Rate of Initial Optic Nerve Head Capillary Density Loss and Risk of Visual Field Progression.

Importance: Rapid initial optic nerve head capillary density loss may be used to assess the risk of glaucoma visual field progression. Objective: To investigate the association between the rate of initial optic nerve head capillary density loss from optical coherence tomography angiography (OCTA) and visual field progression. Design, Setting, Participants: This was a retrospective study of a longitudinal cohort at a glaucoma referral center. A total of 167 eyes (96 with primary open-angle glaucoma and 71 with glaucoma suspect) of 109 patients were monitored for a mean (SD) of 5.7 (1.4) years from January 2015 to December 2022. Data analysis was undertaken in April 2023. Main Outcomes and Measures: The rates of initial capillary density and average retinal nerve fiber layer loss were calculated from the first 3 optic nerve head OCTA and OCT scans, respectively, during the initial follow-up (mean [SD], 2.0 [1.0] years). Based on the median rate, eyes were categorized into fast and slow progressor groups. The association between initial capillary density change or retinal nerve fiber layer thinning and visual field progression was evaluated using linear-mixed and time-varying Cox models. Results: A total of 167 eyes of 109 patients (mean [SD] age, 69.0 [11.1] years; 56 [51.4%] female and 53 [48.6%] male) were assessed. Eighty-three eyes were slow OCTA progressors, while 84 eyes were fast with mean capillary density loss of -0.45% per year and -1.17% per year, respectively (mean difference, -0.72%/year; 95% CI,-0.84 to -0.60; P < .001). Similarly, 83 eyes were slow OCT progressors, while 84 eyes were fast with mean retinal nerve fiber layer thinning of -0.09 µm per year and -0.60 µm per year, respectively (mean difference, -0.51 µm/year; 95% CI,-0.59 to -0.43; P < .001). The fast OCTA and OCT progressors were associated with more rapid visual field loss (mean difference, -0.18 dB/year; 95% CI,-0.30 to -0.06; P = .004 and -0.17 dB/year; 95% CI,-0.29 to -0.06; P = .002, respectively). Fast OCTA progressing eyes were more likely to have visual field progression (hazard ratio, 1.96; 95% CI, 1.04-3.69; P = .04). Seventeen of 52 eyes (32.7%; 95% CI, 32.5-32.8) with fast OCTA and OCT progression developed subsequent visual field likely progression. Conclusion and Relevance: Rapid initial optic nerve head capillary density loss from OCTA was associated with a faster rate of visual field progression and a doubling of the risk of developing event progression in this study. These findings may support clinical use of OCTA and OCT optic nerve head measurements for risk assessment of glaucoma progression.

Smoking Intensity is Associated with Progressive Optic Nerve Head Vessel Density loss in Glaucoma.

PURPOSE: To investigate the relationship of smoking and smoking intensity, with the rate of optic nerve head (ONH) whole image capillary density (wiCD) loss in primary open angle glaucoma (POAG) and glaucoma suspect patients. METHODS: In this longitudinal study, POAG patients who had at least 2 years of follow-up and optical coherence tomography angiography (OCTA) performed at a minimum of 4 visits were selected for study. The smoking intensity was calculated as the pack-year at the baseline OCTA. Univariable and multivariable linear mixed models were used to determine the effect of each parameter on the rates of wiCD loss over time. Nonlinear least-squares estimation with piecewise regression model was used to investigate the cutoff point for the relationship between wiCD loss and smoking intensity. RESULTS: 164 eyes (69 glaucoma suspect and 95 POAG) of 110 patients were included with a mean (95% CI) follow-up of 4.0 (3.9 to 4.1) years. Of the 110 patients, 50 (45.5%) had a reported history of smoking. Greater smoking intensity was associated with faster wiCD loss (-0.11 (-0.23 to 0.00)) %/year per 10 pack-year higher; P=0.048) after adjusting for covariates. The wiCD thinning became significantly faster when smoking intensity was greater than 22.2 pack-years. Smoking had no effect on the rate of wiCD thinning in patients who smoked < 22.2 pack-years during their lifetime. CONCLUSIONS: A history of greater smoking consumption was associated with faster vessel density loss, suggesting smoking intensity as a potential risk factor for glaucoma.

