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Group 3 innate lymphoid cells (ILC3s) are abundant in the developing or healthy intestine to critically support tissue homeostasis in response to microbial colonization. However, intestinal ILC3s are reduced during chronic infections, colorectal cancer, or inflammatory bowel disease (IBD), and the mechanisms driving these alterations remain poorly understood. Here we employed RNA sequencing of ILC3s from IBD patients and observed a significant upregulation of RIPK3, the central regulator of necroptosis, during intestinal inflammation. This was modeled in mice where we found that intestinal ILC3s express RIPK3, with conventional (c)ILC3s exhibiting high RIPK3 and low levels of pro-survival genes relative to lymphoid tissue inducer (LTi)-like ILC3s. ILC3-specific RIPK3 is promoted by gut microbiota, further upregulated following enteric infection, and dependent upon IL-23R and STAT3 signaling. However, lineage-specific deletion of RIPK3 revealed a redundant role in ILC3 survival, due to a blockade of RIPK3-mediated necroptosis by caspase 8, which was also activated in response to enteric infection. In contrast, lineage-specific deletion of caspase 8 resulted in loss of cILC3s from the healthy intestine and all ILC3 subsets during enteric infection, which increased pathogen burdens and gut inflammation. This function of caspase 8 required catalytic activity induced by TNF or TL1A and was dispensable if RIPK3 was simultaneously deleted. Caspase 8 activation and cell death were associated with increased Fas on ILC3s, and the Fas-FasL pathway was upregulated by cILC3s during enteric infection, which could restrain the abundance of intestinal ILC3s. Collectively, these data reveal that interpretation of key cytokine signals controls ILC3 survival following microbial challenge, and that an imbalance of these pathways, such as in IBD or across ILC3 subsets, provokes depletion of tissue-protective ILC3s from the inflamed intestine.
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BACKGROUND: This study aimed to compare the demographic differences between Maori and NZ Europeans with neck of femur fracture (NOF), identify any differences in management, surgical and post-op care and outcomes. METHODS: All cases in New Zealand between 2018 and 2020 were collected from the Australia & New Zealand Hip Fracture Registry (ANZHFR). Basic demographics, management factors, and surgical factors were collected. Key outcomes at 120 days post-fracture included walking status, residential status and survival. Univariate analysis was performed to compare differences in demographics, and management factors between ethnicities. Multivariable analysis was conducted on key outcome comparisons and management differences. RESULTS: Data from 9432 patients were analyzed. 305 patients were Maori (3.2%). Age-standardized incidence between Maori and NZ European were similar (103 (95% CI 91-115) vs. 95 (95% CI 92-99)/100 000/year). Maori had a longer time to theatre (38.7 vs. 34.5 h, P = 0.01). The only difference between Maori and NZ European in the key outcomes was private residential status (67% vs. 62% P < 0.01). There was no difference in survival (87% vs. 87% P = 0.68) and decrease in walking status (0.43 vs. 0.41 P = 0.99). Following multivariable analysis, Maori ethnicity was an independent risk factor for time to theatre >48 hours after adjustment for other factors (OR 1.44 (95% CI 1.07, 1.93), P = 0.016). DISCUSSION: Although Maori were a small percentage of patients with NOFs, there was similar age-standardized incidence compared to NZ Europeans. While there were no differences in key outcomes, identifying reasons for longer time to theatre for Maori patients is required.
