Retinal Nerve Fiber Layer Optical Texture Analysis: Detecting Axonal Fiber Bundle Defects in Patients with Ocular Hypertension.

PURPOSE: To apply retinal nerve fiber layer (RNFL) optical texture analysis (ROTA) to investigate the prevalence, patterns, and risk factors of RNFL defects in patients with ocular hypertension (OHT) who showed normal optic disc and RNFL configuration in clinical examination, normal RNFL thickness on OCT analysis, and normal visual field (VF) results. DESIGN: Cross-sectional study. PARTICIPANTS: Six hundred eyes of 306 patients with OHT. METHODS: All participants underwent clinical examination of the optic disc and RNFL, OCT RNFL imaging, and 24-2 standard automated perimetry. To detect RNFL defects, ROTA was applied. The risk score for glaucoma development was calculated according to the Ocular Hypertension Treatment Study and European Glaucoma Prevention Study (OHTS-EGPS) risk prediction model. Risk factors associated with RNFL defects were analyzed using multilevel logistic regression analysis. MAIN OUTCOME MEASURES: Prevalence of RNFL defects. RESULTS: The average intraocular pressure (IOP) measured from 3 separate visits within 6 months was 24.9 ± 1.8 mmHg for the eye with higher IOP and 23.7 ± 1.7 mmHg for the eye with lower IOP; the respective central corneal thicknesses were 568.7 ± 30.8 µm and 568.8 ± 31.2 µm. Of 306 patients with OHT, 10.8% (33 patients, 37 eyes) demonstrated RNFL defects in ROTA in at least 1 eye. Of the 37 eyes with RNFL defects, the superior arcuate bundle was the most frequently involved (62.2%), followed by the superior papillomacular bundle (27.0%) and the inferior papillomacular bundle (21.6%). Papillofoveal bundle defects were observed in 10.8% of eyes. The smallest RNFL defect spanned 0.0° along Bruch's membrane opening margin, whereas the widest RNFL defect extended over 29.3°. Age (years) (odds ratio [OR], 1.08; 95% confidence interval [CI], 1.03-1.13), VF pattern standard deviation (decibels [dB]) (OR, 1.82; 95% CI, 1.01-3.29), cup volume (mm3) (OR, 1.24; 95% CI, 1.01-1.53), and the OHTS-EPGS risk score (OR, 1.04; 95% CI, 1.01-1.07) were associated with RNFL defects. CONCLUSIONS: A considerable proportion of patients with OHT who showed no signs of optic disc and RNFL thickness abnormalities on clinical and OCT examination exhibited RNFL defects on ROTA. Axonal fiber bundle defects on ROTA may represent the earliest discernible sign of glaucoma in the glaucoma continuum. FINANCIAL DISCLOSURE(S): Proprietary or commercial disclosure may be found in the Footnotes and Disclosures at the end of this article.

Assessment of Iris Trabecular Contact in Eyes with Gonioscopic Angle-Closure.

PURPOSE: To investigate the extent of iris trabecular contact (ITC) measured by anterior segment OCT (AS-OCT) and its association with primary angle-closure (PAC) and PAC glaucoma (PACG) in eyes with gonioscopic angle-closure and to determine the diagnostic performance of ITC for detection of gonioscopic angle-closure. DESIGN: Multicenter, prospective study. PARTICIPANTS: A total of 119 healthy participants with gonioscopic open-angle and 170 patients with gonioscopic angle-closure (94 with PAC suspect and 76 with PAC/PACG) were included. METHODS: One eye of each subject was randomly selected for AS-OCT imaging. Angle-opening distance (AOD500) and trabecular iris space area (TISA500) were measured every 10° for 360°. Two criteria of ITC500 were examined: (1) AOD500 = 0 mm and (2) TISA500 = 0 mm2. The association between the extent of ITC500 and PAC/PACG in eyes with gonioscopic angle-closure was analyzed with logistic regression analysis. MAIN OUTCOME MEASURES: Sensitivity and specificity of ITC500 for detection of gonioscopic angle-closure; odds ratio (OR) of PAC/PACG. RESULTS: The sensitivity of ITC500 ≥ 10° for detection of gonioscopic angle-closure ranged from 82.4% (AOD500 = 0 mm) to 84.7% (TISA500 = 0 mm2), and the specificity was 85.7% (for both AOD500 = 0 mm and TISA500 = 0 mm2). The extent of ITC500 determined by AS-OCT, not cumulative gonioscopy score (i.e., the sum of the modified Shaffer grades over 4 quadrants), was associated with the odds of PAC/PACG in eyes with gonioscopic angle-closure; the odds of PAC/PACG increased by 5% for every 10° increase in ITC500 (OR, 1.051, 95% confidence interval [CI], 1.022-1.080 for AOD500 = 0 mm; OR, 1.049, 95% CI, 1.022-1.078 for TISA500 = 0 mm2). Axial length and anterior chamber depth were not associated with PAC/PACG in eyes with gonioscopic angle-closure (P ≥ 0.574). CONCLUSIONS: A greater extent of ITC measured by AS-OCT, not angle-closure determined by gonioscopy, was associated with a greater odds of PAC/PACG in eyes with gonioscopic angle-closure.