Association of Long-Term Intraocular Pressure Variability and Rate of Ganglion Complex Thinning in Patients With Glaucoma.

PURPOSE: To evaluate the association of mean intraocular pressure (IOP) and IOP variability (IOP fluctuation [SD of IOP] and the IOP range) with the rate of ganglion cell complex (GCC) layer thinning over time in patients with glaucoma. DESIGN: Prospective cohort study. METHODS: Participants with at least 4 visits and 2 years of follow-up of optical coherence tomography tests were included. A linear mixed-effect model was used to investigate the association of IOP parameters with the rates of GCC thinning. Subgroup analyses were conducted for eyes with early (MD ≥ -6 dB), and moderate to advanced stage (MD < -6 dB) at baseline. RESULTS: The cohort consisted of 369 eyes of 249 glaucoma patients (282 early glaucoma and 87 moderate to advanced glaucoma) with mean (standard deviation [SD]) age of 68.2 (10.7) years over 5.1 years of follow-up. The mean rate of GCC change was -0.59 (95% confidence interval [CI], -0.67 to -0.52) µm per year. In multivariable models, faster annual rate of GCC thinning was associated with a higher IOP fluctuation (-0.17 [95% CI, -0.23 to -0.11] µm per 1-mmHg higher, P < .001) or higher IOP range (-0.07 [95% CI, -0.09 to -0.05] µm per 1-mmHg higher, P < .001) after adjustment for mean IOP and other confounding factors. Similar results were found for early and moderate to advanced stages of glaucoma. CONCLUSIONS: IOP variability showed an independent association with macular change in patients with glaucoma regardless of severity at baseline, even after adjustment for mean IOP, supporting its potential value as a therapeutic target for clinical decision-making.

Time to Glaucoma Progression Detection by Optical Coherence Tomography in Individuals of African and European Descents.

PURPOSE: To examine the time to detectable retinal nerve fiber layer thickness (RNFLT) progression by optical coherence tomography (OCT) among glaucoma patients of African descent (AD) and European descent (ED). DESIGN: Retrospective cohort study. METHODS: AD and ED glaucoma eyes from the Diagnostic Innovations in Glaucoma Study (DIGS)/African Descent and Glaucoma Evaluation Study (ADAGES) with ≥2 years/4 visits of optic nerve head RNFLT measurements were included after homogenization on age, diagnosis, and baseline visual field (VF) measurement. RNFLT variability estimates based on linear mixed-effects models were used to simulate longitudinal RNFLT data for both races. Times to trend-based RNFLT progression detection were calculated under standardized scenarios (same RNFLT baseline/thinning rates for both races) and real-world scenarios (AD and ED cohort-specific RNFLT baseline/thinning rates). RESULTS: We included 332 and 542 eyes (216 and 317 participants) of AD and ED, respectively. In standardized scenarios, the time to detect RNFLT progression appeared to be similar (difference, <0.2 years) for AD and ED across different assumed RNFLT thinning rates/baseline. In real-world scenarios, compared to ED, AD had a faster RNFLT thinning rate (-0.8 vs -0.6 µm/y) and thicker baseline RNFLT (84.6 vs 81.8 µm). With a faster thinning rate, the mean (SD) time to progression detection was shorter in AD (4.8 [2.0] vs ED: 5.4 [2.4] years), and the 5-year progression rate appeared to be higher (AD: 59% vs ED: 47%). CONCLUSIONS: Time to progression detection was similar for both races when assuming identical RNFLT baseline/thinning rates, and shorter in AD eyes under real-world simulation when AD had faster RNFLT thinning. In contrast to prior results on VF, which detected progression later in AD eyes than in ED eyes, OCT may detect progression more consistently across these races.

Detection and agreement of event-based OCT and OCTA analysis for glaucoma progression.