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Understanding the impact of splicing and nonsense variants on RNA is crucial for the resolution of variant classification as well as their suitability for precision medicine interventions. This is primarily enabled through RNA studies involving transcriptomics followed by targeted assays using RNA isolated from clinically accessible tissues (CATs) such as blood or skin of affected individuals. Insufficient disease gene expression in CATs does however pose a major barrier to RNA based investigations, which we show is relevant to 1,436 Mendelian disease genes. We term these "silent" Mendelian genes (SMGs), the largest portion (36%) of which are associated with neurological disorders. We developed two approaches to induce SMG expression in human dermal fibroblasts (HDFs) to overcome this limitation, including CRISPR-activation-based gene transactivation and fibroblast-to-neuron transdifferentiation. Initial transactivation screens involving 40 SMGs stimulated our development of a highly multiplexed transactivation system culminating in the 6- to 90,000-fold induction of expression of 20/20 (100%) SMGs tested in HDFs. Transdifferentiation of HDFs directly to neurons led to expression of 193/516 (37.4%) of SMGs implicated in neurological disease. The magnitude and isoform diversity of SMG expression following either transactivation or transdifferentiation was comparable to clinically relevant tissues. We apply transdifferentiation and/or gene transactivation combined with short- and long-read RNA sequencing to investigate the impact that variants in USH2A, SCN1A, DMD, and PAK3 have on RNA using HDFs derived from affected individuals. Transactivation and transdifferentiation represent rapid, scalable functional genomic solutions to investigate variants impacting SMGs in the patient cell and genomic context.
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Transdiferenciação Celular , Fibroblastos , Neurônios , Ativação Transcricional , Humanos , Transdiferenciação Celular/genética , Fibroblastos/metabolismo , Fibroblastos/citologia , Neurônios/metabolismo , Neurônios/citologia , RNA/genética , RNA/metabolismo , Sistemas CRISPR-CasRESUMO
Purpose: To describe the clinical, electrophysiological and genetic spectrum of inherited retinal diseases associated with variants in the PRPH2 gene. Methods: A total of 241 patients from 168 families across 15 sites in 9 countries with pathogenic or likely pathogenic variants in PRPH2 were included. Records were reviewed for age at symptom onset, visual acuity, full-field ERG, fundus colour photography, fundus autofluorescence (FAF), and SD-OCT. Images were graded into six phenotypes. Statistical analyses were performed to determine genotype-phenotype correlations. Results: The median age at symptom onset was 40 years (range, 4-78 years). FAF phenotypes included normal (5%), butterfly pattern dystrophy, or vitelliform macular dystrophy (11%), central areolar choroidal dystrophy (28%), pseudo-Stargardt pattern dystrophy (41%), and retinitis pigmentosa (25%). Symptom onset was earlier in retinitis pigmentosa as compared with pseudo-Stargardt pattern dystrophy (34 vs 44 years; P = 0.004). The median visual acuity was 0.18 logMAR (interquartile range, 0-0.54 logMAR) and 0.18 logMAR (interquartile range 0-0.42 logMAR) in the right and left eyes, respectively. ERG showed a significantly reduced amplitude across all components (P < 0.001) and a peak time delay in the light-adapted 30-Hz flicker and single-flash b-wave (P < 0.001). Twenty-two variants were novel. The central areolar choroidal dystrophy phenotype was associated with 13 missense variants. The remaining variants showed marked phenotypic variability. Conclusions: We described six distinct FAF phenotypes associated with variants in the PRPH2 gene. One FAF phenotype may have multiple ERG phenotypes, demonstrating a discordance between structure and function. Given the vast spectrum of PRPH2 disease our findings are useful for future clinical trials.
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Eletrorretinografia , Periferinas , Fenótipo , Distrofias Retinianas , Acuidade Visual , Humanos , Periferinas/genética , Pessoa de Meia-Idade , Adulto , Masculino , Feminino , Adolescente , Distrofias Retinianas/genética , Distrofias Retinianas/fisiopatologia , Distrofias Retinianas/diagnóstico , Idoso , Acuidade Visual/fisiologia , Criança , Adulto Jovem , Pré-Escolar , Tomografia de Coerência Óptica , Mutação , Angiofluoresceinografia , Estudos de Associação Genética , Estudos Retrospectivos , Análise Mutacional de DNA , DNA/genética , LinhagemRESUMO
Amidst rapid advancements in ocular gene therapy, understanding patient perspectives is crucial for shaping future treatment choices and research directions. This international cross-sectional survey evaluated knowledge, attitudes, and perceptions of ocular genetic therapies among potential recipients with inherited retinal diseases (IRDs). Survey instruments included the Attitudes to Gene Therapy-Eye (AGT-Eye), EQ-5D-5L, National Eye Institute Visual Functioning Questionnaire (NEI-VFQ-25), and Patient Attitudes to Clinical Trials (PACT-22) instruments. This study included 496 participant responses (89% adults with IRDs; 11% parents/guardians/carers) from 35 countries, with most from the United States of America (USA; 69%) and the United Kingdom (11%). Most participants (90%) indicated they would likely accept gene therapy if it was available, despite only 45% agreeing that they had good knowledge of gene therapy. The main sources of information were research registries (60% of participants) and the internet (61%). Compared to data from our recently published Australian national survey of people with IRDs (n = 694), USA respondents had higher knowledge of gene therapy outcomes, and Australian respondents indicated a higher perceived value of gene therapy treatments. Addressing knowledge gaps regarding outcomes and financial implications will be central to ensuring informed consent, promoting shared decision-making, and the eventual clinical adoption of genetic therapies.
