Effect of Different Postures on Intraocular Pressure in Open-Angle Glaucoma.

INTRODUCTION: This study aims to investigate the pattern of intraocular pressure (IOP) changes in different postures among patients with open-angle glaucoma (OAG). METHODS: A observational study was conducted on a total of 74 patients with OAG (148 eyes). IOP measurements were taken in a variety of positions, including supine, left lateral decubitus, right lateral decubitus, head tilted downwards position with immediate head-up (transient head tilted downwards), seated, seated with head tilted downwards, standing, and walking. Each position was held for 5 min before measurement. In all positions, the patient maintains both eyes looking forward and remains alert. In the head tilted downwards position, the angle of head tilt with respect to the sagittal plane was 30°. RESULTS: The overall trend of IOP changes showed a significant decrease with an increase in the position height (r = 0.037, p < 0.001). The IOP was significantly higher in the supine, left lateral decubitus, right lateral decubitus, and head tilted downwards positions than in the seated position (p < 0.001). Compared with the seated position with eyes at primary gaze, IOP decreased significantly when standing (p = 0.008) or walking (p < 0.001). The IOP in the left lateral decubitus and right lateral decubitus was significantly higher than in the supine position (p = 0.008, p = 0.001, respectively). The IOP decreased significantly during walking compared with standing (p < 0.001). CONCLUSIONS: The magnitude of IOP strongly correlates with the body position during IOP measurement. The head tilted downwards, supine, left lateral decubitus, and right lateral decubitus positions result in a higher IOP than IOP at the seated position. Patients with OAG can potentially reduce IOP fluctuations by adjusting their daily postures.

Heritable changes of epialleles near genes in maize can be triggered in the absence of CHH methylation.

Trans-chromosomal interactions resulting in changes in DNA methylation during hybridization have been observed in several plant species. However, little is known about the causes or consequences of these interactions. Here, we compared DNA methylomes of F1 hybrids that are mutant for a small RNA biogenesis gene, Mop1 (Mediator of paramutation1), with that of their parents, wild-type siblings, and backcrossed progeny in maize (Zea mays). Our data show that hybridization triggers global changes in both trans-chromosomal methylation (TCM) and trans-chromosomal demethylation (TCdM), most of which involved changes in CHH methylation. In more than 60% of these TCM differentially methylated regions (DMRs) in which small RNAs are available, no significant changes in the quantity of small RNAs were observed. Methylation at the CHH TCM DMRs was largely lost in the mop1 mutant, although the effects of this mutant varied depending on the location of these DMRs. Interestingly, an increase in CHH at TCM DMRs was associated with enhanced expression of a subset of highly expressed genes and suppressed expression of a small number of lowly expressed genes. Examination of the methylation levels in backcrossed plants demonstrates that both TCM and TCdM can be maintained in the subsequent generation, but that TCdM is more stable than TCM. Surprisingly, although increased CHH methylation in most TCM DMRs in F1 plants required Mop1, initiation of a new epigenetic state of these DMRs did not require a functional copy of this gene, suggesting that initiation of these changes is independent of RNA-directed DNA methylation.

Association between contrast sensitivity function and structural damage in primary open-angle glaucoma.

AIMS: To evaluate the association between contrast sensitivity function (CSF) and glaucomatous structural damage in primary open-angle glaucoma (POAG). METHODS: A cross-sectional study was performed with 103 patients (103 eyes) aged 25-50 years who had POAG without any other ocular disease. CSF measurements were obtained by the quick CSF method, a novel active learning algorithm that covers 19 spatial frequencies and 128 contrast levels. The peripapillary retinal nerve fibre layer (pRNFL), macular ganglion cell complex (mGCC), radial peripapillary capillary (RPC) and macular vasculature were measured by optical coherence tomography and angiography. Correlation and regression analyses were used to assess the association of area under log CSF (AULCSF), CSF acuity and contrast sensitivities at multiple spatial frequencies with structural parameters. RESULTS: AULCSF and CSF acuity were positively associated with pRNFL thickness, RPC density, mGCC thickness and superficial macular vessel density (p<0.05). Those parameters were also significantly associated with contrast sensitivity at 1, 1.5, 3, 6, 12, 18 cycles per degree spatial frequencies (p<0.05) and, the lower the spatial frequency, the higher the correlation coefficient. RPC density (p=0.035, p=0.023) and mGCC thickness (p=0.002, p=0.011) had significant predictive value for contrast sensitivity at 1 and 1.5 cycles per degree, with adjusted R 2 of 0.346 and 0.343, respectively. CONCLUSIONS: Full spatial frequency contrast sensitivity impairment, most notably at low spatial frequencies, is a characteristic change in POAG. Contrast sensitivity is a potential functional endpoint for the measurement of glaucoma severity.

