Molecular model for HNBR with tunable cross-link density

We introduce a chemically-inspired, all-atom model of HNBR and assess its perfor- mance by computing the mass density and glass transition temperature as a function of cross-link density in the structure. Our HNBR structures are created by a procedure that mimics the real process used to produce HNBR, i.e., saturation of the carbon- carbon double bonds in NBR, either by hydrogenation or by cross-linking. The atomic interactions are described by the all-atom “Optimized Potentials for Liquid Simula- tions" (OPLS-AA). In this paper we: first assess the use of OPLS-AA in our models, especially using NBR bulk properties, and second evaluate the validity of the proposed model for HNBR by investigating mass density and glass transition as a function of the tunable cross-link density. Experimental densities are reproduced within 3% for both elastomers, and qualitatively correct trends in the glass transition temperature as a function of the monomer composition and cross-link density are obtained

Potential for Collider Bias in Studies Examining the Association of Central Corneal Thickness with Glaucoma

PURPOSE: Central corneal thickness (CCT) may be biologically related to glaucoma or observed as associated with glaucoma simply due to its effect on intraocular pressure (IOP) measurement. We aimed to determine if the previously reported CCT-glaucoma associations, in which the analyses were adjusted for IOP or participants were selected on IOP, could be explained by collider bias. METHODS: We simulated datasets mimicking a longitudinal population-based study (Los Angeles Latino Eye Study) and a trial (Ocular Hypertension Treatment Study) such that: (i) CCT was not truly associated with glaucoma, (ii) CCT and true IOP both contribute to measured IOP, and (iii) true IOP contributes to glaucoma risk.We then tested whether an association between CCT and glaucoma could be spuriously induced simply by adjusting for or selecting on measured IOP. RESULTS: A thinner CCT was significantly associated with higher glaucoma incidence in the simulated longitudinal population-based study when adjusted for measured IOP, but not crudely (unadjusted). A thinner CCT was crudely associated with glaucoma incidence in the simulated trial in which the participants were selected for high measured IOP. Effect sizes in the simulations were similar to those observed in the original studies. CONCLUSIONS: Our findings question whether CCT is biologically associated with glaucoma and suggest that current evidence may be due to collider bias. This indicates that CCT alone cannot be used as a factor to identify people at high risk of glaucoma in the general population. Using CCT in combination with IOP may be superior to using IOP alone

Vitrectomy, Inner Limiting Membrane Peel, and Gas Tamponade in the Management of Traumatic Paediatric Macular Holes: A Case Series of 13 Patients

Purpose: To review the outcomes of pars plana vitrectomy, internal limiting membrane (ILM) peel, and gas tamponade in the management of traumatic paediatric macular holes. Methods: Retrospective case series of children undergoing vitrectomy, ILM peel, and gas tamponade for traumatic macular hole between March 2007 and July 2014. Main outcome measures were postoperative visual acuity at 3 and 12 months, anatomic closure rate, and surgical complications. Results: Anatomic macular hole closure was achieved in 12 (92.3%) of 13 cases. Mean preoperative logMAR visual acuity was 0.91 (95% CI 0.65-1.17) with improvement postoperatively to 0.54 (95% CI 0.43-0.64) at 3 months (p = 0.002) and 0.50 (95% CI 0.39-0.60) at 12 months (p = 0.002). There were no perioperative complications. Conclusion: Pars plana vitrectomy and ILM peel is an effective management option for paediatric macular holes

Burden of Glaucoma in the United Kingdom: A Multicenter Analysis of United Kingdom Glaucoma Services