The frequency and nature of barriers to escalation of care in two Australian teaching hospitals.

BACKGROUND: Nurses and junior doctors are often the first clinicians to recognise signs of deterioration in patients. However, there can be barriers to having conversations about escalation of care. OBJECTIVES: The aim of this study was to study the frequency and nature of barriers encountered during discussions related to escalation of care for deteriorating hospitalised patients. METHODS: This was a prospective observational study with daily experience sampling surveys related to escalation of care discussions. The study setting involved two teaching hospitals in Victoria, Australia. Consented doctors, nurses, and allied health staff members involved in routine care of adult ward patients participated in the study. The main outcome measures included the frequency of escalation conversations and the frequency and nature of barriers encountered during such conversations. RESULTS/FINDINGS: 31 clinicians participated in the study and completed an experience sampling survey 294 times, mean (standard deviation) = 9.48 (5.82). On 166 (56.6%) days, staff members were on clinical duties, and escalation of care discussions occurred on 67 of 166 (40.4%) of these days. Barriers to escalation of care occurred in 25 of 67 (37.3%) of discussions and most frequently involved lack of staff availability (14.9%), perceived stress in the contacted staff member (14.9%), perceptions of criticism (9.0%), being dismissed (7.5%), or indication of lack of clinical appropriateness in the response (6.0%). CONCLUSIONS: Discussions related to escalation of care by ward clinicians occur in almost half of clinical days and are associated with barriers in one-third of discussions. Interventions are needed to clarify roles and responsibilities and outline behavioural expectations on both sides of the conversation and enable respectful communication amongst individuals involved in discussions of escalation of patient care.

Retinal Nerve Fiber Layer Optical Texture Analysis: Involvement of the Papillomacular Bundle and Papillofoveal Bundle in Early Glaucoma.

PURPOSE: To apply retinal nerve fiber layer (RNFL) optical texture analysis (ROTA) in eyes with early glaucoma to investigate (1) the pattern of RNFL defects, (2) how often the papillomacular bundle and papillofoveal bundles are involved, and (3) the association between papillomacular and papillofoveal bundle defects and visual field (VF) sensitivity abnormalities. DESIGN: Cross-sectional study. PARTICIPANTS: Two hundred four eyes with early glaucoma (VF mean deviation, ≥ -6 dB) with RNFL defects from 171 consecutively enrolled patients with glaucoma. METHODS: All eyes underwent 24-2 VF testing and OCT for ROTA. The borders of RNFL defects were delineated from ROTA, and the involvement of the arcuate bundle, papillomacular bundle (i.e., bundles from the macula, excluding the fovea), and papillofoveal bundle (i.e., bundles from the fovea) was determined for each eye. Multilevel logistic regression analysis was applied to evaluate the structure-function association. MAIN OUTCOME MEASURES: Proportions of eyes with papillomacular or papillofoveal bundle defects. RESULTS: Of the 204 eyes, 71.6% and 17.2% demonstrated RNFL defects involving the papillomacular and papillofoveal bundles, respectively; 25.0% showed arcuate bundle defects without involvement of papillomacular or papillofoveal bundles. The pattern of RNFL defects was diverse; the most common was concomitant involvement of the inferior arcuate bundle and the inferior papillomacular bundle (20.6%). Papillomacular or papillofoveal bundle defects were not associated with VF defects (i.e., with ≥ 3 contiguous locations with abnormal VF sensitivity in the pattern deviation probability plot) in the corresponding hemifield, although VF sensitivity of any 1 of the central 4 VF locations of the 24-2 test, which were within the macula, was more likely to be abnormal (P < 0.05 in the pattern deviation probability plot; odds ratio, 12.5; 95% confidence interval, 7.0-22.5) when the VF stimulus was projected onto a papillomacular or papillofoveal bundle defect than that projected onto an intact papillomacular or papillofoveal bundle. CONCLUSIONS: Contrary to the conventional notion that the fovea and macula are not affected until the late stages of glaucoma, papillofoveal and papillomacular bundle defects were common in early glaucoma, and they were associated with central VF sensitivity loss at the corresponding VF test locations.

A critical evaluation of the role of iron overload in fatty liver disease.