Heritable changes of epialleles in maize can be triggered in the absence of DNA methylation.

Trans-chromosomal interactions resulting in changes in DNA methylation during hybridization have been observed in several plant species. However, very little is known about the causes or consequences of these interactions. Here, we compared DNA methylomes of F1 hybrids that are mutant for a small RNA biogenesis gene, Mop1 (mediator of paramutation1) with that of their parents, wild type siblings, and backcrossed progeny in maize. Our data show that hybridization triggers global changes in both trans-chromosomal methylation (TCM) and trans-chromosomal demethylation (TCdM), most of which involved changes in CHH methylation. In more than 60% of these TCM differentially methylated regions (DMRs) in which small RNAs are available, no significant changes in the quantity of small RNAs were observed. Methylation at the CHH TCM DMRs was largely lost in the mop1 mutant, although the effects of this mutant varied depending on the location of the CHH DMRs. Interestingly, an increase in CHH at TCM DMRs was associated with enhanced expression of a subset of highly expressed genes and suppressed expression of a small number of lowly expressed genes. Examination of the methylation levels in backcrossed plants demonstrates that TCM and TCdM can be maintained in the subsequent generation, but that TCdM is more stable than TCM. Surprisingly, although increased CHH methylation in F1 plants did require Mop1, initiation of the changes in the epigenetic state of TCM DMRs did not require a functional copy of this gene, suggesting that initiation of these changes is not dependent on RNA-directed DNA methylation.

Retinal microvasculature is a potential biomarker for acute mountain sickness.

Increased cerebral blood flow resulting from altered capillary level autoregulation at high altitudes leads to capillary overperfusion and then vasogenic cerebral edema, which is the leading hypothesis of acute mountain sickness (AMS). However, studies on cerebral blood flow in AMS have been mostly restricted to gross cerebrovascular endpoints as opposed to the microvasculature. This study aimed to investigate ocular microcirculation alterations, the only visualized capillaries in the central neural system (CNS), during early-stage AMS using a hypobaric chamber. This study found that after high altitude simulation, the optic nerve showed retinal nerve fiber layer thickening (P=0.004-0.018) in some locations, and the area of the optic nerve subarachnoid space (P=0.004) enlarged. Optical coherence tomography angiography (OCTA) showed increased retinal radial peripapillary capillary (RPC) flow density (P=0.003-0.046), particularly on the nasal side of the nerve. The AMS-positive group had the largest increases in RPC flow density in the nasal sector (AMS-positive, Δ3.21±2.37; AMS-negative, Δ0.01±2.16, P=0.004). Among multiple ocular changes, OCTA increase in RPC flow density was associated with simulated early-stage AMS symptoms (beta=0.222, 95%CI, 0.009-0.435, P=0.042). The area under the receiver operating characteristics curve (AUC) for the changes in RPC flow density to predict early-stage AMS outcomes was 0.882 (95%CI, 0.746-0.998). The results further confirmed that overperfusion of microvascular beds is the key pathophysiologic change in early-stage AMS. RPC OCTA endpoints may serve as a rapid, noninvasive potential biomarker for CNS microvascular changes and AMS development during risk assessment of individuals at high altitudes.

Comparison of the Effects of Latanoprostene Bunod and Timolol on Retinal Blood Vessel Density: A Randomized Clinical Trial.