OBJECTIVE: To examine event-based glaucoma progression using optical coherence tomography (OCT) and OCT angiography (OCTA). METHODS: In this retrospective study, glaucoma eyes with ≥2-year and 4-visits of OCT/OCTA imaging were included. Peripapillary capillary density (CD) and retinal nerve fibre layer thickness (RNFL) were obtained from 4.5 mm × 4.5 mm optic nerve head (ONH) scans. Event-based OCT/OCTA progression was defined as decreases in ONH measurements exceeding test-retest variability on ≥2 consecutive visits. Visual field (VF) progression was defined as significant VF mean deviation worsening rates on ≥2 consecutive visits. Inter-instrument agreement on progression detection was compared using kappa(κ) statistics. RESULTS: Among 147 eyes (89 participants), OCTA and OCT identified 33(22%) and 25(17%) progressors, respectively. They showed slight agreement (κ = 0.06), with 7(5%) eyes categorized as progressors by both. When incorporating both instruments, the rate of progressors identified increased to 34%. Similar agreement was observed in diagnosis- and severity-stratified analyses (κ < 0.10). Compared to progressors identified only by OCT, progressors identified only by OCTA tended to have thinner baseline RNFL and worse baseline VF. VF progression was identified in 11(7%) eyes. OCT and VF showed fair agreement (κ = 0.26), with 6(4%) eyes categorized as progressors by both. OCTA and VF showed slight agreement (κ = 0.08), with 4(3%) eyes categorized as progressors by both. CONCLUSIONS: OCT and OCTA showed limited agreement on event-based progression detection, with OCT showing better agreement with VF. Both OCT and OCTA detected more progressors than VF. OCT and OCTA may provide valuable, yet different and complementary, information about glaucoma progression.

Racial Differences in the Diagnostic Accuracy of OCT Angiography Macular Vessel Density for Glaucoma.

PURPOSE: To evaluate and compare the diagnostic accuracy of macular vessel density (VD) measured by OCT angiography (OCTA) in individuals of African descent (AD) and European descent (ED) with open-angle glaucoma. DESIGN: Observational, cross sectional study. PARTICIPANTS: A total of 176 eyes of 123 patients with glaucoma and 140 eyes of 88 healthy participants from the Diagnostic Innovations in Glaucoma Study. METHODS: Whole-image ganglion cell complex (wiGCC) thickness and macular VD (parafoveal VD and perifoveal VD) were obtained from 6 × 6 macula scans. Area under the receiver operating characteristic (AUROC) curves were used to evaluate the diagnostic accuracy of macular VD and ganglion cell complex (GCC) thickness in AD and ED participants after adjusting for confounders such as age, visual field mean deviation (VF MD), signal strength index, axial length, self-reported hypertension and diabetes. MAIN OUTCOME MEASURES: Macular VD and wiGCC measurements. RESULTS: Parafoveal and perifoveal VD were significantly lower in ED than AD patients with glaucoma. Parafoveal and perifoveal VD performed significantly worse in AD participants compared with ED participants for detection of glaucoma (adjusted AUROC, 0.75 [95% confidence interval (CI), 0.62, 0.87], 0.85 [95% CI, 0.79, 0.90], P = 0.035; and 0.82 [95% CI, 0.70, 0.92], 0.91 [95% CI, 0.87, 0.94], respectively; P = 0.020). In contrast to VD, diagnostic accuracy of GCC thickness was similar in AD and ED individuals (adjusted AUROC, 0.89 [95% CI, 0.79, 0.96], 0.92 [95% CI, 0.86, 0.96], respectively; P = 0.313). The diagnostic accuracies of both macular VD and GCC thickness for differentiating between glaucoma and healthy eyes increased with increasing VF MD in both AD and ED participants. CONCLUSIONS: Diagnostic performance of OCTA macular VD, but not GCC thickness, for glaucoma detection varies by race. Moreover, macular VD parameters had lower accuracy for detecting glaucoma in AD individuals than in ED individuals. The diagnostic performance of macular VD is race-dependent, and, therefore, race should be taken into consideration when interpreting macular OCTA results. FINANCIAL DISCLOSURE(S): Proprietary or commercial disclosure may be found in the Footnotes and Disclosures at the end of this article.