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Terapia Genética , Humanos , Terapia Genética/métodos , Adulto , Masculino , Estudos Transversais , Inquéritos e Questionários , Feminino , Pessoa de Meia-Idade , Conhecimentos, Atitudes e Prática em Saúde , Doenças Retinianas/terapia , Doenças Retinianas/genética , Adulto Jovem , Adolescente , Idoso , Estados UnidosRESUMO
BACKGROUND: KCNV2-associated retinopathy is an autosomal recessive inherited retinal disease classically named cone dystrophy with supernormal rod response (CDSRR). This study aims to identify the best biomarker for evaluating the condition. METHODS: A retrospective review of eight patients from seven families with genetically confirmed KCNV2-associated retinopathy was performed. The best corrected visual acuity (BCVA), full-field electroretinogram (ffERG), pattern ERG (pERG), fundus imaging: retinal photograph and fundus autofluorescence (FAF), and optical coherence tomography (OCT) were analysed. RESULTS: There was a disproportionate increase in b-wave amplitude with a relatively small light intensity increase, especially between the two dimmest stimuli of DA 0.002 and 0.01 (-2.7 and -2.0 log cd.s/m2). The a-wave amplitude was normal. The a-wave peak time was delayed in all stimuli. The b-wave peak time was delayed compared to normal, but the gap tightened as intensity increased. The b:a wave ratio was above or at the upper limit for the reference values. FAF bull's eye maculopathy pattern was prominent and variable foveal disruption on OCT was apparent in all patients. Legal blindness was reached before the age of 25. CONCLUSIONS: We identified three potential electrophysiology biomarkers to assist in evaluating future therapies: the disproportionate b-wave amplitude jump, delayed a-wave and b-wave peak time, and the higher than normal b:a wave ratio. Any of these biomarkers found with photoreceptor ellipsoid zone foveal-perifoveal disruption should prompt consideration for KCNV2 retinopathy. The BCVA natural history data suggests the probable optimum therapeutic window in the first three decades of life.