OBJECTIVE: ,To determine the spectrum of glaucoma-associated health care resource utilization among outpatients attending National Health Service (NHS) hospital glaucoma clinics and the costs of managing glaucoma in this setting. DESIGN: Retrospective observational cohort study using electronic medical record data. SUBJECTS: Patients aged ≥ 18 years attending 5 NHS glaucoma clinics in the United Kingdom (2013‒2018) with ≥ 12 months of continuous electronic medical record data. METHODS: Deidentified Medisoft Ophthalmology electronic medical record data (January 2013‒December 2018) from 43 742 eligible patients were categorized by year of clinic visit. Extracted information included patient demographics, glaucoma diagnoses, topical glaucoma medication prescription start/stop dates, types/numbers of glaucoma clinic visits, glaucoma investigations (visual acuity, intraocular pressure, visual field, and OCT), and glaucoma procedures received over 12 months after the first (“index”) visit of the specified year. Direct glaucoma-related health care costs (clinic visits, investigations, procedures, and ongoing glaucoma medication initiated in the clinic) were estimated from event volumes and unit costs (UK national tariffs) and expressed from the direct-payer perspective. MAIN OUTCOME MEASURES: Glaucoma diagnoses and topical glaucoma medication use at the index clinic visit; numbers of glaucoma clinic visits, investigations and procedures; and glaucoma-related health care costs over 12 months postindex. RESULTS: For the 2016 cohort (n = 21 719), the estimated average total cost of NHS-provided glaucoma care over 12 months was £405 per patient (medical staff services £209, glaucoma investigations £126, glaucoma medication £40, glaucoma procedures £26). Among this cohort, 40.8% had ocular hypertension/suspected glaucoma, 70% had 0-to-mild visual field impairment, and 14% had undergone a glaucoma procedure. Over 12 months, patients received (mean) 2.0 glaucoma clinic visits and 1.5 visual field tests, and 7% underwent glaucoma procedure(s). Results were similar for the other years examined. CONCLUSIONS: Cost estimates for managing patients with glaucoma in the UK are required for effective service planning. Appreciable proportions of patients managed in NHS glaucoma clinics may be considered at low risk of blindness (glaucoma suspects and those with ocular hypertension with mild visual field loss) and may be more appropriately managed with alternative, more affordable models of care

Visual Impairment, Eye Diseases, and Dementia Risk: A Systematic Review and Meta-Analysis

BACKGROUND: Visual impairment and eye diseases have been associated with dementia, though with mixed findings and often in cross-sectional studies. OBJECTIVE: To identify prospective studies investigating associations between visual impairment or common eye diseases and risk of all-cause dementia or key dementia subtypes. METHODS: We searched Medline, PsycINFO, and Embase from inception to January 2020. We also conducted backward and forward citation searches of included studies and set up alerts to identify studies published after the search date. Random-effects meta-analysis was used to combine adjusted estimates across studies. RESULTS: Thirty studies met our eligibility criteria. For visual impairment, pooled estimates indicated an increased risk of all-cause dementia (37,705 participants, 3,415 cases, risk ratio [RR] = 1.38, 95% confidence interval [CI]: 1.19-1.59, I2 = 28.6%). Pooled estimates also suggested an increased dementia risk associated with cataract (6,659 participants, 1,312 cases, hazard ratio [HR] = 1.17, 95% CI: 1.00-1.38, I2 = 0.0%) and diabetic retinopathy (43,658 participants, 7,060 cases, HR = 1.34, 95% CI: 1.11-1.61, I2 = 63.9%), respectively. There was no evidence of an association between glaucoma (175,357 participants, 44,144 cases, HR = 0.97, 95% CI: 0.90-1.04, I2 = 51.5%) or age-related macular degeneration (7,800,692 participants, > 2,559 cases, HR = 1.15, 95% CI: 0.88-1.50, I2 = 91.0%) and risk of dementia, respectively. CONCLUSION: As visual impairment, cataract, and diabetic retinopathy are associated with an increased likelihood of developing dementia, early diagnosis may help identify those at risk of dementia. Given most causes of visual impairment are treatable or preventable, the potential for dementia prevention warrants further investigation

The Association of Ambient Air Pollution With Cataract Surgery in UK Biobank Participants: Prospective Cohort Study