Nonalcoholic fatty liver disease (NAFLD) has been associated with a condition known as the dysmetabolic iron overload syndrome, but the frequency and severity of iron overload in NAFLD is not well described. There is emerging evidence that mild to moderate excess hepatic iron can aggravate the risk of progression of NAFLD to nonalcoholic steatohepatitis and eventually cirrhosis. Mechanisms are postulated to be via reactive oxygen species, inflammatory cytokines, lipid oxidation, and oxidative stress. The aim of this review is to assess the evidence for true hepatic iron overload in NAFLD, to discuss the pathogenesis by which excess iron may be toxic, and to critically evaluate the studies designed to deplete iron by regular venesection. In brief, the studies are inconclusive due to heterogeneity in eligibility criteria, sample size, randomization, hepatic iron measurement, serial histological endpoints, target ferritin levels, length of venesection, and degree of confounding lifestyle intervention. We propose a trial designed to overcome the limitations of these studies.

Wide-field Trend-based Progression Analysis of Combined Retinal Nerve Fiber Layer and Ganglion Cell Inner Plexiform Layer Thickness: A New Paradigm to Improve Glaucoma Progression Detection.

OBJECTIVE: Evaluation of glaucoma progression with OCT has been centered on the analysis of progressive retinal nerve fiber layer (RNFL) thinning over the parapapillary region and/or progressive ganglion cell inner plexiform layer (GCIPL) thinning over the macula. We investigated (1) whether combining the RNFL and GCIPL as a single layer (i.e., RNFL-GCIPL) for wide-field progression analysis outperforms wide-field progression analysis of the RNFL or the GCIPL, and (2) whether eyes with progressive RNFL-GCIPL thinning are at risk of visual field (VF) progression. DESIGN: Prospective, longitudinal study. PARTICIPANTS: A total of 440 eyes from 236 glaucoma patients; 98 eyes from 49 healthy individuals. METHODS: OCT RNFL/GCIPL/RNFL-GCIPL thickness and VF measurements were obtained at ∼4-month intervals for ≥3 years. Progressive changes of the RNFL/GCIPL/RNFL-GCIPL thicknesses were analyzed over a wide field (12×9 mm2) covering the parapapillary region and the macula with trend-based progression analysis (TPA) controlled at a false discovery rate of 5%. VF progression was determined by the Early Manifest Glaucoma Trial criteria. MAIN OUTCOME MEASURES: Proportions of eyes with progressive RNFL/GCIPL/RNFL-GCIPL thinning; hazard ratios (HRs) for development of VF progression. RESULTS: More eyes showed progressive RNFL-GCIPL thinning (127 eyes; 28.9%, 95% confidence interval [CI]: 23.9%-33.8%) than progressive RNFL thinning (74 eyes; 16.8%, 95% CI: 13.1%-20.6%) and progressive GCIPL thinning (26 eyes; 5.9%, 95% CI: 3.7%-8.1%) in the glaucoma group over the study follow-up. Progressive RNFL-GCIPL thinning was almost always detected before or simultaneously with progressive RNFL thinning or progressive GCIPL thinning. The specificity of TPA (estimated from the healthy group) for detection of progressive RNFL-GCIPL thinning, progressive RNFL thinning, and progressive GCIPL thinning was 83.7% (95% CI: 74.9%-92.4%), 94.9% (95% CI: 90.6%-99.2%), and 96.9% (95% CI: 93.5%-100.0%), respectively. Eyes with progressive RNFL-GCIPL thinning had a higher risk to develop possible (HR: 2.4, 95% CI: 1.2-5.0) or likely (HR: 4.6, 95% CI: 1.5-14.0) VF progression, with adjustment of covariates, compared with eyes without progressive RNFL-GCIPL thinning. CONCLUSIONS: Progression analysis of RNFL-GCIPL thickness reveals a significant portion of progressing eyes that neither progression analysis of RNFL thickness nor GCIPL thickness would identify. Wide-field progression analysis of RNFL-GCIPL thickness is effective to inform the risk of VF progression in glaucoma patients.

Impact of PTEN/SOCS3 deletion on amelioration of dendritic shrinkage of retinal ganglion cells after optic nerve injury.