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Biomarcadores , Eletrorretinografia , Tomografia de Coerência Óptica , Acuidade Visual , Humanos , Masculino , Feminino , Tomografia de Coerência Óptica/métodos , Estudos Retrospectivos , Adulto , Acuidade Visual/fisiologia , Biomarcadores/metabolismo , Adulto Jovem , Adolescente , Pessoa de Meia-Idade , Criança , Angiofluoresceinografia/métodos , Canais de Potássio de Abertura Dependente da Tensão da Membrana/genética , Distrofia de Cones/genética , Distrofia de Cones/diagnóstico , Distrofia de Cones/fisiopatologia , MutaçãoRESUMO
OBJECTIVE: To assess the long-term efficacy and safety of oral saffron, a natural antioxidant, in treating mild/moderate age-related macular degeneration (AMD). METHODS AND ANALYSIS: Open-label, extension trial of 93 adults (>50 years) with mild/moderate AMD and vision >20/70 Snellen equivalent in at least 1 eye. Exclusion criteria included confounding visual lesions or significant gastrointestinal disease impairing absorption.Participants were given oral saffron supplementation (20 mg/day) for 12 months. Those already consuming Age-Related Eye Diseases Study (AREDS) supplements or equivalent maintained these.Primary outcomes included changes in multifocal electroretinogram (mfERG) response density and latency, and changes in best-corrected visual acuity (BCVA). Secondary outcomes included safety outcomes, changes in mfERG and BCVA among participants on AREDS supplements and changes in microperimetry. RESULTS: At 12 months, mean mfERG response density was significantly higher in rings 1, 2 and overall (p<0.001 for all) but not in rings 3-6, and there was no difference in response between those taking AREDS supplements and those not (p>0.05). Mean mfERG latency was not significantly different in any of rings 1-6 or overall (p>0.05 for all), again with no difference between those taking AREDS supplements or not (p>0.05). Mean BCVA was 1.6 letters worse (p<0.05) with no difference between those on AREDS supplements or not, and this may have been related to cataract progression. No saffron-related serious adverse events were detected. CONCLUSION: Saffron supplementation modestly improved mfERG responses in participants with AMD, including those using AREDS supplements. Given the chronic nature of AMD, longer-term supplementation may produce greater benefits.
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Crocus , Degeneração Macular , Humanos , Antioxidantes , Suplementos Nutricionais , Degeneração Macular/tratamento farmacológico , Acuidade VisualRESUMO
PURPOSE: Economic evaluations of interventions for ocular disease require utility scores that accurately represent quality of life in the target population. This study aimed to describe the distribution of EQ-5D-5L utility values among Australian adults with symptomatic inherited retinal diseases (IRDs) and to assess the relationship between these scores and vision-related quality of life. METHODS: A survey was administered predominantly online in 2021. Participants completed the EQ-5D-5L general health utility instrument, the EQ vertical visual analogue scale (EQ-VAS) and the National Eye Institute Visual Functioning Questionnaire (NEI-VFQ-25). Self-reported IRD diagnoses were classified as being associated with central or widespread retinal involvement. RESULTS: Responses from 647 participants aged 18-93 years were included, 50.1% were men and 77.6% had an IRD associated with widespread retinal involvement. The majority reported no problems with self-care and no pain/discomfort but did report anxiety/depression and problems with work, study, housework, or family/leisure activities. Most people with widespread involvement reported problems with mobility. Median EQ-5D-5L utility was 0.88 and 0.91 among people with widespread and central involvement, respectively (age and sex-adjusted p = 0.029); and median EQ-VAS was 75 and 80, respectively (adjusted p = 0.003). A moderate curvilinear correlation was observed between EQ-5D-5L and NEI-VFQ-25 composite score (Spearman's ρ 0.69), but not all people with poor vision-related quality of life had low EQ-5D-5L utility values. CONCLUSIONS: EQ-5D-5L health utility values are correlated with vision-related quality of life among adults with IRDs. However, the EQ-5D-5L may not be sensitive to the full impact of vision impairment on quality of life.
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Qualidade de Vida , Doenças Retinianas , Humanos , Adulto , Masculino , Pessoa de Meia-Idade , Feminino , Idoso , Estudos Transversais , Adolescente , Adulto Jovem , Austrália/epidemiologia , Idoso de 80 Anos ou mais , Doenças Retinianas/fisiopatologia , Doenças Retinianas/psicologia , Doenças Retinianas/diagnóstico , Inquéritos e Questionários , Nível de Saúde , Acuidade Visual/fisiologia , Perfil de Impacto da Doença , Anos de Vida Ajustados por Qualidade de VidaRESUMO
Severe vision impairment and blindness in childhood have a significant health burden on the child, family and society. This review article seeks to provide a structured framework for managing the apparently blind child presenting in the first year of life, starting from a comprehensive history and examination. Different investigation modalities and the increasingly important role of genetics will also be described, in addition to common causes of severe vision impairment. Crucially, a systematic approach to the blind infant is key to correct diagnoses and timely management. Incorrect diagnoses can be costly to all involved, however it is important to note that diagnoses can change with ongoing follow-up and investigations. Furthermore, the modern age of ophthalmology requires a multi-disciplinary approach and close collaboration with specialists including paediatricians, neurologists and geneticists, in addition to rehabilitation and low vision services, to ensure the best care for these vulnerable infants.