Central visual field damage in glaucoma eyes with choroidal microvasculature dropout with and without high axial myopia.

PURPOSE: To characterise the relationship between a deep-layer microvasculature dropout (MvD) and central visual field (VF) damage in primary open-angle glaucoma (POAG) patients with and without high axial myopia. DESIGN: Cross-sectional study. METHODS: Seventy-one eyes (49 patients) with high axial myopia and POAG and 125 non-highly myopic POAG eyes (97 patients) were enrolled. Presence, area and angular circumference of juxtapapillary MvD were evaluated on optical coherence tomography angiography B-scans and en-face choroidal images. RESULTS: Juxtapapillary MvD was detected more often in the highly myopic POAG eyes (43 eyes, 86%) than in the non-highly myopic eyes (73 eyes, 61.9%; p=0.002). In eyes with MvD, MvD area and angular circumference (95% CI) were significantly larger in the highly myopic eyes compared with the non-highly myopic eyes (area: (0.69 (0.40, 0.98) mm2 vs 0.31 (0.19, 0.42) mm2, p=0.011) and (angular circumference: 84.3 (62.9, 105.8) vs 74.5 (58.3, 90.9) degrees, p<0.001), respectively. 24-2 VF mean deviation (MD) was significantly worse in eyes with MvD compared with eyes without MvD in both groups (p<0.001). After adjusting for 24-2 MD VF, central VF defects were more frequently found in eyes with MvD compared with eyes without MvD (82.7% vs 60.9%, p<0.001). In multivariable analysis, higher intraocular pressure, worse 24-2 VF MD, longer axial length and greater MvD area and angular circumference were associated with worse 10-2 VF MD. CONCLUSIONS: MvD was more prevalent and larger in POAG eyes with high myopia than in non-highly myopic POAG eyes. In both groups, eyes with MvD showed worse glaucoma severity and more central VF defects.

Relationship of Choroidal Microvasculature Dropout and Beta Zone Parapapillary Area With Visual Field Changes in Glaucoma.

PURPOSE: To evaluate the association between rates of choroidal microvasculature dropout (MvD) change, beta zone parapapillary atrophy (ß-PPA) area change, and visual field (VF) changes in eyes with primary open-angle glaucoma (POAG). DESIGN: Retrospective, observational cohort study. METHODS: In a tertiary glaucoma clinic, we included 76 eyes from 58 patients with POAG with and without localized MvD, who had ≥2 years of follow-up with a minimum of 4 visits with optical coherence tomography angiography and optical coherence tomography scans. ß-PPA area was evaluated using scanning laser ophthalmoscopy-like images and compared with the area of MvD on an en face choroidal vessel density map during the follow-up period. Joint longitudinal mixed effects models were used to estimate the rates of change in ß-PPA area or MvD area and VF mean deviation (MD). RESULTS: Mean rates of change in ß-PPA and MvD area were 0.037 mm2 (95% confidence interval [CI] 0.030-0.043 mm2) per year and 0.039 mm2 (95% CI 0.029-0.048 mm2) per year, respectively, over the mean follow-up of 4.1 years. In multivariable models, MvD area enlargement was significantly associated with faster rates of VF MD loss (0.03 mm2 [95% CI 0.02-0.04 mm2] per 1-dB worse, P < .001) but not ß-PPA area enlargement (0.04 mm2 [95% CI 0.03-0.05 mm2] per 1-dB worse, P = .252). CONCLUSION: MvD area rates, but not ß-PPA area rates, were associated with VF MD loss changes in eyes with POAG. Assessment of MvD is useful for the detection of patients with glaucoma who are at an increased risk of faster VF loss.

Deep Learning Estimation of 10-2 Visual Field Map Based on Macular Optical Coherence Tomography Angiography Measurements.

