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Keratoconus is characterised by reduced rigidity of the cornea with distortion and focal thinning that causes blurred vision, however, the pathogenetic mechanisms are unknown. It can lead to severe visual morbidity in children and young adults and is a common indication for corneal transplantation worldwide. Here we report the first large scale genome-wide association study of keratoconus including 4,669 cases and 116,547 controls. We have identified significant association with 36 genomic loci that, for the first time, implicate both dysregulation of corneal collagen matrix integrity and cell differentiation pathways as primary disease-causing mechanisms. The results also suggest pleiotropy, with some disease mechanisms shared with other corneal diseases, such as Fuchs endothelial corneal dystrophy. The common variants associated with keratoconus explain 12.5% of the genetic variance, which shows potential for the future development of a diagnostic test to detect susceptibility to disease.

Primary open-angle glaucoma (POAG), is a heritable common cause of blindness world-wide. To identify risk loci, we conduct a large multi-ethnic meta-analysis of genome-wide association studies on a total of 34,179 cases and 349,321 controls, identifying 44 previously unreported risk loci and confirming 83 loci that were previously known. The majority of loci have broadly consistent effects across European, Asian and African ancestries. Cross-ancestry data improve fine-mapping of causal variants for several loci. Integration of multiple lines of genetic evidence support the functional relevance of the identified POAG risk loci and highlight potential contributions of several genes to POAG pathogenesis, including SVEP1, RERE, VCAM1, ZNF638, CLIC5, SLC2A12, YAP1, MXRA5, and SMAD6. Several drug compounds targeting POAG risk genes may be potential glaucoma therapeutic candidates.

Elevated intraocular pressure (IOP) is an important risk factor for glaucoma. Mechanisms involved in its homeostasis are not well understood, but associations between metabolic factors and IOP have been reported. To investigate the relationship between levels of circulating metabolites and IOP, we performed a metabolome-wide association using a machine learning algorithm, and then employing Mendelian Randomization models to further explore the strength and directionality of effect of the metabolites on IOP. We show that O-methylascorbate, a circulating Vitamin C metabolite, has a significant IOP-lowering effect, consistent with previous knowledge of the anti-hypertensive and anti-oxidative role of ascorbate compounds. These results enhance understanding of IOP control and may potentially benefit future IOP treatment and reduce vision loss from glaucoma.

Refractive error (RE) is a complex, multifactorial disorder characterized by a mismatch between the optical power of the eye and its axial length that causes object images to be focused off the retina. The two major subtypes of RE are myopia (nearsightedness) and hyperopia (farsightedness), which represent opposite ends of the distribution of the quantitative measure of spherical refraction. We performed a fixed effects meta-analysis of genome-wide association results of myopia and hyperopia from 9 studies of European-derived populations: AREDS, KORA, FES, OGP-Talana, MESA, RSI, RSII, RSIII and ERF. One genome-wide significant region was observed for myopia, corresponding to a previously identified myopia locus on 8q12 (p = 1.25×10(-8)), which has been reported by Kiefer et al. as significantly associated with myopia age at onset and Verhoeven et al. as significantly associated to mean spherical-equivalent (MSE) refractive error. We observed two genome-wide significant associations with hyperopia. These regions overlapped with loci on 15q14 (minimum p value = 9.11×10(-11)) and 8q12 (minimum p value 1.82×10(-11)) previously reported for MSE and myopia age at onset. We also used an intermarker linkage- disequilibrium-based method for calculating the effective number of tests in targeted regional replication analyses. We analyzed myopia (which represents the closest phenotype in our data to the one used by Kiefer et al.) and showed replication of 10 additional loci associated with myopia previously reported by Kiefer et al. This is the first replication of these loci using myopia as the trait under analysis. "Replication-level" association was also seen between hyperopia and 12 of Kiefer et al.'s published loci. For the loci that show evidence of association to both myopia and hyperopia, the estimated effect of the risk alleles were in opposite directions for the two traits. This suggests that these loci are important contributors to variation of refractive error across the distribution.

