Uveitis masquerade syndromes: An approach to diagnosis.

Uveitis masquerade syndromes are a diverse group of clinical entities which mimic conventional immune-mediated uveitis due to the presence of inflammatory signs but are resistant to anti-inflammatory therapy. Misdiagnosis hinders appropriate management in these conditions and may result in poor outcomes. This review discusses commonly encountered neoplastic and non-neoplastic disease processes that masquerade as intraocular inflammation with a focus on relevant clinical features and adjunctive investigations that are helpful in reaching a correct diagnosis.

Long term outcome and prognostic indicators in Posner Schlossman syndrome.

BACKGROUND: Posner Schlossman syndrome is a well-defined uveitis entity that is characterised by relapsing remitting unilateral anterior uveitis with markedly raised intraocular pressure. The aim of this study was to determine the risk factors for progression in patients with Posner Schlossman syndrome. METHODS: Ninety-eight patients were enrolled in a retrospective case series. Progression was defined as a composite endpoint of any of development of permanent glaucoma (in patients with no evidence of glaucomatous loss on presentation), corneal failure, or chronic inflammation. Relapse was defined as a resolving episode of inflammation not meeting the criteria for progression. RESULTS: Seventy seven percent of patients relapsed on average each 2.2 years. Forty percent of patients progressed. On univariate analysis, increased age at enrolment, immunocompromise at enrolment, the presence of glaucomatous optic neuropathy at enrolment, the performance of an anterior chamber tap and a positive anterior chamber tap were all associated with increased risk of progression. On multivariate analysis, age at enrolment, immunocompromise at enrolment, the performance of an anterior chamber tap, and the presence of glaucomatous optic neuropathy at enrolment were independently associated with increased risk of disease progression. CONCLUSIONS: Posner Schlossman syndrome is not a benign uveitis entity and risk of both relapse and progression are high. Older patients, immunocompromised patients, patients with glaucomatous optic neuropathy at enrolment and those with a positive anterior chamber tap are all at increased risk of progression.

Coordinated circadian timing through the integration of local inputs in Arabidopsis thaliana.

Individual plant cells have a genetic circuit, the circadian clock, that times key processes to the day-night cycle. These clocks are aligned to the day-night cycle by multiple environmental signals that vary across the plant. How does the plant integrate clock rhythms, both within and between organs, to ensure coordinated timing? To address this question, we examined the clock at the sub-tissue level across Arabidopsis thaliana seedlings under multiple environmental conditions and genetic backgrounds. Our results show that the clock runs at different speeds (periods) in each organ, which causes the clock to peak at different times across the plant in both constant environmental conditions and light-dark (LD) cycles. Closer examination reveals that spatial waves of clock gene expression propagate both within and between organs. Using a combination of modeling and experiment, we reveal that these spatial waves are the result of the period differences between organs and local coupling, rather than long-distance signaling. With further experiments we show that the endogenous period differences, and thus the spatial waves, can be generated by the organ specificity of inputs into the clock. We demonstrate this by modulating periods using light and metabolic signals, as well as with genetic perturbations. Our results reveal that plant clocks can be set locally by organ-specific inputs but coordinated globally via spatial waves of clock gene expression.

Medical and surgical treatment of thyroid eye disease.

Thyroid eye disease is an autoimmune inflammatory disease strongly associated with thyroid disease, principally Graves disease. It can range from mild disease requiring observation or symptomatic treatments only, through to sight-threatening disease requiring major drug therapy and orbital surgery. Severity is graded by the NOSPECS system and activity by the clinical activity score (CAS) to assist in treatment selection. Non-surgical management can extend from observation alone to minor therapy such as oral selenium, then glucocorticoid therapy, cyclosporin, mycophenolate, rituximab, immunoglobulin, teprotumumab, and orbital radiotherapy. High-dose intravenous methylprednisolone therapy is used in active vision-threatening disease with early use of tarsorrhaphy and orbital decompression. Inactive but moderate to severe disease may be treated by orbital decompression, strabismus and eyelid surgery. Systematic assessment and management by both an endocrinologist and ophthalmologist to achieve and maintain euthyroidism and select and sequence treatments according to activity and severity of thyroid eye disease gives the best results for quality of life and vision.

