OP-09 Structural correlations between brain magnetic resonance image-derived phenotypes and retinal neuroanatomy

Ophthalmology

PurposeTo compare the effectiveness and safety of the MicroShunt (Santen Inc) versus trabeculectomy in patients with primary open-angle glaucoma (POAG).DesignProspective, randomized, multicenter trial conducted in the United States and Europe.ParticipantsAdult patients (aged 40–85 years) with mild to severe POAG inadequately controlled on maximum tolerated medical therapy and intraocular pressure (IOP) ≥ 15 mmHg and ≤ 40 mmHg.MethodsPatients were randomized 3:1 to stand-alone MicroShunt implantation (n = 395) or trabeculectomy (n = 132), both augmented with mitomycin C (MMC) 0.2 mg/ml for 2 minutes.Main Outcome MeasuresThe primary effectiveness end point was surgical success, defined as ≥ 20% reduction in mean diurnal IOP from baseline with no increase in glaucoma medications. Secondary end points included changes in mean IOP and medication use from baseline and the …

BMJ Open

Introduction Remyelination failure hampers symptomatic recovery in multiple sclerosis (MS), underlining the importance of developing remyelinating therapies. Optic neuritis is currently the most established method of measuring remyelination in MS trials. Complementary more generalisable methods of measuring remyelination are required to confirm treatment efficacy. Measuring internuclear ophthalmoplegia (INO) with infrared oculography provides such a method. Moreover, this method can be expanded with a test for selecting likely treatment responders by using fampridine. The aim of this trial is to investigate the (long-term) remyelinating effects of clemastine fumarate in patients with MS and INO and to evaluate if treatment response can be predicted using fampridine.Methods and analysis RESTORE is a single-centre double-blind randomised placebo-controlled trial of clemastine fumarate versus placebo …

medRxiv

The potential value of large scale datasets is constrained by the ubiquitous problem of missing data, arising in either a structured or unstructured fashion. While there is considerable work on imputation methods, much is focused on small-scale datasets with just tens of variables. When imputation methods are proposed for large scale data, one limitation is the simplicity of existing evaluation methods. Specifically, most evaluations create synthetic data with only a simple, unstructured missing data mechanism, and do not resemble the missing data patterns found in real data. For example, in UK Biobank missing data tends to appear in blocks, because non-participation in one of the sub-studies leads to missingness for all of the sub-study variables.

Authorea Preprints

Optical coherence tomography (OCT) offers clinicians detailed in vivo structural imaging of individual retinal layers. This has lead to novel observations which were impossible by direct ophthalmoscopy. The technique also helps to re-introduce the concept of retinotopy to clinical practise. This review illustrates the anatomical foundation for retinotopy through detailed sketches of the pre- and post-laminar axons forming the optic nerve and their post-synaptic path from the dorsal lateral geniculate nucleus to the primary visual cortex in humans. With the mapped neuroanatomy in mind we use OCT-MRI pairs to discuss the patterns of neurodegeneration in eye and brain that are a consequence of the hard wired retinotopy: antero- and retrograde axonal degeneration which can, within the visual system, propagate trans-synaptically. The technical advances of OCT and MRI for the first time enable us to trace the signals of axonal degeneration through the visual system entirely at spectacular resolution. In addition to atrophic processes, we also summarize novel insights on tissue thickening mainly at the level of the optic disc, in particular peripaphillary hyperreflecitive ovoid mass like structures (PHOMS). In conclusion, the neuroanatomical insights provided by the combination of OCT and MRI allows us to separate incidental findings from sinister pathology and gives us new opportunities to tailor and monitor novel neuroprotective strategies.