Reports on a survey questionnaire of 130 Michigan college faculty who incorporate service-learning into academic courses, focusing on faculty motivation, satisfaction, and the intersection of the two. Results indicate significant differences concerning faculty motivation for using service learning, but also commonalities with other findings concerning faculty motivation and satisfaction. Initial motivation to use service-learning and later satisfaction were correlated. (Author/MSE)

Purpose: Genetic variants identified through population-based genome-wide studies are generally of high frequency, exerting their action in the central part of the refractive error spectrum. However, the power to identify associations with variants of lower minor allele frequency is greatly reduced, requiring considerable sample sizes. Here we aim to assess the impact of rare variants on genetic variation of refractive errors in a very large general population cohort. Methods: Genetic association analyses of non-cyclopaedic autorefraction calculated as mean spherical equivalent (SPHE) used whole-exome sequence genotypic information from 50,893 unrelated participants in the UK Biobank of European ancestry. Gene-based analyses tested for association with SPHE using an optimised SNP-set kernel association test (SKAT-O) restricted to rare variants (minor allele frequency < 1%) within protein-coding regions of the genome. All models were adjusted for age, sex and common lead variants within the same locus reported by previous genome-wide association studies. Potentially causal markers driving association at significant loci were elucidated using sensitivity analyses by sequentially dropping the most associated variants from gene-based analyses. Results: We found strong statistical evidence for association of SPHE with the SIX6 (p-value = 2.15 x 10−10, or Bonferroni-Corrected p = 4.41x10-06) and the CRX gene (p-value = 6.65 x 10−08, or Bonferroni-Corrected p = 0.001). The SIX6 gene codes for a transcription factor believed to be critical to the eye, retina and optic disc development and morphology, while CRX regulates photoreceptor specification and expression of over 700 genes in the retina. These novel associations suggest an important role of genes involved in eye morphogenesis in refractive error. Conclusion: The results of our study support previous research highlighting the importance of rare variants to the genetic risk of refractive error. We explain some of the origins of the genetic signals seen in GWAS but also report for the first time a completely novel association with the CRX gene. [ABSTRACT FROM AUTHOR]

Background: To investigate the relationship between dietary intake of niacin (water‐soluble form of vitamin B3) and retinal nerve fibre layer (RNFL) thickness in healthy eyes. Methods: This cross‐sectional study examined the association between daily niacin intake and RNFL thickness in three large population‐based cohorts with varied age differences. RNFL thickness was extracted from optical coherence tomography data; energy‐adjusted niacin intake was estimated from food frequency questionnaires. Linear mixed‐effects models were utilised to examine the association between RNFL thickness and energy‐adjusted niacin intake. Three separate analyses were conducted, with niacin treated as a continuous, a categorical (quartiles) or a dichotomous (above/below Australian recommended daily intake) variable. Results: In total, 4937 subjects were included in the study [Raine Study Gen2, n = 1204, median age 20; Busselton Healthy Ageing Study (BHAS), n = 1791, median age 64; TwinsUK, n = 1942, median age 64). When analysed as a continuous variable, there was no association between RNFL thickness and niacin intake in any of the three cohorts (95% CI β: Raine Study Gen 2, −0.174 to 0.074; BHAS, −0.066 to 0.078; TwinsUK −0.435 to 0.350). Similar findings were observed with quartiles of niacin intake and for niacin intakes above or below Australian recommended daily intake levels in all three cohorts. Conclusions: Dietary intake of niacin from a standard diet does not appear to be associated with age‐related RNFL thinning in healthy eyes. Supraphysiological doses of niacin may be required for therapeutic effect in the retina. [ABSTRACT FROM AUTHOR]

