Convalescent human plasma candidate reference materials protect against Crimean-Congo haemorrhagic fever virus (CCHFV) challenge in an A129 mouse model.

Crimean-Congo Haemorrhagic Fever Virus (CCHFV) is spread by infected ticks or direct contact with blood, tissues and fluids from infected patients or livestock. Infection with CCHFV causes severe haemorrhagic fever in humans which is fatal in up to 83 % of cases. CCHFV is listed as a priority pathogen by the World Health Organization (WHO) and there are currently no widely-approved vaccines. Defining a serological correlate of protection against CCHFV infection would support the development of vaccines by providing a 'target threshold' for pre-clinical and clinical immunogenicity studies to achieve in subjects and potentially obviate the need for in vivo protection studies. We therefore sought to establish titratable protection against CCHFV using pooled human convalescent plasma, in a mouse model. Convalescent plasma collected from seven individuals with a known previous CCHFV virus infection were characterised using binding antibody and neutralisation assays. All plasma recognised nucleoprotein and the Gc glycoprotein, but some had a lower Gn glycoprotein response by ELISA. Pooled plasma and two individual donations from convalescent donors were administered intraperitoneally to A129 mice 24 h prior to intradermal challenge with CCHFV (strain IbAr10200). A partial protective effect was observed with all three convalescent plasmas characterised by longer survival post-challenge and reduced clinical score. These protective responses were titratable. Further characterisation of the serological reactivities within these samples will establish their value as reference materials to support assay harmonisation and accelerate vaccine development for CCHFV.

Polygenic Risk Scores Driving Clinical Change in Glaucoma.

Glaucoma is a clinically heterogeneous disease and the world's leading cause of irreversible blindness. Therapeutic intervention can prevent blindness but relies on early diagnosis, and current clinical risk factors are limited in their ability to predict who will develop sight-threatening glaucoma. The high heritability of glaucoma makes it an ideal substrate for genetic risk prediction, with the bulk of risk being polygenic in nature. Here, we summarize the foundations of glaucoma genetic risk, the development of polygenic risk prediction instruments, and emerging opportunities for genetic risk stratification. Although challenges remain, genetic risk stratification will significantly improve glaucoma screening and management.

Phenotypic consequences of a nanophthalmos-associated TMEM98 variant in human and mouse.

Nanophthalmos is characterised by shorter posterior and anterior segments of the eye, with a predisposition towards high hyperopia and primary angle-closure glaucoma. Variants in TMEM98 have been associated with autosomal dominant nanophthalmos in multiple kindreds, but definitive evidence for causation has been limited. Here we used CRISPR/Cas9 mutagenesis to recreate the human nanophthalmos-associated TMEM98 p.(Ala193Pro) variant in mice. The p.(Ala193Pro) variant was associated with ocular phenotypes in both mice and humans, with dominant inheritance in humans and recessive inheritance in mice. Unlike their human counterparts, p.(Ala193Pro) homozygous mutant mice had normal axial length, normal intraocular pressure, and structurally normal scleral collagen. However, in both homozygous mice and heterozygous humans, the p.(Ala193Pro) variant was associated with discrete white spots throughout the retinal fundus, with corresponding retinal folds on histology. This direct comparison of a TMEM98 variant in mouse and human suggests that certain nanophthalmos-associated phenotypes are not only a consequence of a smaller eye, but that TMEM98 may itself play a primary role in retinal and scleral structure and integrity.

High Polygenic Risk Is Associated with Earlier Initiation and Escalation of Treatment in Early Primary Open-Angle Glaucoma.