Purpose: Air pollution is associated with chronic diseases of later life. Cataract is the most common cause of blindess globally. It is biologically plausible that cataract risk is increased by pollution exposure. Therefore, the relationship between air pollution and incident cataract surgery was examined. Methods: This was a prospective, observational study involving 433,727 UK Biobank participants. Ambient air pollution measures included particulates, nitrogen dioxide (NO2) and nitrogen oxides (NOx). Outdoor air pollution was estimated based on land use regression models. Participants undergoing cataract surgery in either eye were ascertained via data linkage to the National Health Service procedure statistics. Those undergoing cataract surgery within 1 year of baseline assessment and those reporting cataract at baseline were excluded. Cox proportional hazards models were used to examine the associations between air pollutants and incident cataract surgery, adjusting for sociodemographic and lifestyle factors. Results: There were 16,307 incident cases of cataract surgery. Higher exposure to PM2.5 was associated with a 5% increased risk of incident cataract surgery (per interquartile range [IQR] increase). Compared to the lowest quartile, participants with exposures to PM2.5, NO2, and NOx in the highest quartile were 14%, 11%, and 9% more likely to undergo cataract surgery, respectively. A continuous exposure-response relationship was observed, with the likelihood of undergoing cataract surgery being progressively higher with greater levels of PM2.5, NO2, and NOx (P for trend P < 0.001). Conclusions: Although the results of our study showed a 5% increased risk of future cataract surgery following an exposure to PM2.5, NO2, and NOx, the effect estimates were relatively small. Further research is required to determine if the associations identified are causal

Metabolite and Lipid Biomarkers Associated With Intraocular Pressure and Inner Retinal Morphology: ¹H NMR Spectroscopy Results From the UK Biobank

Purpose: The purpose of this study was to assess metabolites associated with intraocular pressure (IOP) and inner retina structure. / Methods: We cross-sectionally assessed 168 non-fasting plasma metabolites measured by nuclear magnetic resonance (NMR) spectroscopy with IOP (n = 28,195), macular retinal nerve fiber layer thickness (mRNFL; n = 10,584), and macular ganglion cell inner plexiform layer thickness (mGCIPL; n = 10,554) in the UK Biobank. We used multiple linear regression models adjusting for various covariates with probit-transformed metabolite levels as predictors for each outcome. Each estimate represents the difference in outcome variable per standard deviation increase in the probit-transformed metabolite values. We used the number of effective (NEF) tests and false discovery rate (FDR) to adjust for multiple comparisons for metabolites and metabolite classes, respectively. / Results: In individual metabolite analysis, multiple amino acids, especially branched-chain amino acids, were associated with lower IOP (-0.12 mm Hg; 95% confidence interval = -0.16 to -0.07; NEF = 2.7E-05). Albumin, 3 hydroxybutyrate, lactate, and several lipids were associated with higher IOP (range = 0.07 to 0.18 mm Hg, NEF = ≤ 0.039). In IOP-adjusted analyses, five HDL-related metabolites were associated with thinner mRNFL (-0.15 microns for all metabolites, NEF = ≤ 0.027), whereas five LDL-related metabolites were associated with thicker mGCIPL (range = 0.17 to 0.20 microns; NEF = ≤ 0.044). In metabolite class analysis, the lipid components of lipoproteins (cholesterol, triglycerides, etc.) were not associated with our outcomes (FDR > 0.2 for all); yet multiple lipoproteins were significantly (FDR < 0.05) associated with all outcomes. / Conclusions: Branched-chain amino acids were associated with lower IOP, HDL metabolites were associated with thinner mRNFL, and LDL metabolites were associated with thicker mGCIPL

Statin Use in Relation to Intraocular Pressure, Glaucoma, and Ocular Coherence Tomography Parameters in the UK Biobank