PURPOSE: To develop deep learning (DL) models estimating the central visual field (VF) from optical coherence tomography angiography (OCTA) vessel density (VD) measurements. DESIGN: Development and validation of a deep learning model. METHODS: A total of 1051 10-2 VF OCTA pairs from healthy, glaucoma suspects, and glaucoma eyes were included. DL models were trained on en face macula VD images from OCTA to estimate 10-2 mean deviation (MD), pattern standard deviation (PSD), 68 total deviation (TD) and pattern deviation (PD) values and compared with a linear regression (LR) model with the same input. Accuracy of the models was evaluated by calculating the average mean absolute error (MAE) and the R2 (squared Pearson correlation coefficients) of the estimated and actual VF values. RESULTS: DL models predicting 10-2 MD achieved R2 of 0.85 (95% confidence interval [CI], 74-0.92) for 10-2 MD and MAEs of 1.76 dB (95% CI, 1.39-2.17 dB) for MD. This was significantly better than mean linear estimates for 10-2 MD. The DL model outperformed the LR model for the estimation of pointwise TD values with an average MAE of 2.48 dB (95% CI, 1.99-3.02) and R2 of 0.69 (95% CI, 0.57-0.76) over all test points. The DL model outperformed the LR model for the estimation of all sectors. CONCLUSIONS: DL models enable the estimation of VF loss from OCTA images with high accuracy. Applying DL to the OCTA images may enhance clinical decision making. It also may improve individualized patient care and risk stratification of patients who are at risk for central VF damage.

Comparison of the TEMPO binocular perimeter and Humphrey field analyzer.

This study compared between TEMPO, a new binocular perimeter, with the Humphrey Field Analyzer (HFA). Patients were tested with both TEMPO 24-2 Ambient Interactive Zippy Estimated by Sequential Testing (AIZE)-Rapid and HFA 24-2 Swedish Interactive Threshold Algorithm (SITA)-Fast in a randomized sequence on the same day. Using a mixed-effects model, visual field (VF) parameters and reliability indices were compared. Retinal nerve fiber layer (RNFL) thickness was measured using Cirrus optical coherence tomography (OCT), and coefficient of determinations for VF and OCT parameters were calculated and compared using Akaike information criteria. 740 eyes (including 68 healthy, 262 glaucoma suspects, and 410 glaucoma) of 370 participants were evaluated. No significant differences were seen in mean deviation and visual field index between the two perimeters (P > 0.05). A stronger association between VF mean sensitivity (dB or 1/L) and circumpapillary RNFL was found for TEMPO (adjusted R2 = 0.25; Akaike information criteria [AIC] = 5235.5 for dB, and adjusted R2 = 0.29; AIC = 5200.8 for 1/L, respectively) compared to HFA (adjusted R2 = 0.22; AIC = 5263.9 for dB, and adjusted R2 = 0.22; AIC = 5262.7 for 1/L, respectively). Measurement time was faster for TEMPO compared to HFA (261 s vs. 429 s, P < 0.001). Further investigations are needed to assess the long-term monitoring potential of this binocular VF test.

Optical Coherence Tomography and Optical Coherence Tomography Angiography: Essential Tools for Detecting Glaucoma and Disease Progression.

Early diagnosis and detection of disease progression are critical to successful therapeutic intervention in glaucoma, the leading cause of irreversible blindness worldwide. Optical coherence tomography (OCT) is a non-invasive imaging technique that allows objective quantification in vivo of key glaucomatous structural changes in the retina and the optic nerve head (ONH). Advances in OCT technology have increased the scan speed and enhanced image quality, contributing to early glaucoma diagnosis and monitoring, as well as the visualization of critically important structures deep within the ONH, such as the lamina cribrosa. OCT angiography (OCTA) is a dye-free technique for noninvasively assessing ocular microvasculature, including capillaries within each plexus serving the macula, peripapillary retina and ONH regions, as well as the deeper vessels of the choroid. This layer-specific assessment of the microvasculature has provided evidence that retinal and choroidal vascular impairments can occur during early stages of glaucoma, suggesting that OCTA-derived measurements could be used as biomarkers for enhancing detection of glaucoma and its progression, as well as to reveal novel insights about pathophysiology. Moreover, these innovations have demonstrated that damage to the macula, a critical region for the vision-related quality of life, can be observed in the early stages of glaucomatous eyes, leading to a paradigm shift in glaucoma monitoring. Other advances in software and hardware, such as artificial intelligence-based algorithms, adaptive optics, and visible-light OCT, may further benefit clinical management of glaucoma in the future. This article reviews the utility of OCT and OCTA for glaucoma diagnosis and disease progression detection, emphasizes the importance of detecting macula damage in glaucoma, and highlights the future perspective of OCT and OCTA. We conclude that the OCT and OCTA are essential glaucoma detection and monitoring tools, leading to clinical and economic benefits for patients and society.