The Harlequin Duck (Histrionicus histrionicus) is a species of conservation priority in western North America. Harlequin Ducks breed in small, isolated populations and have specific nesting requirements. Archival, light-level geolocators are increasingly being used as a low-cost, non-invasive tracking technology to explore migratory connectivity. From 2015-2019, geolocators were deployed on 70 Harlequin Ducks in breeding streams of the Rocky Mountains, Canada and USA, to obtain information on connectivity (breeding to non-breeding), molt-winter sites, dispersal, and breeding phenology. Twenty-two of the 70 geolocators were retrieved from locations in the Rocky Mountains (Alberta, Canada; Montana and Wyoming, USA) and analyzed using the TwGeos and FLightR R packages. Harlequin Ducks from the warmer climate of northwest Montana migrated in spring and started incubation one to two weeks earlier than ducks in west-central Alberta and the greater Yellowstone area. During the non-breeding period, individuals dispersed along the Pacific coast, from Oregon to the Alaskan Panhandle, independent of breeding site. Females that incubated successfully spent 32-34 days incubating, which is several days longer than what is in the literature. Use of geolocators provided detailed information about migration connectivity and breeding behavior in a cost effective and relatively non-invasive manner. [ABSTRACT FROM AUTHOR]

Zero electron kinetic energy (ZEKE) spectroscopy is employed to gain information on the vibrational energy levels of the para-fluorotoluene (pFT) cation. Vibrationally resolved spectra are obtained following excitation through a range of intermediate vibrational energy levels in the S1 state. These spectra allow the observation of different cationic vibrational modes, whose assignment is achieved both from a knowledge of the S1 vibrational states and also by comparison with density functional calculations. In one notable case, clean ZEKE spectra were obtained from two overlapped S1 features. From the authors' data, the adiabatic ionization energy of pFT was derived as 70 946±4 cm-1. The information on the cationic energy levels obtained will be useful in untangling the intramolecular vibrational redistribution dynamics of pFT in the S1 state. [ABSTRACT FROM AUTHOR]

Aims/Purpose: Glaucoma is an eye disease that is the commonest cause of irreversible blindness worldwide. It has been suggested that gut microbiota can produce reactive oxygen species and pro‐inflammatory cytokines that may travel from the gastric mucosa to distal sites, such as the optic nerve head or trabecular meshwork. There is evidence for a gut‐eye axis, as microbial dysbiosis has been associated with retinal diseases. Here, we investigated the association between glaucoma prevalence and the gut microbiome. Moreover, we analysed the association of the gut microbiome with intraocular pressure (IOP; risk factor of glaucoma) and vertical cup‐to‐disc ratio (VCDR; quantifying glaucoma severity). Methods: The discovery analyses included participants of the Rotterdam Study and the Erasmus Glaucoma Cohort. A total of 225 glaucoma patients were matched on age and sex with 1247 participants without glaucoma. Stool samples were collected and used to generate 16S rRNA gene profiles. We assessed associations with 233 taxa. We used data from the TwinsUK and the Study of Health in Pomerania (SHIP) to replicate our findings. The TwinsUK dataset consisted of 32 participants with glaucoma and 1542 unrelated, unmatched participants without glaucoma. The SHIP dataset consisted of a total of 2546 participants. Results: Several butyrate‐producing taxa (e.g., Butyrivibrio, Caproiciproducens, Clostridium sensu stricto 1, Coprococcus 1, Ruminococcaceae UCG 007, Shuttleworthia) were associated with lower glaucoma prevalence, lower IOP, and smaller VCDR. The replication analyses confirmed the findings from the discovery analyses. Conclusions: Large human studies exploring the link between the gut microbiome and glaucoma are lacking. Our results support the hypothesis that microbial dysbiosis plays a role in the pathophysiology of glaucoma. This research may support future research into the mediating role of butyrate‐producing taxa in the relation between dietary intake and glaucoma. [ABSTRACT FROM AUTHOR]

We employ zero-kinetic-energy (ZEKE) photoelectron spectroscopy with nanosecond laser pulses to study intramolecular vibrational redistribution (IVR) in S1 para-fluorotoluene. The frequency resolution of the probe step is superior to that obtained in any studies on this molecule to date. We focus on the behavior of the 131 (C–CH3 stretch) and 7a1 (C–F stretch) vibrational states whose dynamics have previously received significant attention, but with contradictory results. We show conclusively that, under our experimental conditions, the 7a1 vibrational state undergoes significantly more efficient IVR than does the 131 state. Indeed, under the experimental conditions used here, the 131 state undergoes very little IVR. These two states are especially interesting because their energies are only 36 cm-1 apart, and the two vibrational modes have the same symmetry. We discuss the role of experimental conditions in observations of IVR in some detail, and thereby suggest explanations for the discrepancies reported to date. [ABSTRACT FROM AUTHOR]