PURPOSE. The purpose of this study was to evaluate the relationship between statin use and glaucoma-related traits. METHODS. In a cross-sectional study, we included 118,153 UK Biobank participants with data on statin use and corneal-compensated IOP. In addition, we included 192,283 participants (8982 cases) with data on glaucoma status. After excluding participants with neurodegenerative diseases, 41,638 participants with macular retinal nerve fiber layer thickness (mRNFL) and 41,547 participants with macular ganglion cell inner plexiform layer thickness (mGCIPL) were available for analysis. We examined associations of statin use with IOP, mRNFL, mGCIPL, and glaucoma status utilizing multivariable-adjusted regression models. We assessed whether a glaucoma polygenic risk score (PRS) modified associations. We performed Mendelian randomization (MR) experiments to investigate associations with various glaucoma-related outcomes. RESULTS. Statin users had higher unadjusted mean IOP ± SD than nonusers, but in a multivariable-adjusted model, IOP did not differ by statin use (difference = 0.05 mm Hg, 95% confidence interval [CI] = −0.02 to 0.13, P = 0.17). Similarly, statin use was not associated with prevalent glaucoma (odds ratio [OR] = 1.05, 95% CI = 0.98 to 1.13). Statin use was weakly associated with thinner mRNFL (difference = −0.15 microns, 95% CI = −0.28 to −0.01, P = 0.03) but not with mGCIPL thickness (difference = −0.12 microns, 95% CI = −0.29 to 0.05, P = 0.17). No association was modified by the glaucoma PRS (Pinteraction ≥ 0.16). MR experiments showed no evidence for a causal association between the cholesterol-altering effect of statins and several glaucoma traits (inverse weighted variance P ≥ 0.14). CONCLUSIONS. We found no evidence of a protective association between statin use and glaucoma or related traits after adjusting for key confounders

TIE1 and TEK signalling, intraocular pressure, and primary open-angle glaucoma: a Mendelian randomization study

BACKGROUND: In primary open-angle glaucoma (POAG), lowering intraocular pressure (IOP) is the only proven way of slowing vision loss. Schlemm's canal (SC) is a hybrid vascular and lymphatic vessel that mediates aqueous humour drainage from the anterior ocular chamber. Animal studies support the importance of SC endothelial angiopoietin-TEK signalling, and more recently TIE1 signalling, in maintaining normal IOP. However, human genetic support for a causal role of TIE1 and TEK signalling in lowering IOP is currently lacking. METHODS: GWAS summary statistics were obtained for plasma soluble TIE1 (sTIE1) protein levels (N = 35,559), soluble TEK (sTEK) protein levels (N = 35,559), IOP (N = 139,555) and POAG (Ncases = 16,677, Ncontrols = 199,580). Mendelian randomization (MR) was performed to estimate the association of genetically proxied TIE1 and TEK protein levels with IOP and POAG liability. Where significant MR estimates were obtained, genetic colocalization was performed to assess the probability of a shared causal variant (PPshared) versus distinct (PPdistinct) causal variants underlying TIE1/TEK signalling and the outcome. Publicly available single-nucleus RNA-sequencing data were leveraged to investigate differential expression of TIE1 and TEK in the human ocular anterior segment. RESULTS: Increased genetically proxied TIE1 signalling and TEK signalling associated with a reduction in IOP (- 0.21 mmHg per SD increase in sTIE1, 95% CI = - 0.09 to - 0.33 mmHg, P = 6.57 × 10-4, and - 0.14 mmHg per SD decrease in sTEK, 95% CI = - 0.03 to - 0.25 mmHg, P = 0.011), but not with POAG liability. Colocalization analysis found that the probability of a shared causal variant was greater for TIE1 and IOP than for TEK and IOP (PPshared/(PPdistinct + PPshared) = 0.98 for TIE1 and 0.30 for TEK). In the anterior segment, TIE1 and TEK were preferentially expressed in SC, lymphatic, and vascular endothelium. CONCLUSIONS: This study provides novel human genetic support for a causal role of both TIE1 and TEK signalling in regulating IOP. Here, combined evidence from cis-MR and colocalization analyses provide stronger support for TIE1 than TEK as a potential IOP-lowering therapeutic target