Retinal ganglion cell (RGC) degeneration, leading to irreversible blindness in chronic optic neuropathies, commonly begins with dendritic shrinkage followed by axon degeneration. Although limited axon regeneration in the optic nerve is possible with a genetic deletion of PTEN/SOCS3 after optic nerve injury, the roles of PTEN/SOCS3 on dendritic preservation and regeneration remain unclear. This study investigated the effect of PTEN/SOCS3 genetic deletion on the structural integrity of RGC dendrites and axons in the retina following optic nerve crush. Using time-lapse, in vivo confocal scanning laser ophthalmoscopy to serially image dendritic and axonal arborizations of RGCs over six months after injury, RGC dendrites and axons were only preserved in Thy-1-YFP/PTEN-/- and Thy-1-YFP/PTEN-/-SOCS3-/- mice, and axons in the retina regenerated at a rate of 21.1 µm/day and 15.5 µm/day, respectively. By contrast, dendritic complexity significantly decreased in Thy-1-YFP-SOCS3-/- and control mice at a rate of 7.0 %/day and 7.1 %/day, respectively, and no axon regeneration in the retina was observed. RGC survival probability was higher in Thy-1-YFP/PTEN-/- and Thy-1-YFP/PTEN-/-SOCS3-/- mice compared with Thy-1-YFP-SOCS3-/- and control mice. The differential responses between the transgenic mice demonstrate that although a genetic deletion of PTEN, SOCS3, or PTEN/SOCS3 allows partial axon regeneration in the optic nerve after optic nerve crush, a deletion of PTEN, but not SOCS3, ameliorates RGC dendritic shrinkage. This shows that the signaling pathways involved in promoting axon regeneration do not equally contribute to the preservation of dendrites, which is crucial to the translational application of neuroregenerative therapies for visual restoration.

Hepatitis B virus activity is not associated with degree of liver steatosis in patients with hepatitis B-related chronic liver disease.

BACKGROUND & AIMS: The recently published manuscript by Zhu and colleagues "Hepatitis B virus infection and risk of non-alcoholic fatty liver disease: A population-based cohort study" found no correlation between presence of chronic HBV and presence of common risk factors for non-alcoholic fatty liver disease on primary analysis. A limitation to this study, like most population based research, is the absence of liver histology, which is considered gold standard for assessment of non-alcoholic fatty liver disease. METHODS: Our group studied the association between hepatitis B viral activity and non-alcoholic fatty liver disease activity as measured by grade of steatohepatitis/fibrosis on liver biopsy by analysing consecutive liver histology samples from patients with chronic hepatitis B at a single quaternary liver transplant centre. RESULTS: Linear regression modelling for active viral hepatitis on histological examination against degree of steatohepatitis showed no correlation (r2  = .018, all P> .1). Linear regression of degree of steatohepatitis vs hepatitis B viral load also showed no correlation. CONCLUSIONS: Our work is concordant with the manuscript from Zhu et al; we found no significant correlation between hepatitis B viral activity and degree of steatohepatitis.

Association of the CAV1-CAV2 locus with normal-tension glaucoma in Chinese and Japanese.

BACKGROUND: The CAV1-CAV2 locus has been associated with primary open-angle glaucoma (POAG) and intraocular pressure. However, its association with normal-tension glaucoma (NTG) was inconclusive. Therefore, we evaluated this association in Chinese and Japanese. METHODS: Two single-nucleotide polymorphisms (SNPs, rs4236601 and rs1052990) from previous genome-wide association studies of POAG were genotyped in a total of 2220 study subjects: a Hong Kong Chinese cohort of 537 NTG patients and 490 controls, a Shantou Chinese cohort of 102 NTG and 731 controls and an Osaka Japanese cohort of 153 NTG and 207 controls. Subgroup analysis by gender was conducted. Outcomes from different cohorts were combined using meta-analysis. RESULTS: SNP rs4236601 was significantly associated with NTG in the two Chinese cohorts (Pmeta = .0019, OR = 4.55, I2 = 0). In contrast, rs4236601 was monomorphic in the Osaka cohort. The association of rs1052990 was insignificant in a meta-analysis combining Chinese and Japanese cohorts (Pmeta = .81, OR = 1.05; I2 = 64%), and the OR tended towards opposite directions between Chinese (OR = 1.26) and Japanese (OR = 0.69). Gender-specific effects of the SNPs were not statistically significant in the logistic regression or Breslow-day tests of ORs (P > .05), although rs4236601 was significant in males (P = .0068; OR = 10.30) but not in females (P = .14; OR = 2.65) in the meta-analysis of Chinese subjects. CONCLUSIONS: In this study, we confirmed the association of rs4236601 at the CAV1-CAV2 locus with NTG in Chinese. SNP rs4236601 is monomorphic, and rs1052990 tends towards a different direction in the Japanese cohort. Further studies are warranted to verify the ethnic difference and gender-specific effects of this locus.

Factors governing the transduction efficiency of adeno-associated virus in the retinal ganglion cells following intravitreal injection.