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Cegueira , Humanos , Cegueira/diagnóstico , Lactente , Recém-Nascido , Baixa Visão/reabilitação , Baixa Visão/diagnósticoRESUMO
BACKGROUND: Ophthalmology education in medical school has historically neglected the impact of autonomous motivation on student learning and wellbeing. This study aimed to understand ophthalmology educators' consideration and application of student motivation in ophthalmology medical education. MATERIAL AND METHODS: Lead ophthalmology educators from Australian and New Zealand medical schools participated in an online semi-structured in-depth interview. Interview transcripts were analysed using thematic analysis. Codes were generated and aligned into overarching themes. FINDINGS: Six educators participated in the study. Five main themes arose from the transcripts: the lack of explicit consideration of student motivation, implicit consideration of motivation in curriculum design and in teaching practices, the impact of innovation on motivation and the relationship between teacher and student motivation. Participants also commented on trends in ophthalmology education including generalists' confidence in managing ophthalmic disease, the role of fundoscopy in medical education and time pressure on ophthalmology in medical schools. CONCLUSION: There has only been an implicit instead of explicit consideration of motivation in ophthalmology education in medical school, which leaves an unfulfilled potential for teaching practices to impact the affective along with cognitive and metacognitive aspects of learning. This study highlights the need for motivation to be explicitly incorporated into the development of teaching practices and curriculum reform.
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Motivação , Oftalmologia , Humanos , Faculdades de Medicina , Oftalmologia/educação , Austrália , Currículo , Ensino/psicologiaRESUMO
Key Clinical Message: Inherited retinal dystrophies typically affect vision in early childhood; however, this case highlights a late onset retinal dystrophy presenting in midlife and the need for extended visual electrophysiology testing to determine the etiology. Abstract: A 53-year-old female was referred for visual electrophysiology following a routine optometric eye examination in which yellow flecks were noted in both fundi and the patient had reported a recent near accident whilst driving at night. There was no reported family history of eye disease. Retinal examination identified bilateral yellow punctate and irregularly shaped lesions throughout the posterior poles sparing the macula region. Fundus autofluorescence showed coinciding hyperfluorescence with the lesions and bilateral hypofluorescent crescents superior to the macular with corresponding retinal thinning. Visual fields and color vision were normal. ISCEV standard 20 min and extended 60-min dark adapted electroretinograms were recorded. Recovery to normal b-wave amplitudes was noted in the DA0.01 flash but reduced a-wave amplitudes were noted in the DA3 and DA10 flash following both dark adapted periods. Cone function was reduced but within normal limits. Genetic screening revealed a previously unreported variant of unknown significance in the gene PLA2G5:c.40 + 5del (rs1364254561) which is a member of the phospholipase A2 family and is associated with familial benign flecked retina.
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PURPOSE: To describe the natural history of autosomal dominant (AD) GUCY2D-associated cone-rod dystrophies (CRDs), and evaluate associated structural and functional biomarkers. METHODS: Retrospective analysis was conducted on 16 patients with AD GUCY2D-CRDs across two sites. Assessments included central macular thickness (CMT) and length of disruption to the ellipsoid zone (EZ) via optical coherence tomography (OCT), electroretinography (ERG) parameters, best corrected visual acuity (BCVA), and fundus autofluorescence (FAF). RESULTS: At first visit, with a mean age of 30 years (range 5-70 years), 12 patients had a BCVA below Australian driving standard (LogMAR ≥ 0.3 bilaterally), and 1 patient was legally blind (LogMAR ≥ 1). Longitudinal analysis demonstrated a deterioration of LogMAR by - 0.019 per year (p < 0.001). This accompanied a reduction in CMT of - 1.4 µm per year (p < 0.0001), lengthened EZ disruption by 42 µm per year (p = < 0.0001) and increased area of FAF by 0.05 mm2 per year (p = 0.027). Similarly, cone function decreased with increasing age, as demonstrated by decreasing b-wave amplitude of the light-adapted 30 Hz flicker and fused flicker (p = 0.005 and p = 0.018, respectively). Reduction in CMT and increased EZ disruption on OCT were associated with functional changes including poorer BCVA and decreased cone function on ERG. CONCLUSION: We have described the natural long-term decline in vision and cone function associated with mutations in GUCY2D and identified a set of functional and structural biomarkers that may be useful as outcome parameters for future therapeutic clinical trials.