PURPOSE: To assess the association between a glaucoma polygenic risk score (PRS) and treatment outcomes in primary open-angle glaucoma. DESIGN: Prospective, observational cohort study. PARTICIPANTS: Participants from the Progression Risk of Glaucoma: Relevant SNPs with Significant Association Study were divided into a cohort with suspect glaucoma who were treatment naive at enrollment and one with early manifest and suspect glaucoma receiving treatment at enrollment. METHODS: A per-allele weighted glaucoma PRS was calculated for 1107 participants. Multivariable mixed-effects Cox proportional regression analysis assessed the association between PRS and time to commencement of intraocular pressure (IOP)-lowering therapy in 416 patients with suspect glaucoma who were treatment naive at study enrollment. Secondary analysis evaluated the association between PRS and escalation of IOP-lowering therapy among 691 patients with suspect and early manifest glaucoma who were receiving IOP-lowering therapy at enrollment. MAIN OUTCOME MEASURES: Commencement or escalation of IOP-lowering therapy. RESULTS: A higher PRS was associated with a greater risk of commencing IOP-lowering therapy within 5 years (hazard ratio [HR], 1.45 per 1 standard deviation [/SD]; 95% confidence interval [CI], 1.27-1.62; P < 0.001). Participants in the upper population-based quintile showed a 3.3 times greater risk of commencing therapy by 5 years than those in the lowest quintile (HR, 3.30; 95% CI, 1.63-6,70; P < 0.001) and a 5.4 times greater risk of commencing IOP-lowering therapy by 2 years than the those in the lowest quintile (HR, 5.45; 95% CI, 2.08-14.25; P < 0.001). A higher PRS was associated with a greater risk of treatment escalation among patients receiving treatment at enrollment (HR, 1.19/SD; 95% CI, 1.09-1.31; P < 0.001). In combined analysis of all participants, participants in the top population-based quintile were at 2.3 times greater risk of requiring initiation or escalation of IOP-lowering therapy than those in the lowest quintile (HR, 2.33; 95% CI, 1.75-3.01; P < 0.001). CONCLUSIONS: This study demonstrated novel associations between glaucoma polygenic risk and risk of commencement or escalation of IOP-lowering therapy, building on previous work highlighting the potential clinical usefulness of genetic risk stratification in glaucoma. FINANCIAL DISCLOSURE(S): Proprietary or commercial disclosure may be found after the references.

No Strong Association between the Apolipoprotein E E4 Allele and Glaucoma: A Multicohort Study.

Purpose: To elucidate a potential association between the apolipoprotein E (APOE) E4 allele and glaucoma prevalence in large cohorts. Design: A cross-sectional analysis of baseline and prospectively collected cohort data. Participants: UK Biobank (UKBB) participants of genetically determined European ancestry (n = 438 711). Replication analyses were performed using clinical and genotyping data collected from European participants recruited to the Canadian Longitudinal Study of Aging (CLSA; n = 18 199), the Australian and New Zealand Registry of Advanced Glaucoma (ANZRAG; n = 1970), and the Blue Mountains Eye Study (BMES; n = 2440). Methods: Apolipoprotein E alleles and genotypes were determined, and their distributions were compared on the basis of glaucoma status. Similar analyses were performed using positive control outcomes associated with the APOE E4 allele (death, dementia, age-related macular degeneration) and negative control outcomes not associated with the APOE E4 allele (cataract, diabetic eye disease). Outcome phenotypes were also correlated with Alzheimer's dementia (AD), a clinical outcome highly associated with the APOE E4 allele. Main Outcome Measures: Results of APOE E4 genotype-phenotype comparisons were reported as odds ratios (ORs) with 95% confidence intervals (CIs). Replication analyses investigated APOE E4 associations in 2 replication cohorts (CLSA and ANZRAG/BMES). Results: The APOE E4 allele was inversely associated with glaucoma (OR, 0.96; 95% CI, 0.93-0.99; P = 0.016) and both negative controls (cataract: OR, 0.98; 95% CI, 0.96-0.99; P = 0.015; diabetic eye disease: OR, 0.92; 95% CI, 0.87-0.97; P = 0.003) in the UKBB cohort. A paradoxical positive association was observed between AD and both glaucoma (OR, 1.30; 95% CI, 1.08-1.54; P < 0.01) and cataract (OR, 1.15; 1.04-1.28; P = 0.018). No association between the APOE E4 allele and glaucoma was observed in either replication cohort (CLSA: OR, 1.03; 95% CI, 0.89-1.19; P = 0.66; ANZRAG/BMES: OR, 0.97; 95% CI, 0.84-1.12; P = 0.65). Conclusions: A small negative association observed between APOE E4 and glaucoma within the UKBB was not evident in either replication cohort and may represent an artifact of glaucoma underdiagnosis in APOE E4 carriers. Financial Disclosures: The author(s) have no proprietary or commercial interest in any materials discussed in this article.