Patient-specific Implants for Orbital Fractures: A Systematic Review.

PURPOSE: Orbital fractures are common facial fractures that can be challenging to repair and require careful attention to avoid unacceptable ophthalmic complications. Customized implants that are unique to an individual patient, or patient-specific implants (PSIs), have been increasingly used to repair orbital wall fractures. This systematic review summarizes the current evidence regarding custom-made orbital wall implants. METHODS: A keyword search of published literature from January 2010 to September 2021 was performed using Ovid MEDLINE, PubMed, and the Cochrane Library databases. Original articles that included more than 3 human subjects with an orbital fracture repaired with a PSI were included. The search results were reviewed, duplicates were removed and relevant articles were included for analysis. RESULTS: Fifteen articles meeting the inclusion criteria. The articles were categorized into 3 separate groups based on the method of PSI fabrication: manual molding of a PSI on a 3D-printed orbital model (53%), directly from a 3D printer (27%), or via a template fabricated from a 3D printer (20%). Three primary postoperative outcomes were assessed: rates of diplopia, enophthalmos, and orbital volume. Postoperative rates of diplopia and enophthalmos improved regardless of the PSI technique, and postoperative orbital volumes were reduced compared with their preoperative state. When PSIs were compared to conventional implants, patient outcomes were comparable. CONCLUSIONS: This review of existing PSI orbital implant literature highlights that while PSI can accurately and safely repair orbital fractures, patient outcomes are largely comparable to orbital fractures repaired by conventional methods, and PSI do not offer a definitive benefit over conventional implants.

Recommendations for the management of childhood juvenile idiopathic arthritis-type chronic anterior uveitis.

IMPORTANCE: Australian- and New Zealand-based, uveitis-specialized ophthalmologists have produced recommendations for the management of juvenile idiopathic arthritis (JIA)-type chronic anterior uveitis. BACKGROUND: Historically, the visual prognosis of JIA-type chronic anterior uveitis has been poor. New medical advances are likely to improve outcomes, but recently published guidelines are tailored for ophthalmic care in Europe and the United States. DESIGN: This work involved a consensus survey and a panel meeting. PARTICIPANTS: The Australian and New Zealand JIA-Uveitis Working Group (29 ophthalmologists) participated in the work. METHODS: The Delphi technique was used to achieve consensus. MAIN OUTCOME MEASURES: This work yielded consensus statements. RESULTS: The Working Group achieved consensus around 18 statements related to clinical evaluation, use of topical and regional corticosteroids, use of systemic corticosteroid and non-corticosteroid immunomodulatory drugs, and management of secondary cataract and glaucoma in childhood JIA-type uveitis. CONCLUSIONS AND RELEVANCE: Recommendations of the Australian and New Zealand JIA-Uveitis Working Group provide current and regionally applicable advice for managing chronic anterior uveitis in children with JIA.

Patterns of Vitamin D Levels and Exposures in Active and Inactive Noninfectious Uveitis Patients.

PURPOSE: To compare serum vitamin D levels and patterns of ultraviolet light and dietary exposure among patients with active and inactive noninfectious uveitis and population controls. DESIGN: Prospective case-control study. All participants (n = 151) underwent serum 25-hydroxy vitamin D measurement and completed a questionnaire on vitamin D intake and ultraviolet light exposure. Serum 25-hydroxy vitamin D levels were compared between active and inactive uveitis groups and with local population estimates. PARTICIPANTS: Adult patients with active and inactive noninfectious uveitis were recruited from 2 Victorian tertiary hospitals and 1 private ophthalmic practice. METHODS: Serum 25-hydroxy vitamin D levels were compared between patients with active and inactive uveitis and population-based estimates of serum 25-hydroxy vitamin D levels, stratified by geographic region and season. Vitamin D intakes and exposures based on questionnaire results, including vitamin D supplementation and sunlight exposures on weekdays and weekends, were compared between active and inactive uveitis groups. MAIN OUTCOME MEASURES: Serum vitamin D levels, intake of vitamin D, and exposure to sources of vitamin D. RESULTS: The median level of serum vitamin D in those with active uveitis (n = 74) was 46 nmol/l (interquartile range [IQR], 29-70 nmol/l), significantly lower than in the inactive control group (n = 77) at 64 nmol/l (IQR, 52-79 nmol/l; P < 0.001). The active uveitis group also showed lower median serum vitamin D levels than the local population median of 62 nmol/l (IQR, 46-77 nmol/l). Vitamin D supplementation also was associated significantly with uveitis inactivity (P = 0.026, Kendall's τ test). In a subanalysis of vitamin D-deficient participants, sun exposure was associated significantly with uveitis inactivity (P = 0.014 for weekday and weekend analyses). CONCLUSIONS: Participants with active uveitis showed significantly lower serum 25-hydroxy vitamin D levels than inactive uveitis patients and local population-based estimates. Vitamin D supplementation was found to be associated with decreased uveitis activity, as was sun exposure in those with vitamin D deficiency. These results suggest that vitamin D supplementation should be studied as an option for the prevention of uveitis relapse in at-risk patients.