We have prepared a coherent superposition of the two components of a Fermi resonance in the S1 state of toluene at ∼460 cm-1 with a ∼1 ps laser pulse and monitored time-resolved photoelectron velocity-map images. The photoelectron intensities oscillate with time in a manner that depends on their kinetic energy, even though full vibrational resolution in the cation is not achieved. Analysis of the time-dependent photoelectron spectra enables information on the composition of the S1 wavepacket to be deduced. Such an experiment, in which a whole set of partially dispersed cation vibrational states are detected simultaneously, suggests an efficient method of studying intramolecular vibrational energy redistribution processes in excited states. [ABSTRACT FROM AUTHOR]

Objectives: The aim of this study was to assess the feasibility of quantitative ultrasound imaging (QUI) in assessing the biceps brachii muscle and gastrocnemius muscle in adults with multiple sclerosis (MS). Methods: From May to October 2018, we prospectively performed B‐mode ultrasound imaging and ultrasound strain elastography of the biceps brachii muscle and gastrocnemius muscle in 24 patients with MS and 10 age‐matched healthy volunteers. ImageJ (https://imagej.nih.gov/ij) was used to assess the muscle pixel intensity in grayscale images. Using 2‐dimensional speckle‐tracking software, we estimated the muscle axial peak strain (maximum deformation) produced by manual compression with an ultrasound transducer and the muscle longitudinal peak strain (maximum displacement) produced by passive elbow and ankle movements. Muscle QUI parameters used in the study included the mean pixel intensity, axial peak strain ratio (SR = muscle strain/subcutaneous tissue strain), and longitudinal peak SR. Statistical analyses included 1‐way analysis of variance and a post hoc test to examine the differences in QUI parameters among 3 groups (1, affected muscle in patients with MS; 2, unaffected muscle in patients with MS; and 3, healthy muscle in controls) and, in all paired groups, an unpaired t test to compare the muscle SR in patients with MS with a Modified Ashworth Scale (MAS) score of 1 or higher to those with an MAS score of 0. Results: The mean age of the 24 patients with MS was 43 years, and all patients and volunteers were female. We observed a significant difference in QUI parameters among the affected muscle in MS, unaffected muscle in MS, and healthy muscle in all paired groups and in patients with MS between an MAS score of 1 or higher and an MAS score of 0 (all P < .05). Interobserver and intraobserver variability in performing QUI was good (intraclass correlation coefficients >0.75). Conclusions: Our results suggest that QUI is feasible to assess muscle echogenicity and mechanical behaviors in adult MS. [ABSTRACT FROM AUTHOR]

This study investigates a range of commercially available γ-Al2O3 powders by using a combination of integrated experimental techniques. These included general measurements of powder properties by using helium density, BET surface area, and scanning electron microscopy (SEM) analyses. In addition, dynamic light scattering and zeta potential measurements were used to investigate nanoparticle dispersions. Bulk crystal structures were analysed by using comparative X-ray and neutron powder diffraction (XRD and NPD) analyses. Conventional transmission electron microscopy (TEM) was used to determine particle morphology, particle size, composition, and structure. Aberration-corrected TEM was used to investigate the crystallinity of nanoparticles including the existence of any surface reconstruction on commonly observed facetted, cubeoctahedral γ -Al2O3 nanoparticles. From the observation of peak splittings in diffraction data, we favour a description of the γ-Al2O3 structure based on a distortion of the conventionally accepted face-centred cubic ( Fd $\bar 3$ m) structure into a tetragonal I41/ amd structure. Distinct differences between TEM, XRD, and NPD data indicate the presence of some cation disorder within a rigid close-packed oxygen framework. The Rietveld refinement of the NPD data suggests a high level of microstrain of 1.2 %. An improvement to the model is achieved by reducing the aluminium content in the unit cell, which is commensurate with the migration of aluminium ions to the surface and some degree of nonstoichiometry in the particle core. Aberration-corrected TEM imaging and exit wave reconstruction confirm previous evidence for the presence of enhanced surface contrast at {1 1 1} surface facets, which we associate with the presence of excess cation termination. In addition, these {1 1 1} facets are observed to be heavily stepped. These results may have important implications for the thermal stability of metal catalyst nanoparticles on these high-surface area supports; the migration of aluminium ions to the surface provides clear evidence of why these materials perform so well as catalyst supports. [ABSTRACT FROM AUTHOR]