Associations of smoking and alcohol consumption with the development of open angle glaucoma: a retrospective cohort study.

OBJECTIVES: To investigate the associations of alcohol consumption and smoking with the development of perimetric glaucoma in patients with suspected glaucoma. DESIGN: A retrospective cohort study of patients suspected to have glaucoma enrolled in the Diagnostic Innovations in Glaucoma Study (DIGS) and the African Descent and Glaucoma Evaluation Study (ADAGES). SETTING: Three tertiary glaucoma centres in the USA. PARTICIPANTS: 825 eyes of 610 patients with glaucoma suspect eyes with normal visual fields (VF) at baseline were followed over an average of 9 years from the DIGS and ADAGES studies. OUTCOME MEASURES: Development of glaucoma was defined as occurrence of three consecutive abnormal VF tests during follow-up. Univariable and multivariable Cox regression models were used to investigate lifestyle-related factors associated with development of VF loss over time. RESULTS: VF tests were abnormal three times in a row in 235 (28.5%) eyes. Alcohol consumption was associated with a higher risk of developing glaucoma (HR 1.57, 95% CI 1.03 to 2.38, p=0.037). In men, the risk of developing glaucoma in alcohol drinkers (HR 1.92, 95% CI 1.00 to 3.68, p=0.048) was greater than non-alcohol drinkers. In individuals of African descent, the risk of developing glaucoma in alcohol drinkers (HR 1.79, 95% CI 1.02 to 3.15, p=0.043) was greater than non-alcohol drinkers. Age was a modifier of the relationship between smoking and glaucomatous VF defects (p=0.048). The risk of developing glaucoma in smokers (HR 1.73, 95% CI 1.10 to 2.72, p=0.019) was greater than never smokers after adjustment for confounding factors in older patients (age >61 years). CONCLUSION: Alcohol consumption was associated with an increased risk of developing glaucoma, particularly in men and individuals of African descent. The risk of developing glaucoma among smokers suspected of having glaucoma was influenced by age, with older individuals having a higher risk than younger people. TRIAL REGISTRATION NUMBER: NCT00221897 and NCT00221923.

Impact of smoking on choroidal microvasculature dropout in glaucoma: a cross-sectional study.

OBJECTIVE: To investigate the effect of smoking on choroidal microvasculature dropout (MvD) in glaucoma. DESIGN: Cross-sectional study. SETTING: Tertiary glaucoma centre. PARTICIPANTS: 223 eyes of 163 patients with primary open-angle glaucoma who had undergone imaging with optical coherence tomography angiography and completed a questionnaire on smoking from the Diagnostic Innovations in Glaucoma Study. PRIMARY OUTCOME MEASURES: Linear mixed-effects models were used to determine the effect of each parameter on MvD area and angular circumference. The sensitivity analysis was performed by categorising the glaucoma severity determined by visual field mean deviation (MD). RESULTS: MvD was found in 37 (51.4%) eyes with smoking history and in 67 (44.4%) eyes with non-smokers (p=0.389). Larger MvD area and wider angular circumference were found in smokers compared with non-smokers (p=0.068 and p=0.046, respectively). In a multivariable model, smoking intensity was significantly associated with MvD area (0.30(95% CI 0.01 to 0.60) each 0.01 mm2 per 10 pack-years; p=0.044). In eyes with moderate-severe glaucoma (MD <-6), smoking intensity was associated with larger MvD area (0.47 (95% CI 0.11 to 0.83) each 0.01 mm2 per 10 pack-years; p=0.011), whereas no significant association was found in early glaucoma (MD ≥-6) (-0.08 (95% CI -0.26 to 0.11), p=0.401). CONCLUSIONS: Smoking intensity was associated with larger choroidal MvD area in eyes with glaucoma, especially in patients with more severe disease. TRIAL REGISTRATION NUMBER: NCT00221897.