Efficient transduction of the retinal ganglion cells (RGCs) is a prerequisite to maximize therapeutic outcomes in any form of gene therapy for optic neuropathies. Whereas subretinal injection of adeno-associated virus 2 (AAV2) has been well-characterized, the serotype, viral load, and promoter combinations that govern RGC transduction efficiency following intravitreal injection remains poorly understood. We evaluated the transduction efficiency of seven AAV2 serotypes (AAV2/1, AAV2/2, AAV2/4, AAV2/5, AAV2/6, AAV2/8, and AAV2/9) for the RGCs at 4 weeks following intravitreal injection in C57BL/6J mice. Intravitreal injection of 1 × 109 vg of AAV2/2 with eGFP driven by the CMV promoter attained a higher transduction efficiency for the RGCs (60.0 ± 4.2%) compared with the six other AAV2 serotypes with eGFP driven by the same promoter injected at the same viral load ( < 3.0%). Reporter driven by the CAG promoter had a lower transduction efficiency (up to 42.0 ± 5.8%) compared with that driven by the CMV reporter (60.0 ± 4.2%, p ≤ 0.024). There was a viral dose-dependent transduction effect of AAV2/2-CMV-eGFP and the transduction efficiency was 40.2 ± 3.9%, 16.6 ± 4.2%, and 2.6 ± 0.2% when the viral load decreased to 5 × 108 vg, 1 × 108 vg, and 1 × 107 vg, respectively. Optimizing viral serotype, viral load, and promoter construct of AAV2 is important to maximize transgene expression in RGC-targeted gene therapy.

Mutant RAMP2 causes primary open-angle glaucoma via the CRLR-cAMP axis.

PURPOSE: Primary open-angle glaucoma (POAG) is the leading cause of irreversible blindness worldwide and mutations in known genes can only explain 5-6% of POAG. This study was conducted to identify novel POAG-causing genes and explore the pathogenesis of this disease. METHODS: Exome sequencing was performed in a Han Chinese cohort comprising 398 sporadic cases with POAG and 2010 controls, followed by replication studies by Sanger sequencing. A heterozygous Ramp2 knockout mouse model was generated for in vivo functional study. RESULTS: Using exome sequencing analysis and replication studies, we identified pathogenic variants in receptor activity-modifying protein 2 (RAMP2) within three genetically diverse populations (Han Chinese, German, and Indian). Six heterozygous RAMP2 pathogenic variants (Glu39Asp, Glu54Lys, Phe103Ser, Asn113Lysfs*10, Glu143Lys, and Ser171Arg) were identified among 16 of 4763 POAG patients, whereas no variants were detected in any exon of RAMP2 in 10,953 control individuals. Mutant RAMP2s aggregated in transfected cells and resulted in damage to the AM-RAMP2/CRLR-cAMP signaling pathway. Ablation of one Ramp2 allele led to cAMP reduction and retinal ganglion cell death in mice. CONCLUSION: This study demonstrated that disruption of RAMP2/CRLR-cAMP axis could cause POAG and identified a potential therapeutic intervention for POAG.

Association of the SIX6 locus with primary open angle glaucoma in southern Chinese and Japanese.

The purpose of the study was to evaluate the association profiles of the SIX6 locus with primary open-angle glaucoma (POAG) in southern Chinese and Japanese. In this study, we tested single marker and haplotype-based associations of 11 tagging single nucleotide polymorphisms (SNPs) covering the SIX6 locus with POAG in a Hong Kong Chinese cohort (N = 1402). A novel SNP (i.e., rs12436579) and two SNPs (i.e., rs33912345 and rs10483727) from previous genome-wide association studies were further tested in a Chinese cohort from Shantou (N = 888) and a Japanese cohort from Osaka (N = 463). Results from the three cohorts were meta-analysed using a random-effect model. We found rs12436579, which has not been previously reported, was associated with POAG in Hong Kong and Shantou Chinese (Pcombined = 4.3 × 10-5, OR = 0.72, I2 = 0). Additionally, we replicated the association of one known SNP, rs33912345 (Pcombined = 0.0061, OR = 0.69, I2 = 45%), with POAG in the Chinese cohorts but not in the Japanese cohort (P > 0.6). Another known SNP, rs10483727, was nominally associated with POAG in the two Chinese cohorts (Pcombined = 0.017, OR = 0.70, I2 = 53%). All these three SNPs were significantly associated with POAG when the three cohorts were combined in meta-analysis (Pcombined<0.005). Furthermore, two haplotypes, C-C (Pcombined = 1.13 × 10-5, OR = 1.41, I2 = 0) and A-A (Pcombined = 0.045, OR = 0.68, I2 = 70%), defined by rs33912345-rs12436579 were associated with POAG in Chinese but not in Japanese. In conclusion, this study confirmed the association between two GWAS SNPs in SIX6 (rs33912345 and rs10483727) and POAG. Also, a SNP, rs12436579, not associated with POAG before, was found to be associated with POAG in Chinese. Further studies are warranted to elucidate the role of this novel SNP in POAG.