Preliminary findings are reported following the detailed analysis of intramolecular vibrational energy redistribution (IVR) in S1 para-fluorotoluene following the excitation of one quantum in the CF stretching mode ?7. It is shown that the method proposed has the potential to enable not only the determination of a rate constant for IVR, but also the identification of the dark states into which energy has redistributed. In addition energy flow has been observed from a bright state (11 1 ) previously thought to be below the onset for IVR in this molecule, and evidence of mode-specificity in the IVR process. [ABSTRACT FROM AUTHOR]

Few environmental risk factors are known for glaucoma, in contrast to other common age‐related eye diseases such as AMD and cataract. With the advent of genome‐wide association studies (GWAS), we are increasingly understanding the importance of genetic factors influencing risk of glaucoma. This presentation will discuss results from the largest GWAS of intraocular pressure from the UK Biobank study of over 100 000 people, showing that ~700 common genetic risk variants can predict risk of glaucoma, with an AUC (area under the curve) for high‐tension glaucoma of 0.75 and for normal tension glaucoma of 0.70. Pharmacogenomics is an increasingly important arena, and I will present novel work in large population‐based studies exploring the prediction of response to prostaglandin agonists using genetics. The International Glaucoma Genetics Consortium GWAS of over 30 000 people with glaucoma and 300,000 controls is currently being analysed and preliminary results will be discussed. [ABSTRACT FROM AUTHOR]

The article provides an account of basic statistics and measurement issues as applied to organization development (OD) including reliability and a sampling of inferential statistics. Topics include keeping in mind the characteristics such as relevance or acceptability, need of quantitative measurement in organizational intervention, and internal consistency estimate.

Abstract: Heritability is the proportion of phenotypic variation in a population that is attributable to genetic variation among individuals. Many ophthalmic disorders and biometric traits are known to have a genetic basis and consequently much work has been published in the literature estimating the heritability of various ocular parameters. We collated and summarized the findings of heritability studies conducted in the field of ophthalmology. We grouped the various studies broadly by phenotype as follows: refraction, primary open-angle glaucoma, age-related macular degeneration (AMD), cataract, diabetic retinopathy, and others. A total of 82 articles were retrieved from the literature relating to estimation of heritability for an ocular disease or biometric trait; of these, 37 papers were concerned with glaucoma, 28 with refraction, 4 with AMD, 5 with diabetic retinopathy, and 4 with cataract. The highest reported heritability for an ophthalmic trait is 0.99 for the phenotype ≥ 20 small hard drusen, indicating that observed variation in this parameter is largely governed by genetic factors. Over 60% of the studies employed a twin study design and a similar percentage utilized variance components methods and structural equation modeling (SEM) to derive their heritability values. Using modern SEM techniques, heritability estimates derived from twin subjects were generally higher than those from family data. Many of the estimates are in the moderate to high range, but to date the majority of genetic variants accounting for these findings have not been uncovered, hence much work remains to be undertaken to elucidate fully their molecular etiology. [ABSTRACT FROM AUTHOR]