Physical Activity Is Associated With Macular Thickness: A Multi-Cohort Observational Study.

Purpose: To assess the association between physical activity and spectral-domain optical coherence tomography (SD-OCT)-measured rates of macular thinning in an adult population with primary open-angle glaucoma. Methods: The correlation between accelerometer-measured physical activity and rates of macular ganglion cell-inner plexiform layer (GCIPL) thinning was measured in 735 eyes from 388 participants of the Progression Risk of Glaucoma: RElevant SNPs with Significant Association (PROGRESSA) study. The association between accelerometer-measured physical activity and cross-sectional SD-OCT macular thickness was then assessed in 8862 eyes from 6152 participants available for analysis in the UK Biobank who had SD-OCT, ophthalmic, comorbidity, and demographic data. Results: Greater physical activity was associated with slower rates of macular GCIPL thinning in the PROGRESSA study (beta = 0.07 µm/y/SD; 95% confidence interval [CI], 0.03-0.13; P = 0.003) after adjustment for ophthalmic, demographic and systemic predictors of macular thinning. This association persisted in subanalyses of participants characterized as glaucoma suspects (beta = 0.09 µm/y/SD; 95% CI, 0.03-0.15; P = 0.005). Participants in the upper tertile (greater than 10,524 steps/d) exhibited a 0.22-µm/y slower rate of macular GCIPL thinning than participants in the lower tertile (fewer than 6925 steps/d): -0.40 ± 0.46 µm/y versus -0.62 ± 0.55 µm/y (P = 0.003). Both time spent doing moderate/vigorous activity and mean daily active calories were positively correlated with rate of macular GCIPL thinning (moderate/vigorous activity: beta = 0.06 µm/y/SD; 95% CI, 0.01-0.105; P = 0.018; active calories: beta = 0.06 µm/y/SD; 95% CI, 0.006-0.114; P = 0.032). Analysis among 8862 eyes from the UK Biobank revealed a positive association between physical activity and cross-sectional total macular thickness (beta = 0.8 µm/SD; 95% CI, 0.47-1.14; P < 0.001). Conclusions: These results highlight the potential neuroprotective benefits of exercise on the human retina.

VelcroVax: a "Bolt-On" Vaccine Platform for Glycoprotein Display.

Having varied approaches to the design and manufacture of vaccines is critical in being able to respond to worldwide needs and newly emerging pathogens. Virus-like particles (VLPs) form the basis of two of the most successful licensed vaccines (against hepatitis B virus [HBV] and human papillomavirus). They are produced by recombinant expression of viral structural proteins, which assemble into immunogenic nanoparticles. VLPs can be modified to present unrelated antigens, and here we describe a universal "bolt-on" platform (termed VelcroVax) where the capturing VLP and the target antigen are produced separately. We utilize a modified HBV core (HBcAg) VLP with surface expression of a high-affinity binding sequence (Affimer) directed against a SUMO tag and use this to capture SUMO-tagged gp1 glycoprotein from the arenavirus Junín virus (JUNV). Using this model system, we have solved the first high-resolution structures of VelcroVax VLPs and shown that the VelcroVax-JUNV gp1 complex induces superior humoral immune responses compared to the noncomplexed viral protein. We propose that this system could be modified to present a range of antigens and therefore form the foundation of future rapid-response vaccination strategies. IMPORTANCE The hepatitis B core protein (HBc) forms noninfectious virus-like particles, which can be modified to present a capturing molecule, allowing suitably tagged antigens to be bound on their surface. This system can be adapted and provides the foundation for a universal "bolt-on" vaccine platform (termed VelcroVax) that can be easily and rapidly modified to generate nanoparticle vaccine candidates.