PURPOSE: To compare the differences in retinal vessel density (VD) between topical administration of latanoprostene bunod (LBN) ophthalmic solution 0.024% and timolol maleate 0.5% in patients with open-angle glaucoma (OAG) or ocular hypertension (OHT) and normal subjects. DESIGN: Randomized, single center, crossover clinical trial. METHODS: Eligible subjects were examined during 6 study visits over 12 weeks. All subjects were randomized in a 1:1 ratio to LBN dosed once daily or timolol dosed twice daily in both eyes (OU) for a duration of 4 weeks each, separated by a 2-week washout period. A comprehensive eye examination OU was performed at each visit. Testing was performed with optical coherence tomography and optical coherence tomography angiography (optic nerve and macula), as well as visual field examination, on the study eye at baseline and before and after each treatment. RESULTS: One eye from each of 50 patients was enrolled (10 healthy patients, 26 patients with OHT, and 14 patients with OAG). After administration of LBN there was significantly increased macular VD (0.76% [0.20%-1.33%], P = 0.009) and a trend in increasing peripapillary VD in patients with OAG and patients with OHT. In contrast, after administration of timolol, there were no differences in macular VD, and a decrease in peripapillary VD only was observed in the nasal inferior sector (-0.56% [-1.08% to -0.03%], P = .04) in patients with OAG and patients with OHT. No change in peripapillary or macular VD was observed in the normal subjects (P > .05 for all). CONCLUSIONS: Topical administration of LBN enhanced macular VD in patients with OAG or patients with OHT. In contrast, timolol administration did not have any effect on VD.

Neddylation of Coro1a determines the fate of multivesicular bodies and biogenesis of extracellular vesicles.

Multivesicular bodies (MVBs) fuse with not only the plasma membranes to release extracellular vesicles (EVs) but also lysosomes for degradation. Rab7 participates in the lysosomal targeting of MVBs. However, the proteins on MVB that directly bind Rab7, causing MVB recruitment of Rab7 remain unidentified. Here, we show that Coro1a undergoes neddylation modification at K233 by TRIM4. Neddylated Coro1a is associated with the MVB membrane and facilitates MVB recruitment and activation of Rab7 by directly binding Rab7. Subsequently, MVBs are targeted to lysosomes for degradation in a Rab7-dependent manner, leading to reduced EV secretion. Furthermore, a decrease in neddylated Coro1a enhances the production of tumour EVs, thereby promoting tumour progression, indicating that neddylated Coro1a is an ideal target for the regulation of EV biogenesis. Altogether, our data identify a novel substrate of neddylation and reveal an unknown mechanism for MVB recruitment of Rab7, thus providing new insight into the regulation of EV biogenesis.

The mop1 mutation affects the recombination landscape in maize.

Meiotic recombination is a fundamental process that generates genetic diversity and ensures the accurate segregation of homologous chromosomes. While a great deal is known about genetic factors that regulate recombination, relatively little is known about epigenetic factors, such as DNA methylation. In maize, we examined the effects on meiotic recombination of a mutation in a component of the RNA-directed DNA methylation pathway, Mop1 (Mediator of paramutation1), as well as a mutation in a component of the trans-acting small interference RNA biogenesis pathway, Lbl1 (Leafbladeless1). MOP1 is of particular interest with respect to recombination because it is responsible for methylation of transposable elements that are immediately adjacent to transcriptionally active genes. In the mop1 mutant, we found that meiotic recombination is uniformly decreased in pericentromeric regions but is generally increased in gene rich chromosomal arms. This observation was further confirmed by cytogenetic analysis showing that although overall crossover numbers are unchanged, they occur more frequently in chromosomal arms in mop1 mutants. Using whole genome bisulfite sequencing, our data show that crossover redistribution is driven by loss of CHH (where H = A, T, or C) methylation within regions near genes. In contrast to what we observed in mop1 mutants, no significant changes were observed in the frequency of meiotic recombination in lbl1 mutants. Our data demonstrate that CHH methylation has a significant impact on the overall recombination landscape in maize despite its low frequency relative to CG and CHG methylation.

Analysis of CACTA transposase genes unveils the mechanism of intron loss and distinct small RNA silencing pathways underlying divergent evolution of Brassica genomes.

In comparison with retrotransposons, DNA transposons make up a smaller proportion of most plant genomes. However, these elements are often proximal to genes to affect gene expression depending on the activity of the transposons, which is largely reflected by the activity of the transposase genes. Here, we show that three AT-rich introns were retained in the TNP2-like transposase genes of the Bot1 (Brassica oleracea transposon 1) CACTA transposable elements in Brassica oleracea, but were lost in the majority of the Bot1 elements in Brassica rapa. A recent burst of transposition of Bot1 was observed in B. oleracea, but not in B. rapa. This burst of transposition is likely related to the activity of the TNP2-like transposase genes as the expression values of the transposase genes were higher in B. oleracea than in B. rapa. In addition, distinct populations of small RNAs (21, 22 and 24 nt) were detected from the Bot1 elements in B. oleracea, but the vast majority of the small RNAs from the Bot1 elements in B. rapa are 24 nt in length. We hypothesize that the different activity of the TNP2-like transposase genes is likely associated with the three introns, and intron loss is likely reverse transcriptase mediated. Furthermore, we propose that the Bot1 family is currently undergoing silencing in B. oleracea, but has already been silenced in B. rapa. Taken together, our data provide new insights into the differentiation of transposons and their role in the asymmetric evolution of these two closely related Brassica species.