To describe and compare associations with macular retinal nerve fiber layer (mRNFL), ganglion cell complex (GCC), and ganglion cell–inner plexiform layer (GCIPL) thicknesses in a large cohort. Cross-sectional study. We included 42 044 participants in the UK Biobank. The mean age was 56 years. Spectral-domain OCT macular images were segmented and analyzed. Corneal-compensated intraocular pressure (IOPcc) was measured with the Ocular Response Analyzer (Reichert, Corp., Buffalo, NY). Multivariable linear regression was used to examine associations with mean mRNFL, GCC, and GCIPL thicknesses. Factors examined were age, sex, ethnicity, height, body mass index (BMI), smoking status, alcohol intake, Townsend deprivation index, education level, diabetes status, spherical equivalent, and IOPcc. Thicknesses of mRNFL, GCC, and GCIPL. We identified several novel independent associations with thinner inner retinal thickness. Thinner inner retina was associated with alcohol intake (most significant for GCIPL: –0.46 μm for daily or almost daily intake compared with special occasion only or never [95% confidence interval (CI), 0.61–0.30]; P = 1.1×10–8), greater social deprivation (most significant for GCIPL: –0.28 μm for most deprived quartile compared with least deprived quartile [95% CI, –0.42 to –0.14]; P = 6.6×10–5), lower educational attainment (most significant for mRNFL: –0.36 μm for less than O level compared with degree level [95% CI, –0.45 to 0.26]; P = 2.3×10–14), and nonwhite ethnicity (most significant for mRNFL comparing blacks with whites: –1.65 μm [95% CI, –1.86 to –1.43]; P = 2.4×10–50). Corneal-compensated intraocular pressure was associated most significantly with GCIPL (–0.04 μm/mmHg [95% CI, –0.05 to –0.03]; P = 4.0×10–10) and was not associated significantly with mRNFL (0.00 μm/mmHg [95% CI, –0.01 to 0.01]; P = 0.77). The variables examined explained a greater proportion of the variance of GCIPL (11%) than GCC (6%) or mRNFL (7%). The novel associations we identified may be important to consider when using inner retinal parameters as a diagnostic tool. Associations generally were strongest with GCIPL, particularly for IOP. This suggests that GCIPL may be the superior inner retinal biomarker for macular pathophysiologic processes and especially for glaucoma. [ABSTRACT FROM AUTHOR]

Purpose: Glaucoma is an eye disease that is the most common cause of irreversible blindness worldwide. It has been suggested that gut microbiota can produce reactive oxygen species and pro-inflammatory cytokines that may travel from the gastric mucosa to distal sites, for example, the optic nerve head or trabecular meshwork. There is evidence for a gut-eye axis, as microbial dysbiosis has been associated with retinal diseases. We investigated the microbial composition in patients with glaucoma and healthy controls. Moreover, we analyzed the association of the gut microbiome with intraocular pressure (IOP; risk factor of glaucoma) and vertical cup-to-disc ratio (VCDR; quantifying glaucoma severity)., Methods: The discovery analyses included participants of the Rotterdam Study and the Erasmus Glaucoma Cohort. A total of 225 patients with glaucoma and 1247 age- and sex-matched participants without glaucoma were included in our analyses. Stool samples were used to generate 16S rRNA gene profiles. We assessed associations with 233 genera and species. We used data from the TwinsUK and the Study of Health in Pomerania (SHIP) to replicate our findings., Results: Several butyrate-producing taxa (e.g. Butyrivibrio, Caproiciproducens, Clostridium sensu stricto 1, Coprococcus 1, Ruminococcaceae UCG 007, and Shuttleworthia) were less abundant in people with glaucoma compared to healthy controls. The same taxa were also associated with lower IOP and smaller VCDR. The replication analyses confirmed the findings from the discovery analyses., Conclusions: Large human studies exploring the link between the gut microbiome and glaucoma are lacking. Our results suggest that microbial dysbiosis plays a role in the pathophysiology of glaucoma.