The Role of Tocilizumab in Glucocorticoid Resistant Giant Cell Arteritis: A Case Series and Literature Review.

BACKGROUND: Glucocorticoid-resistant giant cell arteritis (GCA) describes a subgroup of patients whose visual acuity further declines despite immediate administration of high-dose intravenous glucocorticoids. Tocilizumab, a recombinant humanized anti-interleukin-6 receptor monoclonal antibody may be used as "rescue" therapy in these cases but requires more research. METHODS: We present a literature review on tocilizumab as rescue therapy and a retrospective case series of 5 consecutive glucocorticoid (GC) resistant, temporal artery biopsy (TAB)-positive [corrected] patients. RESULTS: The use of tocilizumab as rescue therapy for GC-resistant GCA is limited to 3 case reports. Two cases saw visual acuity improvement in the newly affected contralateral eye after 8 mg/kg of intravenous tocilizumab (from 6/60 to 6/15 in one case and hand motion to 6/6 in another). The third described stabilization and prevention of further best-corrected visual acuity (BCVA) decline. All 5 of our patients presented with acute monocular vision loss. BCVA ranged from 6/12 to light perception (LP). All patients were promptly commenced on 1 g intravenous methylprednisolone daily. Weekly 162 mg of subcutaneous tocilizumab was commenced once contralateral eye involvement was noted. Tocilizumab resulted in bilateral BCVA gains in 2 cases, recovery of the contralateral eye in one, and no effect in the remaining 2 cases. BCVA recovery was no light perception to 6/6 after 6 weeks of tocilizumab. Tocilizumab had no effect in cases with severe vision loss and high C-reactive protein on presentation. CONCLUSIONS: We agree with existing hypothesis that tocilizumab likely prevents a "pending" central retinal artery occlusion by maintaining retinal vasculature perfusion. Our case series suggests that there is a role for tocilizumab as "rescue" therapy for GC-resistant GCA, where vision loss would otherwise be imminent.

The APOE E4 Allele Is Associated with Faster Rates of Neuroretinal Thinning in a Prospective Cohort Study of Suspect and Early Glaucoma.

Purpose: To investigate the association between the apolipoprotein E (APOE) E4 dementia-risk allele and prospective longitudinal retinal thinning in a cohort study of suspect and early manifest glaucoma. Design: Retrospective analysis of prospective cohort data. Participants: This study included all available eyes from participants recruited to the Progression Risk of Glaucoma: Relevant SNPs [single nucleotide polymorphisms] with Significant Association (PROGRESSA) study with genotyping data from which APOE genotypes could be determined. Methods: Apolipoprotein E alleles and genotypes were determined in PROGRESSA, and their distributions were compared with an age-matched and ancestrally matched normative cohort, the Blue Mountains Eye Study. Structural parameters of neuroretinal atrophy measured using spectral-domain OCT were compared within the PROGRESSA cohort on the basis of APOE E4 allele status. Main Outcome Measures: Longitudinal rates of thinning in the macular ganglion cell-inner plexiform layer (mGCIPL) complex and the peripapillary retinal nerve fiber layer (pRNFL). Results: Rates of mGCIPL complex thinning were faster in participants harboring ≥1 copies of the APOE E4 allele (ß = -0.13 µm/year; P ≤0.001). This finding was strongest in eyes affected by normal-tension glaucoma (NTG; ß = -0.20 µm/year; P = 0.003). Apolipoprotein E E4 allele carriers were also more likely to be lost to follow-up (P = 0.01) and to demonstrate a thinner average mGCIPL complex (70.9 µm vs. 71.9 µm; P = 0.011) and pRNFL (77.6 µm vs. 79.2 µm; P = 0.045) after a minimum of 3 years of monitoring. Conclusions: The APOE E4 allele was associated with faster rates of mCGIPL complex thinning, particularly in eyes with NTG. These results suggest that the APOE E4 allele may be a risk factor for retinal ganglion cell degeneration in glaucoma.