Author Correction: EpCAM-dependent extracellular vesicles from intestinal epithelial cells maintain intestinal tract immune balance.

An amendment to this paper has been published and can be accessed via a link at the top of the paper.

Capillary Density Measured by Optical Coherence Tomography Angiography in Glaucomatous Optic Disc Phenotypes.

PURPOSE: To compare optical coherence tomography angiography (OCTA)-measured capillary density of the optic disc among 4 glaucomatous optic disc phenotypes. DESIGN: Cross-sectional study. METHODS: Circumpapillary capillary density (cpCD) of 4 glaucomatous optic disc phenotypes in 193 eyes of 141 glaucoma patients and cpCD in 92 eyes of 55 healthy subjects from the Diagnostic Innovations in Glaucoma Study (DIGS) were compared. Areas under the receiver operating characteristic (AUROC) curves were used to evaluate diagnostic accuracy among groups after adjusting for confounders. RESULTS: Four glaucoma phenotypes were assessed: focal ischemic (n = 45), generalized cup enlargement (n = 60), myopic glaucoma (n = 38), and senile sclerotic (n = 50). Sex, mean ocular perfusion pressure, intraocular pressure, mean deviation, and the quality score did not differ among phenotypes. However, there were differences in age (P = .050), race (P = .039), axial length (P = .033), and retinal nerve fiber layer thickness (P < .001) among the groups. After adjusting for confounders, senile sclerotic discs had the lowest cpCD (37.1% [95% confidence interval, 35.3-38.8]), followed by focal ischemic (41.8% [40.0-43.6]), myopic glaucoma (42.1% [40-44.2]), and generalized cup enlargement (45.5% [44-47]) (P < .001) discs. The adjusted AUROC curves of cpCD for discriminating between healthy and glaucomatous eyes were highest in senile sclerotic eyes (0.928) and lowest in generalized cup enlargement eyes (0.704). CONCLUSIONS: OCTA-measured vessel density differs among optic disc phenotypes. Clinicians should be aware that the performance of OCTA for glaucoma diagnosis may be influenced by the optic disc phenotype.

Finite element analysis of trans-lamina cribrosa pressure difference on optic nerve head biomechanics: the Beijing Intracranial and Intraocular Pressure Study.

The present study aims to assess the potential difference of biomechanical response of the optic nerve head to the same level of trans-lamina cribrosa pressure difference (TLCPD) induced by a reduced cerebrospinal fluid pressure (CSFP) or an elevated intraocular pressure (IOP). A finite element model of optic nerve head tissue (pre- and post-laminar neural tissue, lamina cribrosa, sclera, and pia mater) was constructed. Computed stresses, deformations, and strains were compared at each TLCPD step caused by reduced CSFP or elevated IOP. The results showed that elevating TLCPD increased the strain in optic nerve head, with the largest strains occurring in the neural tissue around the sclera ring. Relative to a baseline TLCPD of 10 mmHg, at a same TLCPD of 18 mmHg, the pre-laminar neural tissue experienced 11.10% first principal strain by reduced CSFP and 13.66% by elevated IOP, respectively. The corresponding values for lamina cribrosa were 6.09% and 6.91%. In conclusion, TLCPD has a significant biomechanical impact on optic nerve head tissue and, more prominently, within the pre-laminar neural tissue and lamina cribrosa. Comparatively, reducing CSFP showed smaller strain than elevating IOP even at a same level of TLCPD on ONH tissue, indicating a different potential role of low CSFP in the pathogenesis of glaucoma.

Correlation Between Office-Hour and Peak Nocturnal Intraocular Pressure in Patients Treated with Prostaglandin Analogs.