DAT, deacylating autotransporter toxin, from Bordetella parapertussis demyristoylates Gαi GTPases and contributes to cough.

The pathogenic bacteria Bordetella pertussis and Bordetella parapertussis cause pertussis (whooping cough) and pertussis-like disease, respectively, both of which are characterized by paroxysmal coughing. We previously reported that pertussis toxin (PTx), which inactivates heterotrimeric GTPases of the Gi family through ADP-ribosylation of their α subunits, causes coughing in combination with Vag8 and lipid A in B. pertussis infection. In contrast, the mechanism of cough induced by B. parapertussis, which produces Vag8 and lipopolysaccharide (LPS) containing lipid A, but not PTx, remained to be elucidated. Here, we show that a toxin we named deacylating autotransporter toxin (DAT) of B. parapertussis inactivates heterotrimeric Gi GTPases through demyristoylation of their α subunits and contributes to cough production along with Vag8 and LPS. These results indicate that DAT plays a role in B. parapertussis infection in place of PTx.

Comparison of the TEMPO Binocular Perimeter and Humphrey Field Analyzer.

This study compared between TEMPO, a new binocular perimeter, with the Humphrey Field Analyzer (HFA). Patients were tested with both TEMPO 24 - 2 AIZE-Rapid and HFA 24 - 2 SITA-Fast in a randomized sequence on the same day. Using a mixed-effects model, visual field (VF) parameters and reliability indices were compared. Retinal nerve fiber layer (RNFL) thickness was measured using Cirrus OCT, and coefficient of determinations for visual field and OCT parameters were calculated and compared using Akaike information criteria. 740 eyes (including 68 healthy, 262 glaucoma suspects, and 410 glaucoma) of 370 participants were evaluated. No significant differences were seen in mean deviation and visual field index between the two perimeters (P > 0.05). A stronger association between VF mean deviation and circumpapillary RNFL was found for TEMPO (adjusted R2 = 0.28; AIC = 5210.9) compared to HFA (adjusted R2 = 0.26; AIC = 5232.0). TEMPO had better reliability indices (fixation loss, false positive, and false negative) compared to HFA (all P < 0.05). Measurement time was faster for TEMPO compared to HFA (261sec vs. 429sec, P < 0.001). Further investigations are needed to assess the long-term monitoring potential of this binocular VF test.

Expression and function of CCN2-derived circRNAs in chondrocytes.

Cellular communication network factor 2 (CCN2) molecules promote endochondral ossification and articular cartilage regeneration, and circular RNAs (circRNAs), which arise from various genes and regulate gene expression by adsorbing miRNAs, are known to be synthesized from CCN2 in human vascular endothelial cells and other types of cells. However, in chondrocytes, not only the function but also the presence of CCN2-derived circRNA remains completely unknown. In the present study, we investigated the expression and function of CCN2-derived circRNAs in chondrocytes. Amplicons smaller than those from known CCN2-derived circRNAs were observed using RT-PCR analysis that could specifically amplify CCN2-derived circRNAs in human chondrocytic HCS-2/8 cells. The nucleotide sequences of the PCR products indicated novel circRNAs in the HCS-2/8 cells that were different from known CCN2-derived circRNAs. Moreover, the expression of several Ccn2-derived circRNAs in murine chondroblastic ATDC5 cells was confirmed and observed to change alongside chondrocytic differentiation. Next, one of these circRNAs was knocked down in HCS-2/8 cells to investigate the function of the human CCN2-derived circRNA. As a result, CCN2-derived circRNA knockdown significantly reduced the expression of aggrecan mRNA and proteoglycan synthesis. Our data suggest that CCN2-derived circRNAs are expressed in chondrocytes and play a role in chondrogenic differentiation. Production and role of CCN2-derived RNAs in chondrocytes.

Dual roles of cellular communication network factor 6 (CCN6) in the invasion and metastasis of oral cancer cells to bone via binding to BMP2 and RANKL.