Genetic Risk of Cardiovascular Disease Is Associated with Macular Ganglion Cell-Inner Plexiform Layer Thinning in an Early Glaucoma Cohort.

Purpose: To evaluate the association between genetic risk for cardiovascular disease and retinal thinning in early glaucoma. Design: Prospective, observational genetic association study. Participants: Multicohort study combining a cohort of patients with suspect and early manifest primary open-angle glaucoma (POAG), a cohort of patients with perimetric POAG, and an external normative control cohort. Methods: A cardiovascular disease genetic risk score was calculated for 828 participants from the Progression Risk of Glaucoma: Relevant SNPs [single nucleotide polymorphisms] with Significant Association (PROGRESSA) study. Participants were characterized as showing either predominantly macular ganglion cell-inner plexiform layer (GCIPL), predominantly peripapillary retinal nerve fiber layer (pRNFL) or equivalent macular GCIPL and pRNFL spectral-domain OCT thinning. The cardiovascular disease genetic risk scores for these groups were compared to an internal reference group of stable suspected glaucoma and of an external normative population. Replication was undertaken by comparing the phenotypes of participants from the Australia New Zealand Registry of Advanced Glaucoma (ANZRAG) with the normative control group. Main Outcome Measures: Spectral-domain OCT and Humphrey Visual Field (HVF) change. Results: After accounting for age, sex, and intraocular pressure (IOP), participants with predominantly macular GCIPL thinning showed a higher cardiovascular disease genetic risk score than reference participants (odds ratio [OR], 1.76/standard deviation [SD]; 95% confidence interval [CI], 1.18-2.62; P = 0.005) and than normative participants (OR, 1.32/SD; 95% CI, 1.12-1.54; P = 0.002). This finding was replicated by comparing ANZRAG participants with predominantly macular GCIPL change with the normative population (OR, 1.39/SD; 95% CI, 1.05-1.83; P = 0.022). Review of HVF data identified that participants with paracentral visual field defects also demonstrated a higher cardiovascular disease genetic risk score than reference participants (OR, 1.85/SD; 95% CI, 1.16-2.97; P = 0.010). Participants with predominantly macular GCIPL thinning exhibited a higher vertical cup-to-disc ratio genetic risk score (OR, 1.48/SD; 95% CI, 1.24-1.76; P < 0.001), but an IOP genetic risk score (OR, 1.12/SD; 95% CI, 0.95-1.33; P = 0.179) comparable with that of the normative population. Conclusions: This study highlighted the relationship between cardiovascular disease and retinal thinning in suspect and manifest glaucoma cases.

Diagnostic yield of candidate genes in an Australian corneal dystrophy cohort.

Corneal dystrophies describe a clinically and genetically heterogeneous group of inherited disorders. The International Classification of Corneal Dystrophies (IC3D) lists 22 types of corneal dystrophy, 17 of which have been demonstrated to result from pathogenic variants in 19 identified genes. In this study, we investigated the diagnostic yield of genetic testing in a well-characterised cohort of 58 individuals from 44 families with different types of corneal dystrophy. Individuals diagnosed solely with Fuchs endothelial corneal dystrophy were excluded. Clinical details were obtained from the treating ophthalmologist. Participants and their family members were tested using a gene candidate and exome sequencing approach. We identified a likely molecular diagnosis in 70.5% families (31/44). The detection rate was significantly higher among probands with a family history of corneal dystrophy (15/16, 93.8%) than those without (16/28, 57.1%, p = .015), and among those who had undergone corneal graft surgery (9/9, 100.0%) compared to those who had not (22/35, 62.9%, p = .041). We identified eight novel variants in five genes and identified five families with syndromes associated with corneal dystrophies. Our findings highlight the genetic heterogeneity of corneal dystrophies and the clinical utility of genetic testing in reaching an accurate clinical diagnosis.

Pallid Disc Oedema in a Young Patient: Clinical and Diagnostic Challenge.