PURPOSE: To test the hypothesis that the correlation between office-hour intraocular pressure (IOP) and peak nocturnal IOP is weakened after using a prostaglandin analog. DESIGN: Before-and-after study. METHODS: Twenty-four-hour IOP data obtained in a sleep laboratory of 51 patients (22 patients with open-angle glaucoma and 29 patients with ocular hypertension) were reviewed. Patients had no IOP-lowering medication upon study entry and were then treated with prostaglandin monotherapy for 4 weeks. Measurements of IOP were taken every 2 hours in the sitting and supine positions during the diurnal/wake period (7:30 AM-9:30 PM) and in the supine position during the nocturnal/sleep period (11:30 PM-5:30 AM). Individual and average IOP readings during office hours (9:30 AM-3:30 PM) and peak IOP during the nocturnal/sleep hours were analyzed using the Pearson correlation coefficient and linear regression. RESULTS: There were statistically significant correlations for all the paired variables for the analyses. Average office-hour IOP had a higher correlation with peak nocturnal IOP than individual office-hour IOP. After the treatment with prostaglandin analog, the correlation between average office-hour IOP and nocturnal peak IOP in the sitting position (r = 0.373) and the supine position (r = 0.386) were reduced from the sitting baseline (r = 0.517) and the supine baseline (r = 0.573) in right eyes. Similar change patterns appeared in left eyes. CONCLUSION: There is a correlation between office-hour IOP reading and peak nocturnal IOP under no IOP-lowering treatment as well as under prostaglandin monotherapy. The strength of correlation was weaker under the treatment compared with baseline.

Ganglion Cell Complex Thickness and Macular Vessel Density Loss in Primary Open-Angle Glaucoma.

PURPOSE: To characterize the change rate of ganglion cell complex (GCC) thickness and macular vessel density in healthy, preperimetric glaucoma and primary open-angle glaucoma (POAG) eyes. DESIGN: Prospective, longitudinal study. PARTICIPANTS: One hundred thirty-nine eyes (23 healthy eyes, 36 preperimetric glaucoma eyes, and 80 POAG eyes) of 94 patients who had at least 3 visits were included from the Diagnostic Innovations in Glaucoma Study. The mean follow-up was 2.0 years for healthy eyes, 2.6 years for preperimetric glaucoma eyes, and 2.6 years for POAG eyes. METHODS: OCT angiography (OCTA)-based vessel density and OCT-based structural thickness of the same 3×3-mm2 GCC scan slab were evaluated. The dynamic range-based normalized rates of vessel density and thickness change were calculated and compared within each diagnostic group. The association between the rates of thickness and vessel density change and potential factors were evaluated. MAIN OUTCOME MEASURES: The rates of GCC thinning and macular vessel density loss. RESULTS: Significant rates of GCC thinning and macular vessel density decrease were detectable in all diagnostic groups (all P < 0.05). In healthy eyes and preperimetric glaucoma eyes, the normalized rates of GCC thinning and macular vessel density decrease were comparable (all P > 0.1). In contrast, the normalized rate (mean, 95% confidence interval) of macular vessel density decrease in the POAG eyes (-7.12 [-8.36, -5.88]%/year) was significantly faster than GCC thinning (-2.13 [-3.35, -0.90]%/year; P < 0.001). In the POAG group, more than two thirds of the eyes showed faster macular vessel density decrease than GCC thinning; faster macular vessel density decrease rate was associated significantly with worse glaucoma severity (P = 0.037). The association between GCC thinning rate and glaucoma severity was not significant (P = 0.586). Intraocular pressure during follow-up significantly affected the rate of GCC thinning in all groups (all P < 0.05) but showed no association with the rate of macular vessel density decrease. CONCLUSIONS: Both GCC thinning and macular vessel density decrease were detectable over time in all diagnostic groups. In POAG eyes, macular vessel density decrease was faster than GCC thinning and was associated with severity of disease. Macular vessel density is useful for evaluating glaucoma progression, particularly in more advanced disease.

Association Between Arterial Blood Gas Variation and Intraocular Pressure in Healthy Subjects Exposed to Acute Short-Term Hypobaric Hypoxia.