Epidemiology of episcleritis and scleritis in urban Australia.

IMPORTANCE: The epidemiology of episcleritis and scleritis in Australia is largely unknown. BACKGROUND: To determine the incidence, prevalence and clinical characteristics of episcleritis and scleritis in Melbourne. DESIGN: Retrospective longitudinal study. PARTICIPANTS: Patients aged ≥18 years with episcleritis or scleritis seen at the Royal Victorian Eye and Ear Hospital from November 2014 to October 2015. METHODS: Medical record review confirmed clinical diagnosis and characteristics. Incidence and prevalence were calculated using estimates of the adult population in areas of Melbourne with ≥30 ocular presentations/year to the emergency department. MAIN OUTCOME MEASURES: Diagnosis of active episcleritis or scleritis, aetiology, ocular complications and treatments. RESULTS: From a general population of 3 408 068, we confirmed 149 new and 23 pre-existing cases of active episcleritis, and 35 new and 23 pre-existing cases of active scleritis. Incidence per 100 000 person-years was 4.4 (95% confidence interval [CI] 3.7-5.1) for episcleritis and 1.0 (95% CI 0.7-1.4) for scleritis, while 12-month prevalence was 5.1 (95% CI 4.3-5.9) and 1.7 (1.3-2.2) per 100 000 persons, respectively. Systemic disease was associated with 10% of episcleritis compared with 34% of scleritis (P < .001). Ocular complications were seen in 3% (6/184) of episcleritis eyes and 44% (32/72) of scleritis eyes, with the commonest being anterior uveitis (12/72) and ocular hypertension (14/72). At presentation, scleritis patients were commonly treated with oral non-steroidal anti-inflammatory drugs (60%) and prednisolone (19%). By 12 months, 24% of scleritis patients required immunosuppressants. CONCLUSIONS AND RELEVANCE: Rates of episcleritis and scleritis in our single-centre Australian study were low. Episcleritis was usually benign, whereas scleritis had increased ocular complications and systemic disease.

Uveitis in Patients with Multiple Sclerosis in Clinical Trials of Fingolimod: Incidence, Prevalence, and Impact on Disease Course.

PURPOSE: To determine the incidence and prevalence of uveitis and its effect on multiple sclerosis (MS) disease activity and outcomes in patients with MS who participated in the fingolimod clinical trial program. DESIGN: Analysis of pooled data (N = 27 528) from patients enrolled in fingolimod clinical studies and their extensions. Patients were stratified into 4 cohorts based on the history of uveitis at baseline and uveitis events during the observation period: no history and no uveitis events ("no uveitis"); history and no uveitis events ("history"); no history and uveitis events ("first event"); history and uveitis events ("recurrent event"). PARTICIPANTS: Adult patients diagnosed with relapsing or primary progressive MS. INTERVENTION: Patients received fingolimod (0.5, 1.25, or 5 mg/day), placebo, or intramuscular interferon beta-1a (IFNß-1a IM) during the core studies; patients receiving placebo or IFNß-1a IM were switched to fingolimod 0.5 mg therapy for study extensions. MAIN OUTCOME MEASURES: Incidence and prevalence of uveitis, and MS outcome measures, including annualized relapse rate (ARR), time to first relapse, change in Expanded Disability Status Scale (EDSS) score from baseline, and proportion of patients with 6-month confirmed disability progression. RESULTS: A total of 189 patients in the analysis population had uveitis. Of these, 162 patients had a history of uveitis (prevalence, 0.59%). Uveitis occurred as a first event in 27 patients (incidence, 0.1 per 100 patient-years) and as a recurrent event in 10 of 162 patients (prevalence, 6.17%). Patients with uveitis had a significantly shorter time to first relapse (mean, 2.11 vs. 8.12 years; P = 0.047) and a significantly higher ARR (0.31 vs. 0.21; P = 0.025) than those without uveitis. Mean increase in EDSS score at month 120 and the proportions of patients with 6-month confirmed disability progression, and with EDSS score ≥4 during follow-up, were similar in patients with uveitis compared with those without uveitis. CONCLUSIONS: This pooled analysis involving a large patient cohort showed that patients with MS and uveitis had increased MS relapse activity compared with those without uveitis.