A mid-thirties male with end-stage renal failure receiving haemodialysis on a background of four failed renal transplants, post-transplant lymphoproliferative disorder,and autonomic dysfunction presented with acute vision change in his left eye. Over days his vision in that eye deteriorated from 20/25 to no light perception. Given his complex medical background he was extensively investigated for infective, inflammatory, infiltrative and vasculitic aetiologies to explain acute vision loss with pallid disc swelling. A final diagnosis of non-arteritic anterior ischaemic optic neuropathy secondary to refractive hypotension and haemodialysis was reached.

RNA Sequencing of Lens Capsular Epithelium Implicates Novel Pathways in Pseudoexfoliation Syndrome.

Purpose: Pseudoexfoliation syndrome (PEX) is a common systemic disease that results in severe and often irreversible vision loss. Despite considerable research effort, PEX remains incompletely understood. This study sought to perform the first RNAseq study in elucidate the pathophysiology of PEX, and contribute a publicly available transcriptomic data resource for future research. Methods: Human ocular lens capsular epithelium samples were collected from 25 patients with PEX and 39 non-PEX controls undergoing cataract surgery. RNA extracted from these specimens was subjected to polyadenylated (mRNA) selection and deep bulk RNA sequencing. Differential expression analysis investigated protein-coding gene transcripts. Exploratory analyses used pathway analysis tools, and curated class- and disease-specific gene sets. Results: Differential expression analysis demonstrated that 2882 genes were differentially expressed according to PEX status. Genes associated with viral gene expression pathways were among the most upregulated, alongside genes encoding ribosomal and mitochondrial respiratory transport chain proteins. Cell adhesion protein transcripts including type 4 collagen subunits were downregulated. Conclusions: This comparative transcriptomic dataset highlights novel and previously recognized pathogenic pathways in PEX and provides the first comprehensive transcriptomic resource, adding an additional layer to build further understanding of PEX pathophysiology.

Normal-tension glaucoma is associated with cognitive impairment.

BACKGROUND/AIMS: Recent research suggests an association between normal-tension glaucoma (NTG) and dementia. This study investigated whether cognitive impairment is more strongly associated with NTG than high tension glaucoma (HTG) using cognitive screening within an Australiasian Glaucoma Disease Registry. METHODS: The authors completed a case-control cross-sectional cognitive screening involving 290 age-matched and sex-matched NTG participants and HTG controls aged ≥65 randomly sampled from the Australian and New Zealand Registry of Advanced Glaucoma. Cognitive screening was performed using the Telephone Version of the Montreal Cognitive Assessment (T-MoCA). The T-MoCA omits points requiring visual interpretation, accounting for confounding factors related to vision loss in visually impaired participants. Cognitive impairment was defined by a T-MoCA score of <11/22. Cognition was compared between NTG and HTG participants using predetermined thresholds and absolute screening scores. RESULTS: A total of 290 participants completed cognitive assessment. There were no differences in NTG (n=144) and HTG (n=146) cohort demographics or ocular parameters at baseline. Cognitive impairment was more prevalent in the NTG cohort than the HTG cohort (OR=2.2; 95% CI 1.1 to 6.7, p=0.030). Though a linear trend was also observed between lower absolute T-MoCA scores in the NTG cohort when compared with the HTG cohort, this association was not statistically significant (p=0.108). CONCLUSION: This study demonstrated an association between NTG status and poor cognition, supporting the hypothesis that there exists a disease association and shared pathoaetiological features between NTG and dementia.

Risk Stratification and Clinical Utility of Polygenic Risk Scores in Ophthalmology.

Translational Relevance: Common genetic variants can be used to effectively stratify the risk of disease development and progression and may be used to guide screening, triaging, monitoring, or treatment thresholds.

A novel GSN variant outside the G2 calcium-binding domain associated with Amyloidosis of the Finnish type.