Cardiovascular Diabetology

Diabetes mellitus is a chronic disease which is detrimental to cardiovascular health, often leading to secondary microvascular complications, with huge global health implications. Therapeutic interventions that can be applied to multiple vascular beds are urgently needed. Diabetic retinopathy (DR) and diabetic kidney disease (DKD) are characterised by early microvascular permeability changes which, if left untreated, lead to visual impairment and renal failure, respectively. The heparan sulphate cleaving enzyme, heparanase, has previously been shown to contribute to diabetic microvascular complications, but the common underlying mechanism which results in microvascular dysfunction in conditions such as DR and DKD has not been determined. In this study, two mouse models of heparan sulphate depletion (enzymatic removal and genetic ablation by endothelial specific Exotosin-1 knock down) were utilized …

Avoidant-restrictive food intake disorder (ARFID) is an eating disorder characterised by limited consumption or the avoidance of certain foods, leading to the persistent failure to meet the individual’s nutritional and/or energy needs. The disordered eating is not explained by the lack of available food or cultural beliefs. ARFID is often associated with a heightened sensitivity to the sensory features of different types of food and may be more prevalent among children with autism spectrum disorder (ASD) for this reason. Sight loss from malnutrition is one of the most devastating and life-changing complications of ARFID, but difficult to diagnose in young children and those with ASD who have more difficulty with communicating their visual problems to carers and clinicians, leading to delayed treatment and greater probability of irreversible vision loss. In this article, we highlight the importance of diet and nutrition to vision …

The Journal of Sexual Medicine

Introduction Surgical simulation with use of synthetic materials, animals, or human tissues is an essential part of surgical training. Prior vasovasostomy (VV) simulations have described use of silicone tubules, animal vasa, and vas segments from human prostatectomy specimen. Herein we describe a VV surgical simulation model using benign, en bloc human testicle and spermatic cord specimen acquired via gender-affirming simple orchiectomy. Objective To improve resident confidence in performing VV via a surgical wet lab using benign, en bloc human testicle and spermatic cord specimen acquired via gender-affirming simple orchiectomy. Methods En bloc testicle and spermatic cord specimen from benign orchiectomy procedures were stored in our institution’s tissue bank. After development of a tissue handling protocol, specimens were then …

British Journal of Ophthalmology

Glaucoma is a leading cause of visual impairment and a significant public health concern, but despite ongoing advances in our understanding of the disease, several important clinical challenges remain. With the number of affected people projected to increase substantially over coming decades, novel approaches to screening, risk stratification, therapy and glaucoma research are essential to deal with this expanding burden in an efficient and cost-effective manner. Genomics may hold the key to unlocking further biological insights and enabling precision medicine, in which glaucoma care is tailored to the individual patient, based on their unique profile for disease. Here, we provide an overview of how genomics may enable cost-effective targeted population screening and personalised predictions of risk, response to treatment and effective lifestyle advice. Given rapid advances in genetic testing technology and a …

Purpose:To summarize the main topics discussed during the 28th Annual Glaucoma Foundation Think Tank Meeting “A Patient-Centric Approach to Glaucoma” held in New York on June 9 and 10, 2023.Methods:The highlights of the sessions on BIG DATA, genetics, modifiable lifestyle risk factors, female sex hormones, and neuroprotection in the field of primary open angle glaucoma (POAG) were summarized.Results:The researchers discussed the importance of BIG DATA repositories available at national and international levels for POAG research, including the United Kingdom Biobank. Combining genotyped large cohorts worldwide, facilitated by artificial intelligence (AI) and machine-learning approaches, led to the milestone discovery of 312 genome-wide significant disease loci for POAG. While these loci could be combined into a polygenic risk score with clinical utility, Think Tank meeting participants also …

British Journal of Ophthalmology

Background/aims Topical agents to lower intraocular pressure (IOP) are the most common initial therapeutic measure in glaucoma prevention. This study aims to assess treatment success duration among patients initiating or intensifying topical glaucoma medication.Methods Medical records (2013‒2018) for adults initiating/intensifying topical glaucoma medication were extracted from five secondary-care and tertiary-care UK ophthalmology centres. Main study outcomes were time from treatment initiation/intensification to treatment failure (<20% IOP reduction or IOP >21 mm Hg at consecutive clinic visits, or intensification of glaucoma treatment) and time from treatment change to subsequent treatment intensification.Results Study eyes (n=6587) underwent treatment intensification 0-to-1 glaucoma drop (5358 events), 1-to-2 drops (1469 events) and 2-to-3 drops (857 events) during the observation period. Median …