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Distrofias de Cones e Bastonetes , Retinose Pigmentar , Humanos , Pré-Escolar , Criança , Adolescente , Adulto Jovem , Adulto , Pessoa de Meia-Idade , Idoso , Distrofias de Cones e Bastonetes/diagnóstico , Distrofias de Cones e Bastonetes/genética , Estudos Retrospectivos , Eletrorretinografia , Acuidade Visual , Austrália , Biomarcadores , Tomografia de Coerência Óptica/métodosRESUMO
Purpose: Secondary glaucoma following childhood cataract surgery remains the most common complication in the paediatric population. This study aimed to determine the incidence, time to progression and risk factors associated with the development of secondary glaucoma following childhood cataract surgery in a paediatric population. Outcome measures were the detection of secondary glaucoma, postoperative time frame to development of glaucoma and risk factors in its development. Patients and Methods: A retrospective case series was conducted between 2003 and 2017 at a tertiary children's hospital in Sydney. The patient population included those 16 years or less of age who underwent congenital cataract extraction, with or without an intraocular lens implantation and who had been followed up for a minimum of six months following surgery. Patients were excluded if they had cataract aetiology other than congenital idiopathic cataract. Multivariate Cox Regression analysis was used to determine relevant risk factors. Results: A total of 320 eyes in 216 patients were included in the study. Secondary glaucoma developed in 11.9% of eyes. In those that developed secondary glaucoma, the average time to onset from surgery was 3.2 years (median 2.75 years). The mean age of diagnosis of secondary glaucoma was 4.58 years (median 3.5 years, range 2.5 months to 13.23 years). Microcornea was the only adverse characteristic significantly associated with an increased risk of secondary glaucoma (HR 6.30, p 0.003). Conclusion: Despite modern surgical techniques, glaucoma remains a significant long-term sequela in children following cataract surgery.
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BACKGROUND: Inosine monophosphate dehydrogenase (IMPDH) is a key regulatory enzyme in the de novo synthesis of the purine base guanine. Mutations in the inosine monophosphate dehydrogenase 1 gene (IMPDH1) are causative for RP10 autosomal dominant retinitis pigmentosa (adRP). This study reports a novel variant in a family with IMPDH1-associated retinopathy. We also performed a comprehensive review of all reported IMPDH1 disease causing variants with their associated phenotype. MATERIALS AND METHODS: Multimodal imaging and functional studies documented the phenotype including best-corrected visual acuity (BCVA), fundus photograph, fundus autofluorescence (FAF), full field electroretinogram (ffERG), optical coherence tomography (OCT) and visual field (VF) data were collected. A literature search was performed in the PubMed and LOVD repositories. RESULTS: We report 3 cases from a 2-generation family with a novel heterozygous likely pathogenic variant p. (Lys314Gln) (exon 10). The ophthalmic phenotype showed diffuse outer retinal atrophy with mild pigmentary changes with sparse pigmentary changes. FAF showed early macular involvement with macular hyperautofluorescence (hyperAF) surrounded by hypoAF. Foveal ellipsoid zone island can be found in the youngest patient but not in the older ones. The literature review identified a further 56 heterozygous, 1 compound heterozygous, and 2 homozygous variant. The heterozygous group included 43 missense, 3 in-frame, 1 nonsense, 2 frameshift, 1 synonymous, and 6 intronic variants. Exon 10 was noted as a hotspot harboring 18 variants. CONCLUSIONS: We report a novel IMPDH1 variant. IMPDH1-associated retinopathy presents most frequently in the first decade of life with early macular involvement.