Gelsolin (GSN) variants have been implicated in amyloidosis of the Finnish type. This case series reports a novel GSN:c.1477T>C,p.(Trp493Arg) variant in a family with ocular and systemic features consistent with Finnish Amyloidosis. Exome sequencing performed on affected individuals from two families manifesting cutis laxa and polymorphic corneal stromal opacities demonstrated the classic GSN:c.654G>A,p.Asp214Asn variant in single affected individual from one family, and a previously undocumented GSN:c.1477T>C variant in three affected first-degree relatives from a separate family. Immunohistochemical studies on corneal tissue from a proband with the c.1477T>C variant identified gelsolin protein within histologically defined corneal amyloid deposits. This study reports a novel association between the predicted pathogenic GSN:c.1477T>C variant and amyloidosis of the Finnish type, and is the first to provide functional evidence of a pathological GSN variant at a locus distant to the critical G2 calcium-binding region, resulting in the phenotype of amyloidosis of the Finnish type.

A Polygenic Risk Score Predicts Intraocular Pressure Readings Outside Office Hours and Early Morning Spikes as Measured by Home Tonometry.

PURPOSE: Intraocular pressure (IOP) elevations may occur in early morning or outside office hours and can be missed during routine in-clinic IOP measurements. Such fluctuations or peaks likely contribute to glaucoma progression. We sought to investigate the relationship between an IOP polygenic risk score (PRS) and short-term IOP profile. DESIGN: Cross-sectional study. PARTICIPANTS: Four hundred seventy-three eyes from 239 participants with suspected or established primary open-angle glaucoma sampled from 4 outpatient clinics in Australia between August 2016 and December 2019. METHODS: Participants underwent Icare HOME (Icare Oy, Vanda, Finland) tonometer measurements to record IOP 4 times daily for 5 days. Unreliable measurements were excluded. A minimum of 2 days with at least 3 reliable measurements were required. We used a validated IOP PRS derived from 146 IOP-associated variants in a linear regression model adjusted for central corneal thickness and age. MAIN OUTCOME MEASURES: Highest recorded early morning IOP and mean IOP within and outside office hours. Early morning IOP spikes were defined by a higher early morning IOP than the maximum in-office hours IOP. RESULTS: Reliable measurements were obtained from 334 eyes of 176 participants (mean age, 64 ± 9 years). Eyes in the highest IOP PRS quintile showed an early morning IOP increase of 4.3 mmHg (95% confidence interval [CI], 1.4-7.3; P = 0.005) and mean increase in IOP outside office hours of 2.7 mmHg (95% CI, 0.61-4.7; P = 0.013) than the lowest quintile, which were significant independently after accounting for a recent in-clinic IOP measured by Goldmann applanation tonometry. Eyes in the highest PRS quintile were 5.4-fold more likely to show early morning IOP spikes than the lowest quintile (odds ratio 95% CI, 1.3-23.6; P = 0.023). CONCLUSIONS: A validated IOP PRS was associated with higher early morning IOP and mean IOP outside office hours. These findings support a role for genetic risk prediction of susceptibility to elevated IOP that may not be apparent during in-clinic hours, requiring more detailed clinical phenotyping using home tonometry, the results of which may guide additional interventions to improve IOP control.

Corneal Stiffness Parameters Are Predictive of Structural and Functional Progression in Glaucoma Suspect Eyes.