Investigative Ophthalmology & Visual Science

Purpose: Smoking may influence measured IOP through an effect on corneal biomechanics, but it is unclear whether this factor translates into an increased risk for glaucoma. This study aimed to examine the association of cigarette smoking with corneal biomechanical properties and glaucoma-related traits, and to probe potential causal effects using Mendelian randomization (MR).Methods: Cross-sectional analyses within the UK Biobank (UKB) and Canadian Longitudinal Study on Aging (CLSA) cohorts. Multivariable linear and logistic regression models were used to assess associations of smoking (status, intensity, and duration) with corneal hysteresis (CH), corneal resistance factor, IOP, inner retinal thicknesses, and glaucoma. Two-sample MR analyses were performed.Results: Overall, 68,738 UKB (mean age, 56.7 years; 54.7% women) and 22 845 CLSA (mean age, 62.7 years; 49.1% women) participants were included. Compared with nonsmokers, smokers had a higher CH (UKB,+ 0.48 mm Hg; CLSA,+ 0.57 mm Hg; P< 0.001) and corneal resistance factor (UKB,+ 0.47 mm Hg; CLSA,+ 0.60 mm Hg; P< 0.001) with evidence of a dose–response effect in both studies. Differential associations with Goldmann-correlated IOP (UKB,+ 0.25 mm Hg; CLSA,+ 0.36 mm Hg; P< 0.001) and corneal-compensated IOP (UKB,–0.28 mm Hg; CLSA,–0.32 mm Hg; P≤ 0.001) were observed. Smoking was not associated with inner retinal thicknesses or glaucoma status in either study. MR provided evidence for a causal effect of smoking on corneal biomechanics, especially higher CH.Conclusions: Cigarette smoking seems to increase corneal biomechanical …

Under the next cycle of target setting under the Paris Agreement, countries will be updating and submitting new nationally determined contributions (NDCs) over the next two years. To this end, there is a growing need for the United States to assess potential pathways toward a new, maximally ambitious 2035 NDC. In this study, we use an integrated assessment model with state-level detail to model existing policies from both federal and non-federal actors, including the Inflation Reduction Act, Bipartisan Infrastructure Law, and key state policies, across all sectors and gases. Additionally, we develop a high-ambition scenario, which includes feasible, new and enhanced policies from these actors. We find that existing policies can reduce net greenhouse gas (GHG) emissions by 44%(with a range of 37% to 52%) by 2035, relative to 2005 levels, and the high-ambition scenario can deliver net GHG reductions up to 65%(with a range of 59% to 71%) by 2035. This level of reductions would provide a basis for continued progress toward the country’s 2050 net-zero emissions goal.

Imaging Neuroscience

Automated online and App-based cognitive assessment tasks are becoming increasingly popular in large-scale cohorts and biobanks due to advantages in affordability, scalability, and repeatability. However, the summary scores that such tasks generate typically conflate the cognitive processes that are the intended focus of assessment with basic visuo-motor speeds, testing device latencies, and speed-accuracy tradeoffs. This lack of precision presents a fundamental limitation when studying brain-behaviour associations. Previously, we developed a novel modelling approach that leverages continuous performance recordings from large-cohort studies to achieve an iterative decomposition of cognitive tasks (IDoCT), which outputs data-driven estimates of cognitive abilities, and device and visuo-motor latencies, whilst recalibrating trial-difficulty scales. Here, we further validate the IDoCT approach with UK …

British Journal of Ophthalmology

AimsTo describe the incidence and epidemiology of conjunctival squamous cell carcinoma (CSCC) in South Africa over a 25-year period (1994–2018), with particular reference to the HIV epidemic.MethodsIncident cases of histologically diagnosed CSCC were identified from the pathology-based South African National Cancer Registry. Crude and direct age-standardised incidence rates (ASIRs) per 100 000 persons (Segi World Standard Population) were calculated using national population statistics and compared by age, sex and ethnicity. Trends in the incidence and demographic features of CSCC were described and analysed. Incidence rates were compared with national HIV-related statistics for the same time period.ResultsIn total, there were 9016 reported CSCC cases (women: 56.6%, black: 86.8%, mean age: 41.5 years). The overall ASIR was 0.78 per 100 000. Two distinct epidemiological patterns were …