Refractive errors, particularly myopia, are the most common eye conditions, often leading to serious visual impairment. The age of onset is correlated with the severity of refractive error in adulthood observed in epidemiological and genetic studies and can be used as a proxy in refractive error genetic studies. To further elucidate genetic factors that influence refractive error, we analysed self-reported age of refractive error correction data from the UK Biobank European and perform genome-wide time-to-event analyses on the age of first spectacle wear (AFSW). Genome-wide proportional hazards ratio analyses were conducted in 340 318 European subjects. We subsequently assessed the similarities and differences in the genetic architectures of refractive error correction from different causes. All-cause AFSW was genetically strongly correlated (rg = -0.68) with spherical equivalent (the measured strength of spectacle lens required to correct the refractive error) and was used as a proxy for refractive error. Time-to-event analyses found genome-wide significant associations at 44 independent genomic loci, many of which (GJD2, LAMA2, etc.) were previously associated with refractive error. We also identified six novel regions associated with AFSW, the most significant of which was on chromosome 17q (P = 3.06 × 10-09 for rs55882072), replicating in an independent dataset. We found that genes associated with AFSW were significantly enriched for expression in central nervous system tissues and were involved in neurogenesis. This work demonstrates the merits of time-to-event study design in the genetic investigation of refractive error and contributes additional knowledge on its genetic risk factors in the general population., (© The Author(s) 2022. Published by Oxford University Press. All rights reserved. For Permissions, please email: journals.permissions@oup.com.)

Cardiac catheterization associated with central vein cannulation can involve potential thrombotic and infectious complications due to multiple cannulation trials or improper placement. To minimize the risks, medical simulators are used for training. Simulators are also employed to test medical devices such as catheters before performing animal tests because they are more cost-effective and still reveal necessary improvements. However, commercial simulators are expensive, simplified for their purpose, and provide limited access sites. Inexpensive and anatomical cardiovascular simulators with central venous access for cannulation are sparse. Here, we developed an anatomically and physiologically accurate cardiovascular flow simulator to help train medical professionals and test medical devices. Our simulator includes an anatomical right atrium/ventricle, femoral and radial access sites, and considers the variability of arm position. It simulates physiological pulsatile blood flow with a setting for constant flow from 3 to 6 L/min and mimics physiological temperature (37°C). We demonstrated simulation by inserting a catheter into the system at radial/femoral access sites, passing it through the vasculature, and advancing it into the heart. We expect that our simulator can be used as an educational tool for cardiac catheterization as well as a testing tool that will allow for design iteration before moving to animal trials., Competing Interests: JM and CH are employed by TZ Medical Inc. This study received funding from TZ Medical Inc. The funders were involved in study design, data analysis, and decision to publish. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2021 Johnson, Cupp, Armour, Warren, Stone, Lee, Gilbert, Hammond, Moore and Kang.)

Optical Coherence Tomography (OCT) enables non-invasive imaging of the retina and is used to diagnose and manage ophthalmic diseases including glaucoma. We present the first large-scale genome-wide association study of inner retinal morphology using phenotypes derived from OCT images of 31,434 UK Biobank participants. We identify 46 loci associated with thickness of the retinal nerve fibre layer or ganglion cell inner plexiform layer. Only one of these loci has been associated with glaucoma, and despite its clear role as a biomarker for the disease, Mendelian randomisation does not support inner retinal thickness being on the same genetic causal pathway as glaucoma. We extracted overall retinal thickness at the fovea, representative of foveal hypoplasia, with which three of the 46 SNPs were associated. We additionally associate these three loci with visual acuity. In contrast to the Mendelian causes of severe foveal hypoplasia, our results suggest a spectrum of foveal hypoplasia, in part genetically determined, with consequences on visual function., Competing Interests: I have read the journal’s policy and the authors of this manuscript have the following competing interests: APK is a paid consultant to Aerie, Allergan, Google Health, Novartis, Reichert, Santen and Thea. LRP is consultant for Verily, Eyenovia, Bausch+Lomb, and Nicox. JW is consultant for Allergan, Editas, Maze, Regenxbio and has a sponsored research grant from Aerpio.