PURPOSE: To investigate corneal stiffness parameters (SPs) as predictors of future progression risk in glaucoma suspect eyes. DESIGN: Prospective, longitudinal study. PARTICIPANTS: Three hundred seventy-one eyes from 228 primary open-angle glaucoma suspects, based on optic disc appearance, with normal baseline Humphrey Visual Field (HVF; Carl Zeiss Meditec) results. METHODS: Baseline corneal SPs were measured using Corvis ST (Oculus Optikgeräte GmbH). Participants were followed up every 6 months with clinical examination, HVF testing, and OCT. The baseline SP at first applanation (SP-A1) and highest concavity predicted the prospective outcome measures. MAIN OUTCOME MEASURES: Structural progression was measured by the OCT rate of thinning of the retinal nerve fiber layer (RNFL) and ganglion cell-inner plexiform layer (GCIPL). Functional progression was assessed by permutation analysis of pointwise linear regression criteria on HVF testing. RESULTS: Stiffness parameters correlated positively with central corneal thickness (CCT), which was adjusted for in all analyses. A higher SP-A1, suggestive of a stiffer cornea, was associated with a faster rate of RNFL thinning (P < 0.001), synergistic with thinner CCT (P = 0.004) over a mean follow-up of 4.2 years. Eyes with higher SP-A1 and thinner CCT (thin and stiff corneas) showed accelerated RNFL thinning by 0.72 µm/year relative to eyes with lower SP-A1 and thicker CCT (95% confidence interval [CI], 0.17-1.28; P = 0.011) and were at 2.9-fold higher likelihood of fast RNFL progression of more than 1 µm/year (95% CI, 1.4-6.1; P = 0.006). Consistent results also were observed with GCIPL thinning. Furthermore, a higher SP-A1 was associated with a greater risk of visual field progression (P = 0.002), synergistic with thinner CCT (P = 0.010). Eyes with higher SP-A1 and thinner CCT were at 3.7-fold greater risk of visual field progression relative to eyes with thicker CCT and lower SP-A1 (95% CI, 1.3-10.5; P = 0.014). CONCLUSIONS: Glaucoma suspect eyes with higher corneal SPs and lower CCT, suggestive of thin and stiff corneas, are at greater risk of progression. Corneal SPs seem to act synergistically with CCT as risk factors for glaucoma progression.

Cardiovascular Disease Predicts Structural and Functional Progression in Early Glaucoma.

PURPOSE: To investigate the association between cardiovascular disease and baseline structural defects and disease progression in glaucoma. DESIGN: Prospective, longitudinal study of preperimetric and perimetric glaucoma. PARTICIPANTS: Two thousand six hundred twenty-eight eyes from 1314 participants recruited to the Progression Risk of Glaucoma: Relevant SNPs with Significant Association (PROGRESSA) study were evaluated for baseline and longitudinal structural thinning using spectral-domain OCT and for visual field progression on Humphrey visual field (HVF) assessment. METHODS: Patients were classified as either predominantly macula ganglion cell-inner plexiform layer (mGCIPL), predominantly peripapillary retinal nerve fiber layer (pRNFL), or both mGCIPL and pRNFL structural change at enrollment, and then evaluated for longitudinal OCT or HVF progression. Cardiovascular disease and medication characteristics of the participants were compared with a reference group of stable patients. MAIN OUTCOME MEASURES: OCT and HVF baseline status and longitudinal progression. RESULTS: After accounting for age and cardiovascular characteristics, patients with predominantly mGCIPL thinning at baseline showed a higher prevalence of hypertension (odds ratio [OR], 2.70; 95% confidence interval [CI], 1.66-4.41; P < 0.001), antihypertensive use (OR, 2.03; 95% CI, 1.20-3.46; P = 0.008), and statin use (OR, 1.98; 95% CI, 1.07-3.66; P = 0.029) than reference patients. Patients with predominantly pRNFL thinning exhibited a comparable prevalence of cardiovascular disease or medication with reference patients. Review of longitudinal OCT and HVF data (mean follow-up, 5.34 ± 1.29 years) showed that hypertension was associated with an increased risk of both OCT (OR, 1.79; 95% CI, 1.17-2.75; P = 0.006) and HVF progression (OR, 1.92; 95% CI, 1.18-3.15; P = 0.013). A 1-standard deviation (approximately 21 mmHg) increase in systolic blood pressure at baseline was associated with a greater risk of OCT progression (OR, 1.27; 95% CI, 1.01-1.63; P = 0.041) and HVF progression (OR, 1.32; 95% CI, 1.01-1.73; P = 0.043). The association between systolic blood pressure and structural progression was comparable to that observed between intraocular pressure and structural progression (OR, 1.30; 95% CI, 1.01-1.67; P = 0.039). CONCLUSIONS: Cardiovascular disease is an important risk factor for glaucoma progression.