Patterns of internet and social media use in colorectal surgery.

BACKGROUND: Surgeons use the Internet and social media to provide health information, promote their clinical practice, network with clinicians and researchers, and engage with journal clubs and online campaigns. While surgical patients are increasingly Internet-literate, the prevalence and purpose of searching for online health information vary among patient populations. We aimed to characterise patient and colorectal surgeon (CRS) use of the Internet and social media to seek health information. METHODS: Members of the Colorectal Society of Australia and New Zealand and patients under the care of CRS at the Royal Prince Alfred Hospital, Sydney, were surveyed. Questions pertained to the types of information sought from the Internet, the platforms used to seek it, and the perceived utility of this information. RESULTS: Most CRS spent 2-6 h per week using the Internet for clinical purposes and an additional 2-6 h per week for research. 79% preferred literature databases as an information source. CRS most commonly directed patients to professional healthcare body websites. 59% of CRS use social media, mainly for socialising or networking. Nine percent of surgeons spent > 1 h per week on social media for clinical or research purposes. 72% of surgeons have a surgical practice website. 43% of patients searched the Internet for information on their doctor, and 75% of patients sought information on their symptoms or condition. However, 25% used health-specific websites, and 14% used professional healthcare body websites. Around 84% of patients found the information helpful, and 8% found it difficult to find information on the Internet. 12% of patients used social media to seek health information. CONCLUSIONS: Colorectal surgery patients commonly find health information on the Internet but social media is not a prominent source of health information for patients or CRS.

Integrating Macular Ganglion Cell Inner Plexiform Layer and Parapapillary Retinal Nerve Fiber Layer Measurements to Detect Glaucoma Progression.

PURPOSE: To investigate the temporal relationship among progressive macular ganglion cell inner plexiform layer (GCIPL) thinning, progressive parapapillary retinal nerve fiber layer (RNFL) thinning, and visual field (VF) progression in patients with primary open-angle glaucoma (POAG). DESIGN: Prospective study. PARTICIPANTS: One hundred thirty-six POAG patients (231 eyes) followed up for ≥5 years. METHODS: OCT imaging of the macular GCIPL and parapapillary RNFL and perimetry were performed at ∼ 4-month intervals. Progressive GCIPL and RNFL thinning were determined by Guided Progression Analysis (GPA) of serial GCIPL and RNFL thickness maps. The specificities of GPA were calculated from the proportions of eyes with progressive GCIPL or RNFL thinning in 67 eyes of 36 healthy individuals followed up for ≥5 years. Visual field progression (likely or possible) was determined by the Early Manifest Glaucoma Trial criteria. MAIN OUTCOME MEASURES: Hazard ratios for VF progression, progressive RNFL thinning, and progressive GCIPL thinning, as determined by time-varying Cox models. RESULTS: GPA detected 57 eyes (24.7%) with progressive GCIPL thinning and 66 eyes (28.6%) with progressive RNFL thinning at a specificity of 95.5% and 91.0%, respectively. Thirty-five eyes (15.2%) demonstrated progressive RNFL and GCIPL thinning, whereas 53 eyes (22.9%) demonstrated progressive RNFL or GCIPL thinning. Eyes with progressive GCIPL thinning had a higher risk for progressive RNFL thinning (HR, 5.27; 95% confidence interval [CI], 2.89-9.62), whereas eyes with progressive RNFL thinning were also at a higher risk for progressive GCIPL thinning (HR, 2.99; 95% CI, 1.48-6.02), after adjusting for baseline covariates. The HRs for likely and possible VF progression were 3.48 (95% CI, 1.51-8.01) and 2.74 (95% CI, 1.26-5.98), respectively, on detection of progressive GCIPL thinning and 3.66 (95% CI, 1.68-7.97) and 2.54 (95% CI, 1.23-5.21), respectively, on detection of progressive RNFL thinning after adjusting for baseline covariates. Eyes with VF progression were not at risk of progressive RNFL or GCIPL thinning (P ≥ 0.493). CONCLUSIONS: Progressive macular GCIPL thinning and progressive parapapillary RNFL thinning are mutually predictive. Because progressive RNFL thinning and progressive GCIPL thinning are both indicative of VF progression, integrating macular GCIPL and parapapillary RNFL measurements is relevant to facilitate early detection of disease deterioration in glaucoma patients.

Detection of Bruch's Membrane Opening in Healthy Individuals and Glaucoma Patients with and without High Myopia.

