH in fractures and spinal conditions, and monitoring effects on treatment outcomes and changes over time.

Examining the Association Between the Extent of Anterior Longitudinal Ligament Ossification Progression and Comorbidities in Diffuse Idiopathic Skeletal Hyperostosis.

BACKGROUND:  It has been documented that diffuse idiopathic skeletal hyperostosis (DISH) exhibits a higher prevalence among elderly, male, and obese individuals. Additionally, diabetes mellitus and other comorbidities are more frequently observed in this patient population. However, there is a lack of reports exploring the correlation between the extent of ossification and these demographic and clinical characteristics. OBJECTIVE: To examine the correlation between comorbidities and the severity of ossification of the anterior longitudinal ligament in patients with DISH. MATERIALS AND METHODS: The study included 468 patients who visited our hospital in 2018-2022. They were divided into DISH and non-DISH groups based on computed tomography image evaluation according to the Resnick criteria. The patients in the two groups were matched for age and sex. We compared comorbidity-related factors including body mass index (BMI), serum markers for metabolic syndrome and renal function, and hemoglobin A1c (HbA1c) levels between the matched groups. Moreover, we examined the correlation between the number of fused vertebral bodies and comorbidity-related factors, age, and sex within the DISH group. RESULTS: The DISH group included significantly more men and elderly patients than the non-DISH group. Furthermore, the average BMI and HbA1c levels were significantly higher in the matched-DISH group than in the matched-non-DISH group, whereas no differences were observed in other markers. In the DISH group, the number of fused vertebral bodies did not correlate with age, sex, BMI, or HbA1c levels. DISCUSSION: BMI and HbA1c levels were significantly higher in patients with DISH than those without; however, the number of fused vertebral bodies and the possibility of having coexisting obesity or diabetes mellitus showed no correlation with the age or sex of the patient. Therefore, each patient should be carefully assessed for ossification severity regardless of age, sex, and the comorbidities they possess.

Neuroprotection for Age-Related Macular Degeneration.

Age-related macular degeneration (AMD) is a leading cause of blindness worldwide. Early to intermediate AMD is characterized by the accumulation of lipid- and protein-rich drusen. Late stages of the disease are characterized by the development of choroidal neovascularization, termed "exudative" or "neovascular AMD," or retinal pigment epithelium (RPE) cell and photoreceptor death, termed "geographic atrophy" (GA) in advanced nonexudative AMD. Although we have effective treatments for exudative AMD in the form of anti-VEGF agents, they have no role for patients with GA. Neuroprotection strategies have emerged as a possible way to slow photoreceptor degeneration and vision loss in patients with GA. These approaches include reduction of oxidative stress, modulation of the visual cycle, reduction of toxic molecules, inhibition of pathologic protein activity, prevention of cellular apoptosis or programmed necrosis (necroptosis), inhibition of inflammation, direct activation of neurotrophic factors, delivery of umbilical tissue-derived cells, and RPE replacement. Despite active investigation in this area and significant promise based on preclinical studies, many clinical studies have not yielded successful results. We discuss selected past and current neuroprotection trials for AMD, highlight the lessons learned from these past studies, and discuss our perspective regarding remaining questions that must be answered before neuroprotection can be successfully applied in the field of AMD research.

Prevalence of Glaucoma and Its Systemic Risk Factors in a General Japanese Population: The Hisayama Study.

Purpose: To estimate the prevalence of glaucoma and its risk factors in a Japanese community. Methods: This study included 3405 Japanese community dwellers who were ≥40 years of age and enrolled in the Hisayama Study. This population-based, cross-sectional study was conducted from 2017 to 2018. A glaucoma screening test was performed using stereo fundus images and swept-source optical coherence tomography. Glaucoma was defined based on the International Society of Geographical and Epidemiological Ophthalmology criteria. Results: The prevalence of glaucoma was 7.6% (95% confidence interval [CI], 6.7-8.6) overall. The prevalence of primary open-angle glaucoma (POAG) was 5.8% (95% CI, 5.0-6.6); that of primary angle-closure glaucoma (PACG) was 0.7% (95% CI, 0.5-1.1); and that of exfoliation glaucoma was 1.1% (95% CI, 0.7-1.4). In addition to aging, lower estimated glomerular filtration rate (eGFR) (odds ratio [OR] = 1.15; 95% CI, 1.02-1.33), higher intraocular pressure (OR = 1.06; 95% CI, 1.01-1.12), longer axial length (OR = 1.44; 95% CI, 1.31-1.59), and thinner central corneal thickness (CCT) (OR = 1.09; 95% CI, 1.04-1.15) were significant risk factors for POAG. Diabetes (OR = 2.81; 95% CI, 1.19-6.62) was a significant risk factor for PACG, and diabetes (OR = 2.15; 95% CI, 1.03-4.47) and thinner CCT (OR = 1.14; 95% CI, 1.02-1.28) were significant risk factors for exfoliation glaucoma. Conclusions: The prevalence of glaucoma was approximately 8%, probably due to the increase in the Japanese aging population. Not only ocular factors but also lower eGFR for POAG and diabetes for PACG and exfoliation glaucoma were risk factors in a general Japanese population. Translational Relevance: Systemic factors such as eGFR and diabetes must also be considered when implementing preventive measures against glaucoma.

Intraocular human cytomegaloviruses of ocular diseases are distinct from those of viremia and are capable of escaping from innate and adaptive immunity by exploiting HLA-E-mediated peripheral and central tolerance.

Human cytomegalovirus (HCMV) infections develop into CMV diseases that result in various forms of manifestations in local organs. CMV-retinitis is a form of CMV disease that develops in immunocompromised hosts with CMV-viremia after viruses in the peripheral circulation have entered the eye. In the HCMV genome, extensive diversification of the UL40 gene has produced peptide sequences that modulate NK cell effector functions when loaded onto HLA-E and are subsequently recognized by the NKG2A and NKG2C receptors. Notably, some HCMV strains carry UL40 genes that encode peptide sequences identical to the signal peptide sequences of specific HLA-A and HLA-C allotypes, which enables these CMV strains to escape HLA-E-restricted CD8+T cell responses. Variations in UL40 sequences have been studied mainly in the peripheral blood of CMV-viremia cases. In this study, we sought to investigate how ocular CMV disease develops from CMV infections. CMV gene sequences were compared between the intraocular fluids and peripheral blood of 77 clinical cases. UL40 signal peptide sequences were more diverse, and multiple sequences were typically present in CMV-viremia blood compared to intraocular fluid. Significantly stronger NK cell suppression was induced by UL40-derived peptides from intraocular HCMV compared to those identified only in peripheral blood. HCMV present in intraocular fluids were limited to those carrying a UL40 peptide sequence corresponding to the leader peptide sequence of the host's HLA class I, while UL40-derived peptides from HCMV found only in the peripheral blood were disparate from any HLA class I allotype. Overall, our analyses of CMV-retinitis inferred that specific HCMV strains with UL40 signal sequences matching the host's HLA signal peptide sequences were those that crossed the blood-ocular barrier to enter the intraocular space. UL40 peptide repertoires were the same in the intraocular fluids of all ocular CMV diseases, regardless of host immune status, implying that virus type is likely to be a common determinant in ocular CMV disease development. We thus propose a mechanism for ocular CMV disease development, in which particular HCMV types in the blood exploit peripheral and central HLA-E-mediated tolerance mechanisms and, thus, escape the antivirus responses of both innate and adaptive immunity.