Carbon dioxide removal (CDR) is a critical component of any strategy to limit global warming to well below 2 C and rapidly gaining attention in climate research and policymaking. Despite its importance, there have been few attempts to systematically evaluate the scientific evidence on CDR. Here we use an approach rooted in artificial intelligence to produce a comprehensive systematic map of the CDR literature. In particular, we hand-label 5,339 documents to train machine learning classifiers with high levels of precision and recall to identify a total of 28,976 CDR studies across different technology domains and disciplines published in the period 1990-2022 which is at least 2-3 times more than previous studies suggested. We paint a granular picture of available CDR research in terms of the CDR methods studied, the geographical focus of research, the research method applied, and the broad area of research. The field has grown considerably faster than the climate change literature as a whole. This is driven mainly by the rapid expansion of literature on biochar, which made up about 62% of CDR publications in 2022. Beyond this stark concentration of CDR research on a few individual CDR methods, we find that most studies (86%) focus on improving the CDR methods themselves, but there is little research on their societal implications and ethical foundations. Citations patterns from the most recent IPCC report strongly differ from publication patterns on CDR in terms of its attention to CDR methods, research design and methodological context, as does attention to CDR methods in policy and practice in terms of real-world deployments …

Frontiers in Cellular Neuroscience

Introduction As with any other radial glia in the central nervous system, Müller glia derive from the same neuroepithelial precursors, perform similar functions, and exhibit neurogenic properties as radial glia in the brain. Müller glial cells retain progenitor-like characteristics in the adult human eye and can partially restore visual function upon intravitreal transplantation into animal models of glaucoma. Recently, it has been demonstrated that intracellular communication is possible via the secretion of nano-sized membrane-bound extracellular vesicles (EV), which contain bioactive molecules like microRNA (miRNA) and proteins that induce phenotypic changes when internalised by recipient cells. Methods We conducted high-throughput sequencing to profile the microRNA signature of EV populations secreted by Müller glia in culture and used bioinformatics tools to evaluate their potential role in the neuroprotective signalling attributed to these cells. Results Sequencing of miRNA within Müller EV suggested enrichment with species associated with stem cells such as miR-21 and miR-16, as well as with miRNA previously found to play a role in diverse Müller cell functions in the retina: miR-9, miR-125b, and the let-7 family. A total of 51 miRNAs were found to be differentially enriched in EV compared to the whole cells from which EV originated. Bioinformatics analyses also indicated that preferential enrichment of species was demonstrated to regulate genes involved in cell proliferation and survival, including PTEN, the master inhibitor of the PI3K/AKT pathway. Discussion The results suggest that the release by Müller cells of miRNA-enriched EV …

Journal of Neurology, Neurosurgery & Psychiatry

BackgroundAmyotrophic lateral sclerosis (ALS) is a disease of the motor network associated with brain structure and functional connectivity alterations that are implicated in disease progression. Whether such changes have a causal role in ALS, fitting with a postulated influence of premorbid cerebral architecture on the phenotypes associated with neurodegenerative disorders is not known.MethodsThis study considered causal effects and shared genetic risk of 2240 structural and functional MRI brain scan imaging-derived phenotypes (IDPs) on ALS using two sample Mendelian randomisation, with putative associations further examined with extensive sensitivity analysis. Shared genetic predisposition between IDPs and ALS was explored using genetic correlation analysis.ResultsIncreased white matter volume in the cerebral hemispheres was causally associated with ALS. Weaker causal associations were …

Ophthalmology Science

PurposePeriodontitis, a ubiquitous severe gum disease affecting the teeth and surrounding alveolar bone, can heighten systemic inflammation. We investigated the association between very severe periodontitis and early biomarkers of age-related macular degeneration (AMD), in individuals with no eye disease.DesignCross-sectional analysis of the prospective community-based cohort United Kingdom (UK) Biobank.ParticipantsSixty-seven thousand three hundred eleven UK residents aged 40 to 70 years recruited between 2006 and 2010 underwent retinal imaging.MethodsMacular-centered OCT images acquired at the baseline visit were segmented for retinal sublayer thicknesses. Very severe periodontitis was ascertained through a touchscreen questionnaire. Linear mixed effects regression modeled the association between very severe periodontitis and retinal sublayer thicknesses, adjusting for age, sex …