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Degeneração Retiniana , Retinose Pigmentar , Humanos , Inosina Monofosfato , Retinose Pigmentar/diagnóstico , Retinose Pigmentar/genética , Retinose Pigmentar/patologia , Mutação , Oxirredutases/genética , Tomografia de Coerência Óptica , Eletrorretinografia , Linhagem , IMP Desidrogenase/genéticaRESUMO
OBJECTIVES: To estimate the health care and societal costs of inherited retinal diseases (IRDs) in Australia. DESIGN, SETTING, PARTICIPANTS: Microsimulation modelling study based on primary data - collected in interviews of people with IRDs who had ophthalmic or genetic consultations at the Children's Hospital at Westmead or the Save Sight Institute (both Sydney) during 1 January 2019 - 31 December 2020, and of their carers and spouses - and linked Medicare Benefits Schedule (MBS) and Pharmaceutical Benefits Schedule (PBS) data. MAIN OUTCOME MEASURES: Annual and lifetime costs for people with IRDs and for their carers and spouses, grouped by payer (Australian government, state governments, individuals, private health insurance) and type (health care costs; societal costs: social support, National Disability Insurance Scheme (NDIS), income and taxation, costs associated with caring for family members with IRDs); estimated annual national cost of IRDs. RESULTS: Ninety-four people (74 adults, 20 people under 18 years; 55 girls and women [59%]) and 30 carers completed study surveys (participation rate: adults, 66%; children, 66%; carers, 63%). Total estimated lifetime cost was $5.2 million per person with an IRD, of which 87% were societal and 13% health care costs. The three highest cost items were lost income for people with IRDs ($1.4 million), lost income for their carers and spouses ($1.1 million), and social spending by the Australian government (excluding NDIS expenses: $1.0 million). Annual costs were twice as high for people who were legally blind as for those with less impaired vision ($83 910 v $41 357 per person). The estimated total annual cost of IRDs in Australia was $781 million to $1.56 billion. CONCLUSION: As the societal costs associated with IRDs are much larger than the health care costs, both contributors should be considered when assessing the cost-effectiveness of interventions for people with IRDs. The increasing loss of income across life reflects the impact of IRDs on employment and career opportunities.
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Programas Nacionais de Saúde , Doenças Retinianas , Idoso , Adulto , Criança , Humanos , Feminino , Adolescente , Austrália , Emprego , Custos de Cuidados de Saúde , Efeitos Psicossociais da DoençaRESUMO
BACKGROUND: Childhood ocular disease can be a significant health burden to the child, family and society. Previous studies have examined the spectrum of paediatric ocular disease presenting to tertiary hospitals; however, these studies have broader age ranges, smaller sample sizes, and are largely based in developing countries. This study aims to assess the spectrum of ocular disease in the first 3 years of life presenting to the eye department of an Australian tertiary paediatric hospital. METHODS: The records of 3337 children who had their initial presentation at the eye clinic between the age of 0 and 36 months were reviewed, spanning 6.5 years from 1st July 2012 to 31st December 2018. RESULTS: The most common primary diagnoses overall were strabismic amblyopia (6.0%), retinopathy of prematurity (5.0%) and nasolacrimal duct obstruction (4.5%). Bilateral visual impairment was more common in younger children, while unilateral visual impairment was more common in older children. The proportion of all children presenting with visual impairment was 10.3%, with 5.7% of all children presenting with bilateral visual impairment and 4.6% presenting with unilateral visual impairment. In children with visual impairment, the most common sites of primary abnormality were lens (21.4%), retina (17.3%), and cerebral and visual pathways (12.1%). The most common primary diagnoses in children with visual impairment were cataract (21.4%), strabismic amblyopia (9.3%) and retinoblastoma (6.5%). CONCLUSIONS: The spectrum of eye disease and vision impairment presenting in the first 3 years of life facilitates health care planning, greater community education about vision impairment and importance of early intervention, and guidance for appropriate resource allocation. Health systems can apply these findings to aid in early identification and intervention to reduce preventable blindness and institute appropriate rehabilitation services.