PURPOSE: To determine the proportions of eyes with indiscernible Bruch's membrane opening (BMO) in glaucoma patients and healthy individuals with and without high myopia and to investigate factors contributing to indiscernible BMO. DESIGN: Cross-sectional study. PARTICIPANTS: Five hundred eyes from 315 participants, including 212 high myopic eyes (axial length [AL], ≥26 mm) from 80 glaucoma patients and 60 healthy individuals and 288 non-high myopic eyes (AL, <26 mm) from 96 glaucoma patients and 88 healthy individuals. METHODS: The optic disc was imaged by the Spectralis OCT (Heidelberg Engineering, Heidelberg, Germany) using 24 equally spaced radial B-scans. The BMO was located independently by 2 trained observers and was recorded as discernible or indiscernible over 48 meridians in each eye. The BMO of a meridian was determined to be indiscernible when both observers failed to identify its location. The agreement between the observers was evaluated with κ statistics. Factors associated with indiscernible BMO were identified with multivariable, multilevel logistic regression modeling. MAIN OUTCOME MEASURES: Proportions of eyes with indiscernible BMO and hazard ratios (HRs) of factors associated with indiscernible BMO. RESULTS: The agreement for assessment of BMO visibility between the observers was good (κ, 0.631; 95% confidence interval, 0.602-0.661). In the groups with and without high myopia, 32.1% and 8.2% of glaucomatous eyes had 1 or more meridians with indiscernible BMO, respectively. In the healthy eyes, the respective proportions were 28.0% and 3.9%. The proportions were significantly higher in eyes with high myopia compared to eyes without high myopia in the glaucoma group (P < 0.001) and the healthy group (P < 0.001). The temporal meridian, followed by the inferotemporal and superotemporal meridians, of the optic disc were the most frequent locations with indiscernible BMO. Increased AL, advanced glaucoma, ß parapapillary atrophy, and young age were associated with an increased HR of indiscernible BMO (P ≤ 0.032). CONCLUSIONS: A significant proportion of high myopic eyes have indiscernible BMO at the temporal, superotemporal, and inferotemporal meridians of the optic disc, which may compromise the measurement of neuroretinal rim in the diagnostic evaluation of glaucoma.

Very high volume fly ash green concrete for applications in India.

Safe disposal of fly ash generated by coal-based thermal power plants continues to pose significant challenges around the world and in India in particular. Green structural concrete with 80% cement replaced by local Chinese fly ash has been recently developed to achieve a target characteristic compressive strength of 45 MPa. Such green concrete mixes are not only cheaper in cost, but also embody lower energy and carbon footprint, compared with conventional mixes. This study aims to adopt such materials using no less than 80% fly ash as binder in routine concrete works in countries like India with the commonly used lower target characteristic compressive strength of 30 MPa. It is achieved by the simple and practical method of adjusting the water/binder ratio and/or superplasticiser dosage. The proposed green concrete shows encouraging mechanical properties at 7 days and 28 days, as well as much lower material cost and environmental impact compared with commercial Grade 30 concrete. This technology can play an important role in meeting the huge infrastructure demands in India in a sustainable manner.

A common variant near TGFBR3 is associated with primary open angle glaucoma.

Primary open angle glaucoma (POAG), a major cause of blindness worldwide, is a complex disease with a significant genetic contribution. We performed Exome Array (Illumina) analysis on 3504 POAG cases and 9746 controls with replication of the most significant findings in 9173 POAG cases and 26 780 controls across 18 collections of Asian, African and European descent. Apart from confirming strong evidence of association at CDKN2B-AS1 (rs2157719 [G], odds ratio [OR] = 0.71, P = 2.81 × 10(-33)), we observed one SNP showing significant association to POAG (CDC7-TGFBR3 rs1192415, ORG-allele = 1.13, Pmeta = 1.60 × 10(-8)). This particular SNP has previously been shown to be strongly associated with optic disc area and vertical cup-to-disc ratio, which are regarded as glaucoma-related quantitative traits. Our study now extends this by directly implicating it in POAG disease pathogenesis.

Risk of Visual Field Progression in Glaucoma Patients with Progressive Retinal Nerve Fiber Layer Thinning: A 5-Year Prospective Study.