PURPOSE: To investigate the association between changes in arterial blood gases and intraocular pressure (IOP) after acute, short-term exposure to simulated elevation of 4000 m above sea level. METHODS: Twenty-five healthy young lowlanders participated in this prospective study. IOP was measured in both eyes with an Accupen tonometer. Arterial blood gas parameters (partial oxygen pressure [PaO2], partial carbon dioxide pressure [PaCO2], pH, and bicarbonate ion [HCO3 -]) were checked using a blood gas analyzer. Measurements were taken at sea level (T1), at 15-minute (T2) and at 2-hour (T3) exposure times to simulated 4000 m above sea level in a hypobaric chamber, and upon return to sea level (T4). Associations between arterial blood gas parameters and IOP were evaluated using multivariate linear regression. RESULTS: PaO2 significantly decreased at T2 and T3, resolving at T4 (P < 0.001). pH significantly increased at T2 and returned to baseline at T3 (P = 0.004). Actual and standard bicarbonate ion both dropped with IOP at T3 and T4. IOP significantly decreased from 16.4 ± 3.4 mm Hg at T1 to 15.1 ± 2.1 mm Hg (P = 0.041) at T3 and remained lower (14.9 ± 2.4 mm Hg; P = 0.029) at T4. IOP was not correlated with pH. Multivariate linear regression showed that lower IOP was associated with lower standard bicarbonate ion (beta = -1.061; 95% confidence interval, -0.049 to -2.074; P = 0.04) when adjusted for actual bicarbonate and diastolic blood pressure. CONCLUSIONS: Hypobaric hypoxia triggers plasma bicarbonate ion reduction which, rather than pH, may decrease aqueous humor formation and subsequently cause IOP reduction. These findings may shed light on the mechanism of IOP regulation at high altitude. TRANSLATIONAL RELEVANCE: Hypoxia-triggered reduction in plasma bicarbonate ion may decrease aqueous humor production, leading to IOP reduction at high altitude. These findings may provide new insight into a potential mechanism of IOP regulation. Hypobaric hypoxia at high altitude is an environmental factor that can reduce IOP and, therefore, deserves further study.

Longitudinal observation of intraocular pressure variations with acute altitude changes.

BACKGROUND: Higher intraocular pressure (IOP) is a major risk factor for developing glaucoma, and the leading cause of irreversible blindness worldwide. High altitude (HA) may be involved in IOP, but the reported results were conflicting. Ascent to HA directly by plane from low altitude regions is an acute, effortless exposure. However, the effects of such exposure to different altitudes on IOP have rarely been reported. AIM: To investigate changes in IOP after rapid effortless exposure to HA in stages and compare it with systemic parameters. METHODS: Fifty-eight healthy subjects (116 eyes) were divided into three groups: 17 low-altitude (LA) residents [44 m above sea level (ASL)], 22 HA residents (2261 m ASL) and 19 very HA (VHA) residents (3750 m ASL). The LA group flew to HA first. Three days later, they flew with the HA group to VHA where both groups stayed for 2 d. Then, the LA group flew back to HA and stayed for 1 d before flying back to 44 m. IOP, oxygen saturation (SpO2) and pulse rate were measured. The linear mixed model was used to compare repeated measurements. RESULTS: IOP in the LA group significantly decreased from 18.41 ± 2.40 mmHg at 44 m to 13.60 ± 3.68 mmHg at 2261 m ASL (P < 0.001), and then to 11.85 ± 2.48 mmHg at 3750 m ASL (P = 0.036 compared to IOP at 2261 m ASL) and partially recovered to 13.47 ± 2.57 mmHg upon return to 44 m. IOP in the LA group at HA and VHA was comparable to that in the local residents (12.2 ± 2.4 mmHg for HA,11.5 ± 1.8 mmHg for VHA). IOP was positively associated with SpO2. CONCLUSION: IOP in the LA group gradually reduced as altitude elevated in stages and became comparable to IOP in local residents. Hypoxia may be associated with IOP, which deserves further study.

Development and Validation of a Deep Learning System to Detect Glaucomatous Optic Neuropathy Using Fundus Photographs.