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Ambliopia , Obstrução dos Ductos Lacrimais , Ducto Nasolacrimal , Neoplasias da Retina , Baixa Visão , Recém-Nascido , Criança , Humanos , Lactente , Pré-Escolar , Ambliopia/epidemiologia , Hospitais Pediátricos , Centros de Atenção Terciária , Austrália/epidemiologia , Cegueira , Transtornos da Visão , PrevalênciaRESUMO
BACKGROUND: Neuronal ceroid lipofuscinosis is a group of neurodegenerative disorders with varying visual dysfunction. CLN3 is a subtype which commonly presents with visual decline. Visual symptomatology can be indistinct making early diagnosis difficult. This study reports ocular biomarkers of CLN3 patients to assist clinicians in early diagnosis, disease monitoring, and future therapy. METHODS: Retrospective review of 5 confirmed CLN3 patients in our eye clinic. Best corrected visual acuity (BCVA), electroretinogram (ERG), ultra-widefield (UWF) fundus photography and fundus autofluorescence (FAF), and optical coherence tomography (OCT) studies were undertaken. RESULTS: Five unrelated children, 4 females and 1 male, with median age of 6.2 years (4.6-11.7) at first assessment were investigated at the clinic from 2016 to 2021. Four homozygous and one heterozygous pathogenic CLN3 variants were found. Best corrected visual acuities (BCVAs) ranged from 0.18 to 0.88 logMAR at first presentation. Electronegative ERGs were identified in all patients. Bull's eye maculopathies found in all patients. Hyper-autofluorescence ring surrounding hypo-autofluorescence fovea on FAF was found. Foveal ellipsoid zone (EZ) disruptions were found in all patients with additional inner and outer retinal microcystic changes in one patient. Neurological problems noted included autism, anxiety, motor dyspraxia, behavioural issue, and psychomotor regression. CONCLUSIONS: CLN3 patients presented at median age 6.2 years with visual decline. Early onset maculopathy with an electronegative ERG and variable cognitive and motor decline should prompt further investigations including neuropaediatric evaluation and genetic assessment for CLN3 disease. The structural parameters such as EZ and FAF will facilitate ocular monitoring.
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Eletrorretinografia , Doenças Retinianas , Criança , Feminino , Humanos , Masculino , Retina , Imagem Multimodal , Eletrofisiologia , Tomografia de Coerência Óptica/métodos , Glicoproteínas de Membrana/genética , Chaperonas Moleculares/genéticaRESUMO
Multiple sclerosis (MS) is a complex disease of the CNS thought to require an environmental trigger. Gut dysbiosis is common in MS, but specific causative species are unknown. To address this knowledge gap, we used sensitive and quantitative PCR detection to show that people with MS were more likely to harbor and show a greater abundance of epsilon toxin-producing (ETX-producing) strains of C. perfringens within their gut microbiomes compared with individuals who are healthy controls (HCs). Isolates derived from patients with MS produced functional ETX and had a genetic architecture typical of highly conjugative plasmids. In the active immunization model of experimental autoimmune encephalomyelitis (EAE), where pertussis toxin (PTX) is used to overcome CNS immune privilege, ETX can substitute for PTX. In contrast to PTX-induced EAE, where inflammatory demyelination is largely restricted to the spinal cord, ETX-induced EAE caused demyelination in the corpus callosum, thalamus, cerebellum, brainstem, and spinal cord, more akin to the neuroanatomical lesion distribution seen in MS. CNS endothelial cell transcriptional profiles revealed ETX-induced genes that are known to play a role in overcoming CNS immune privilege. Together, these findings suggest that ETX-producing C. perfringens strains are biologically plausible pathogens in MS that trigger inflammatory demyelination in the context of circulating myelin autoreactive lymphocytes.