PURPOSE: To investigate whether progressive retinal nerve fiber layer (RNFL) thinning is predictive of progressive visual field (VF) loss in glaucoma. DESIGN: Prospective study. PARTICIPANTS: A total of 139 primary open-angle glaucoma patients (240 eyes) followed up for ≥5 years. METHODS: Retinal nerve fiber layer imaging and VF testing were performed at ∼4-month intervals. Progressive RNFL thinning was determined by event analysis (Guided Progression Analysis [GPA]) and trend analysis (Trend-based Progression Analysis [TPA]) of serial registered RNFL thickness maps. VF progression was detected according to the Early Manifest Glaucoma Trial (EMGT) ("likely progression") and pointwise linear regression (PLR) criteria (≥3 contiguous locations with sensitivity change <0 decibels [dB]/year at P < 0.01). Hazard ratios (HRs) for predicting VF progression were calculated by Cox proportional hazard modeling with progressive RNFL thinning as a time-dependent covariate. The specificity of GPA/TPA for detection of RNFL changes was determined by the proportion of eyes with significant RNFL thinning/thickening in 25 normal subjects followed weekly for 8 consecutive weeks and the proportion with significant RNFL thickening in the glaucoma group. MAIN OUTCOME MEASURES: The HRs of VF progression. RESULTS: A total of 65 (27.1%) and 117 eyes (48.8%) had progressive RNFL thinning based on GPA and TPA, respectively, and 30 (12.5%) and 39 eyes (16.3%) had VF progression per the EMGT and PLR criteria, respectively, during follow-up. Eyes with progressive RNFL thinning had lower VF survival estimates and a faster decline of visual field index than eyes without. Progressive RNFL thinning predicted the development of VF progression with HRs of 8.44 (95% confidence interval, 3.30-21.61) (EMGT criteria) and 5.11 (2.51-10.42) (PLR criteria) for TPA and 3.95 (1.74-8.93) (EMGT criteria) and 3.81 (1.83-7.92) (PLR criteria) for GPA after controlling for baseline covariates. The specificities of GPA and TPA were 100% (83.4%-100.0%) in the normal group and 81.7% (76.2%-86.4%) and 84.2% (78.9%-88.6%), respectively, in the glaucoma group. CONCLUSIONS: Progressive RNFL thinning determined by GPA and TPA is predictive of detectable functional decline in glaucoma. This finding underscores the significance of detecting progressive RNFL thinning and its relevance to initiate or augment treatment for glaucoma patients. Regulatory authorities may consider progressive RNFL thinning as an outcome measure in clinical trials for evaluation of glaucoma treatment.

Optic Nerve Head Deformation in Glaucoma: A Prospective Analysis of Optic Nerve Head Surface and Lamina Cribrosa Surface Displacement.

PURPOSE: To evaluate long-term, longitudinal displacement of the optic nerve head (ONH) and anterior lamina cribrosa surfaces in glaucoma patients imaged with spectral-domain optical coherence tomography (SD OCT). DESIGN: Prospective study. PARTICIPANTS: A total of 173 eyes of 108 subjects (88 with glaucoma and 20 normal subjects) followed for a mean of 5.3 years. METHODS: The optic disc was imaged with SD OCT at approximately 4-month intervals, and the ONH surface depth (ONHSD), anterior lamina cribrosa surface depth (ALCSD), and prelaminar tissue thickness (PTT) were measured. The reproducibility coefficients of ONHSD, ALCSD, and PTT were calculated from 2 baseline measurements of the glaucoma group. Change in ONHSD/ALCSD/PTT was confirmed when the differences between the first baseline and the latest 2 consecutive follow-up visits were greater than the corresponding reproducibility coefficient. Factors associated with ONHSD and ALCSD changes were identified with linear mixed modeling. MAIN OUTCOME MEASURES: Proportion of eyes with ONHSD/ALCSD change. RESULTS: Within the glaucoma group, 23.9% (33 eyes) had confirmed ONHSD change (15.2% with posterior and 8.7% with anterior displacement) and 24.6% (34 eyes) had confirmed ALCSD change (12.3% with posterior and 12.3% with anterior displacement). Some 9.4% (13 eyes) showed a decrease in PTT, and 2.2% (3 eyes) showed an increase in PTT. The specificity for detection of ONHSD/ALCSD/PTT change was 91.4% (95% confidence interval [CI], 77.6-97.0), 82.9% (95% CI, 67.3-91.9), and 94.3% (95% CI, 81.4-98.4), respectively. There were no significant differences in the proportion of eyes with visual field progression or history of filtration surgery between the groups with anterior and posterior displacement of ONH/anterior laminar surfaces (P ≥ 0.678). For each millimeter of mercury increase in the average intraocular pressure (IOP) during follow-up, the ONH and anterior laminar surfaces displaced posteriorly by 1.6 µm and 2.0 µm, respectively. An older age was associated with a decrease in magnitude of posterior displacement of the ONH and anterior laminar surfaces (P ≤ 0.009). CONCLUSIONS: The ONH and anterior laminar surfaces displaced not only posteriorly but also anteriorly (with reference to Bruch's membrane opening) in a significant portion of glaucoma patients. The magnitude of change was related to age and the averaged IOP during follow-up.