Importance: A deep learning system (DLS) that could automatically detect glaucomatous optic neuropathy (GON) with high sensitivity and specificity could expedite screening for GON. Objective: To establish a DLS for detection of GON using retinal fundus images and glaucoma diagnosis with convoluted neural networks (GD-CNN) that has the ability to be generalized across populations. Design, Setting, and Participants: In this cross-sectional study, a DLS for the classification of GON was developed for automated classification of GON using retinal fundus images obtained from the Chinese Glaucoma Study Alliance, the Handan Eye Study, and online databases. The researchers selected 241 032 images were selected as the training data set. The images were entered into the databases on June 9, 2009, obtained on July 11, 2018, and analyses were performed on December 15, 2018. The generalization of the DLS was tested in several validation data sets, which allowed assessment of the DLS in a clinical setting without exclusions, testing against variable image quality based on fundus photographs obtained from websites, evaluation in a population-based study that reflects a natural distribution of patients with glaucoma within the cohort and an additive data set that has a diverse ethnic distribution. An online learning system was established to transfer the trained and validated DLS to generalize the results with fundus images from new sources. To better understand the DLS decision-making process, a prediction visualization test was performed that identified regions of the fundus images utilized by the DLS for diagnosis. Exposures: Use of a deep learning system. Main Outcomes and Measures: Area under the receiver operating characteristics curve (AUC), sensitivity and specificity for DLS with reference to professional graders. Results: From a total of 274 413 fundus images initially obtained from CGSA, 269 601 images passed initial image quality review and were graded for GON. A total of 241 032 images (definite GON 29 865 [12.4%], probable GON 11 046 [4.6%], unlikely GON 200 121 [83%]) from 68 013 patients were selected using random sampling to train the GD-CNN model. Validation and evaluation of the GD-CNN model was assessed using the remaining 28 569 images from CGSA. The AUC of the GD-CNN model in primary local validation data sets was 0.996 (95% CI, 0.995-0.998), with sensitivity of 96.2% and specificity of 97.7%. The most common reason for both false-negative and false-positive grading by GD-CNN (51 of 119 [46.3%] and 191 of 588 [32.3%]) and manual grading (50 of 113 [44.2%] and 183 of 538 [34.0%]) was pathologic or high myopia. Conclusions and Relevance: Application of GD-CNN to fundus images from different settings and varying image quality demonstrated a high sensitivity, specificity, and generalizability for detecting GON. These findings suggest that automated DLS could enhance current screening programs in a cost-effective and time-efficient manner.

Fas signaling-mediated TH9 cell differentiation favors bowel inflammation and antitumor functions.

Fas induces apoptosis in activated T cell to maintain immune homeostasis, but the effects of non-apoptotic Fas signaling on T cells remain unclear. Here we show that Fas promotes TH9 cell differentiation by activating NF-κB via Ca2+-dependent PKC-ß activation. In addition, PKC-ß also phosphorylates p38 to inactivate NFAT1 and reduce NFAT1-NF-κB synergy to promote the Fas-induced TH9 transcription program. Fas ligation exacerbates inflammatory bowel disease by increasing TH9 cell differentiation, and promotes antitumor activity in p38 inhibitor-treated TH9 cells. Furthermore, low-dose p38 inhibitor suppresses tumor growth without inducing systemic adverse effects. In patients with tumor, relatively high TH9 cell numbers are associated with good prognosis. Our study thus implicates Fas in CD4+ T cells as a target for inflammatory bowel disease therapy. Furthermore, simultaneous Fas ligation and low-dose p38 inhibition may be an effective approach for TH9 cell induction and cancer therapy.

Retinal vessel oxygen saturation and vessel diameter in healthy individuals during high-altitude exposure.

PURPOSE: To assess changes of retinal vessel oxygen saturation and vessel diameter in healthy individuals during high-altitude exposure. METHODS: Retinal oxygen saturation and vessel diameter were obtained at sea level (SL, 40 m) and high altitude (HA, 3681 m) on 17 healthy individuals from Beijing (six males, 28.06 ± 8.06 years) using Oxymap T1 and then compared with 21 residents from Yushu (10 males, 28.63 ± 6.00 years). Systemic and ocular parameters were also measured before and after high-altitude exposure. Data were presented as mean ± SD and analysed using paired and independent Student t-test with significance accepted at p < 0.05. RESULTS: Short-term high-altitude exposure of Beijing Group significantly affected all the systemic and ocular parameters, as well as retinal oxygen saturation and vessel diameter ranging from overall quadrant to different quadrants, other than retinal venous oxygen saturation and retinal arterial diameter. However, these changes were not evident in those permanently living at HA. Pearson's correlation analysis revealed correlations between retinal oxygen saturation and systemic and ocular parameters (all p < 0.05). The multivariate linear regression analysis indicated that retinal arterial oxygen saturation was significantly associated with arterial peripheral arterial oxygen saturation (SpO2 ) and subfoveal choroidal thickness. CONCLUSION: Short-term exposure to HA induces retinal microcirculation disturbance and auto-regulatory response in healthy individuals, which is probably attributed to arterial SpO2 and endothelial dysfunction under hypoxic conditions.