The acquisition of motility via epithelial-mesenchymal transition (EMT) and osteoclast induction are essential for the invasion and metastasis of oral squamous cell carcinoma (OSCC) to bone. However, the molecule suppressing both EMT and osteoclastogenesis is still unknown. In this study, we found that cellular communication network factor 6 (CCN6) was less produced in a human OSCC cell line, HSC-3 with mesenchymal phenotype, than in HSC-2 cells without it. Notably, CCN6 interacted with bone morphogenetic protein 2 (BMP2) and suppressed the cell migration of HSC-3 cells stimulated by BMP2. Moreover, knockdown of CCN6 in HSC-2 cells led to the promotion of EMT and enhanced the effect of transforming growth factor-ß (TGF-ß) on the promotion of EMT. Furthermore, CCN6 combined with BMP2 suppressed EMT. These results suggest that CCN6 strongly suppresses EMT in cooperation with BMP2 and TGF-ß. Interestingly, CCN6 combined with BMP2 increased the gene expression of receptor activator of nuclear factor-κB ligand (RANKL) in HSC-2 and HSC-3 cells. Additionally, CCN6 interacted with RANKL, and CCN6 combined with RANKL suppressed RANKL-induced osteoclast formation. In metastatic lesions, increasing BMP2 due to the bone destruction led to interference with binding of CCN6 to RANKL, which results in the promotion of bone metastasis of OSCC cells due to continuous osteoclastogenesis. These findings suggest that CCN6 plays dual roles in the suppression of EMT and in the promotion of bone destruction of OSCC in primary and metastatic lesions, respectively, through cooperation with BMP2 and interference with RANKL.

Complete genome sequences of nine Burkholderia pseudomallei strains.

We report the complete genome sequences of nine Burkholderia pseudomallei strains preserved in research facilities in Japan; GTC3P0019, GTC3P0050, GTC3P0054, GTC3P0254T (type strain), Kanagawa, Tokushima, KM376, KM390, and KM391. The genomic information of these strains may provide references for comparative studies of B. pseudomallei pathogenicity.

Clinical Factors Associated With Long-Term OCT Variability in Glaucoma.

PURPOSE: To examine clinical factors associated with long-term optical coherence tomography (OCT)-measured retinal nerve fiber layer thickness (RNFLT) variability in glaucoma. STUDY DESIGN: Retrospective cohort study. METHODS: Glaucoma eyes from Diagnostic Innovations in Glaucoma Study (DIGS)/the African Descent and Glaucoma Evaluation Study (ADAGES) with ≥2-years and 4-visit follow-up were included. RNFLT variability was calculated per visit as the absolute error of optic nerve head RNFLT residuals across longitudinal follow-up. Clinical factors examined included general demographics, baseline ocular measurements, prior and intervening cataract extraction (CE) or glaucoma surgery, scan quality, baseline RNFLT and RNFLT thinning rate, follow-up duration, and visit/testing frequency. Three multivariable linear mixed models (full model, baseline model, and parsimonious model) were fit to evaluate the effects of clinical factors on RNFLT variability, with 10-fold cross-validation to estimate real-world model performance. RESULTS: A total of 1140 eyes (634 patients) were included. The overall mean (95% CI) RNFLT variability was 1.51(1.45, 1.58) µm. Across different models, African American race (ß [standard error {SE} = 0.18 [0.06]), intervening CE (ß [SE] = 0.52 [0.07]), intervening glaucoma surgeries (ß [SE] = 0.15 [0.03]), and more positive RNFLT thinning rate (ß [SE] = 0.06 [0.02] per 1 µm/y more positive) showed consistent association with greater RNFLT variability, whereas more frequent visits/testing (ß [SE] = -0.11[0.05] per 1 visit/y higher) was associated with smaller RNFLT variability (P < .05 for all). CONCLUSIONS: Relevant clinical factors affecting long-term RNFLT variability in glaucoma were identified. These data enhance the evaluation of longitudinal structural change. Increasing the testing frequency, especially in eyes at risk for higher measurement variability, and resetting of baseline imaging after intervening procedures may help to more reliably detect OCT progression.