Rethinking professional boundaries: the climate crisis and brain health.

Since climate change affects psychiatric, neurological and neuropsychological disorders, as well as brain development, the Irish Doctors for the Environment working group on mental health has changed its title and remit to brain health. Mental health professionals need to respond coherently and effectively to the climate crisis. This need challenges traditional professional, disciplinary and academic boundaries and demands a holistic, person-centred approach. We propose that meeting this challenge is vital if the public, policy-makers and legislators are to grasp the full extent of the significance of climate's impact on brain health.

Target 5000: a standardized all-Ireland pathway for the diagnosis and management of inherited retinal degenerations.

INTRODUCTION: Inherited retinal degenerations (IRD) are rare genetic disorders with > 300 known genetic loci, manifesting variably progressive visual dysfunction. IRDs were historically underserved due to lack of effective interventions. Many novel therapies will require accurate diagnosis (phenotype and genotype), thus an efficient and effective pathway for assessment and management is required. METHODS: Using surveys of existing practice patterns and advice from international experts, an all-Ireland IRD service (Target 5000) was designed. Detailed phenotyping was followed by next generation genetic sequencing in both a research and accredited laboratory. Unresolved pedigrees underwent further studies (whole gene/whole exome/whole genome sequencing). Novel variants were interrogated for pathogenicity (cascade screening, in silico analysis, functional studies). A multidisciplinary team (MDT; ophthalmologists, physicians, geneticists, genetic counsellors) reconciled phenotype with genotype. A bespoke care plan was created for each patient comprising supports, existing interventions, and novel therapies/clinical trials. RESULTS AND DISCUSSION: Prior to Target 5000, a significant cohort of patients were not engaged with healthcare/support services due to lack of effective interventions. Pathogenic or likely pathogenic variants in IRD-associated genes were detected in 62.3%, with 11.6% having variants of unknown significance. The genotyping arm of Target 5000 allowed a 42.73% cost saving over independent testing, plus the value of MDT expertise/processing. Partial funding has transferred from charitable sources to government resources. CONCLUSION: Target 5000 demonstrates efficacious and efficient clinical/genetic diagnosis, while discovering novel IRD-implicated genes/variants and investigating mechanisms of disease and avenues of intervention. This model could be used to develop similar IRD programmes in small/medium-sized nations.

Systemic IL-1ß production as a consequence of corneal HSV-1 infection-contribution to the development of herpes simplex keratitis.

This study sought to identify potential therapeutic targets in herpes simplex keratitis (HSK) patients with active and inactive infection by investigating peripheral cytokine production. Peripheral blood mononuclear cells (PBMCs) and serum were prepared from healthy controls and HSK patients during active infection or following treatment (inactive infection). Serum antibody titres were determined by ELISA. Protein expression levels were analysed by Western blot. Cytokine levels were determined by multiplex ELISA. Active corneal herpes simplex virus type 1 (HSV-1) infection resulted in significantly elevated peripheral levels of IL-1ß in HSK patients compared to healthy controls, and remained significantly increased following treatment. Elevated production of IL-1ß in inactive patients was associated with significantly increased levels of IRF3 and STAT1, key proteins involved in promoting anti-viral immune responses. Our data suggest that inflammation persists beyond the period that it is clinically evident and that enhanced peripheral production of IL-1ß may have implications for HSV-1 viral clearance in active and inactive HSK patients.

Panel-Based Population Next-Generation Sequencing for Inherited Retinal Degenerations.

Inherited retinopathies affect approximately two and a half million people globally, yet the majority of affected patients lack clear genetic diagnoses given the diverse range of genes and mutations implicated in these conditions. We present results from a next-generation sequencing study of a large inherited retinal disease patient population, with the goal of providing clear and actionable genetic diagnoses. Targeted sequencing was performed on 539 individuals from 309 inherited retinal disease pedigrees. Causative mutations were identified in the majority (57%, 176/309) of pedigrees. We report the association of many previously unreported variants with retinal disease, as well as new disease phenotypes associated with known genes, including the first association of the SLC24A1 gene with retinitis pigmentosa. Population statistics reporting the genes most commonly implicated in retinal disease in the cohort are presented, as are some diagnostic conundrums that can arise during such studies. Inherited retinal diseases represent an exemplar group of disorders for the application of panel-based next-generation sequencing as an effective tool for detection of causative mutations.