Purpose: Refractive errors, particularly myopia, are common and a leading cause of blindness. This study aimed to explore associations between medications and refractive error in an aging adult cohort and to determine whether childhood-onset refractive errors predict future medication use to provide novel insights into disease mechanisms., Methods: The study compared the spherical equivalent values measured in 102,318 UK Biobank participants taking the 960 most commonly used medications. The strengths of associations were evaluated against the self-reported age of spectacle wear. The causality of refractive error changes was inferred using sensitivity and Mendelian randomization analyses., Results: Anti-glaucoma drugs were associated with 1 to 2 diopters greater myopic refraction, particularly in subjects who started wearing correction in the first two decades of life, potentially due to the association of higher intraocular pressure since early years with both myopia and, later in life, glaucoma. All classes of pain-control medications, including paracetamol, opiates, non-steroidal antiinflammatory drugs, and gabapentinoids, were associated with greater hyperopia (+0.68-1.15 diopters), after correction for deprivation, education, and polypharmacy and sensitivity analyses for common diagnoses. Oral hypoglycemics (metformin, gliburonide) were associated with myopia, as was allopurinol, and participants using bronchodilators (ipratropium and salbutamol) were more hyperopic., Conclusions: This study finds for the first time, to our knowledge, that medication use is associated with refractive error in adults. The novel finding that analgesics are associated with hyperopic refraction, and the possibility that multisite chronic pain predisposes to hyperopia, deserves further research. Some drugs, such as antihyperglycemic or bronchodilators, may directly alter refractive error. Intraocular pressure appears causative for myopia.

Purpose: To evaluate the contribution of genetic and early life environmental factors, as reflected by fetal anthropometric growth trajectories, toward the development of myopia during childhood and adolescence., Methods: This analysis included 498 singleton Caucasian participants from the Raine Study, a pregnancy cohort study based in Western Australia. Serial fetal biometric measurements of these participants were collected via ultrasound scans performed at 18, 24, 28, 34, and 38 weeks' gestation. At a 20-year follow-up, the participants underwent a comprehensive ophthalmic examination, including cycloplegic autorefraction and ocular biometry measurements. Using a group-based trajectory modeling approach, we identified groups of participants with similar growth trajectories based on measurements of fetal head circumference (HC), abdominal circumference, femur length (FL), and estimated fetal weight (EFW). Differences between trajectory groups with respect to prevalence of myopia, axial length (AL), and corneal radius of curvature measured at the 20-year follow-up were evaluated via logistic regression and analysis of variance., Results: Prevalence of myopia was highest among participants with consistently short or consistently long FLs (P = 0.04). There was also a trend toward increased prevalence with larger HC in late gestation, although not at a statistically significant level. Trajectory groups reflecting faster HC, FL, or EFW growth correlated with significantly flatter corneas (P = 0.03, P = 0.04, and P = 0.01, respectively) and a general, but not statistically significant, increase in AL., Conclusions: Environmental or genetic factors influencing intrauterine skeletal growth may concurrently affect ocular development, with effects persisting into adulthood.

Elevated intraocular pressure (IOP) is an important risk factor for glaucoma. Mechanisms involved in its homeostasis are not well understood, but associations between metabolic factors and IOP have been reported. To investigate the relationship between levels of circulating metabolites and IOP, we performed a metabolome-wide association using a machine learning algorithm, and then employing Mendelian Randomization models to further explore the strength and directionality of effect of the metabolites on IOP. We show that O-methylascorbate, a circulating Vitamin C metabolite, has a significant IOP-lowering effect, consistent with previous knowledge of the anti-hypertensive and anti-oxidative role of ascorbate compounds. These results enhance understanding of IOP control and may potentially benefit future IOP treatment and reduce vision loss from glaucoma., (Copyright © 2018 The Authors. Published by Elsevier B.V. All rights reserved.)

Lung function measures are used in the diagnosis of chronic obstructive pulmonary disease. In 38,199 European ancestry individuals, we studied genome-wide association of forced expiratory volume in 1 s (FEV1), forced vital capacity (FVC) and FEV1/FVC with 1000 Genomes Project (phase 1)-imputed genotypes and followed up top associations in 54,550 Europeans. We identify 14 novel loci (P<5 × 10(-8)) in or near ENSA, RNU5F-1, KCNS3, AK097794, ASTN2, LHX3, CCDC91, TBX3, TRIP11, RIN3, TEKT5, LTBP4, MN1 and AP1S2, and two novel signals at known loci NPNT and GPR126, providing a basis for new understanding of the genetic determinants of these traits and pulmonary diseases in which they are altered.