Differences in practice of ophthalmology by gender in Australia.

IMPORTANCE: The number of females practising ophthalmology is rising. It is known that practice patterns between female and male ophthalmologists differ. Understanding the differences will help to inform future workforce planning. BACKGROUND: To investigate the differences in clinical practice between female and male ophthalmologists in Australia. DESIGN: Cross-sectional study. PARTICIPANTS: Ophthalmologists participating in the Royal Australian & New Zealand College of Ophthalmologists workforce survey, and/or Medicine in Australia: Balancing Employment and Life survey, and those who made claims from Medicare Benefits Schedule Australia. METHODS: Combined analysis of de-identified 2014 data from the surveys and Medicare Benefits Schedule. MAIN OUTCOME MEASURES: Hours worked, service provision, remuneration and social circumstances. RESULTS: Female ophthalmologists provided 35% fewer services per ophthalmologist per year (2834 vs 4328) than male ophthalmologists. Female ophthalmologists received approximately half the annual income of male ophthalmologists; median self-reported net personal annual income was AUD122 500 (interquartile range [IQR] 96 000-225 000) for females compared to AUD245 000 (IQR 180 000-365 000) for males (P = .01). The median self-reported hours worked per week was 35.0 (IQR 28.0-46.0) for females and 41.8 (IQR 36.5-48.5) for males (P = 0.04). A higher proportion of females practise in medical subspecialties, while a higher proportion of males practise in surgical subspecialties. CONCLUSIONS AND RELEVANCE: Female ophthalmologists earn less compared to male ophthalmologists after accounting for lower service provision and hours worked. Difference in income may be partially accounted for by higher total number of services and procedural services provided by male ophthalmologists. Understanding differences between female and male ophthalmologists will help to inform future medical workforce planning.

GeneMill: A 21st century platform for innovation.

GeneMill officially launched on 4th February 2016 and is an open access academic facility located at The University of Liverpool that has been established for the high-throughput construction and testing of synthetic DNA constructs. GeneMill provides end-to-end design, construction and phenotypic characterization of small to large gene constructs or genetic circuits/pathways for academic and industrial applications. Thus, GeneMill is equipping the scientific community with easy access to the validated tools required to explore the possibilities of Synthetic Biology.

HIGH EXPRESSION OF OSMOTICALLY RESPONSIVE GENES1 is required for circadian periodicity through the promotion of nucleo-cytoplasmic mRNA export in Arabidopsis.

Cold acclimation has been shown to be attenuated by the degradation of the INDUCER OF CBF EXPRESSION1 protein by the E3 ubiquitin ligase HIGH EXPRESSION OF OSMOTICALLY RESPONSIVE GENES1 (HOS1). However, recent work has suggested that HOS1 may have a wider range of roles in plants than previously appreciated. Here, we show that hos1 mutants are affected in circadian clock function, exhibiting a long-period phenotype in a wide range of temperature and light environments. We demonstrate that hos1 mutants accumulate polyadenylated mRNA in the nucleus and that the circadian defect in hos1 is shared by multiple mutants with aberrant mRNA export, but not in a mutant attenuated in nucleo-cytoplasmic transport of microRNAs. As revealed by RNA sequencing, hos1 exhibits gross changes to the transcriptome with genes in multiple functional categories being affected. In addition, we show that hos1 and other previously described mutants with altered mRNA export affect cold signaling in a similar manner. Our data support a model in which altered mRNA export is important for the manifestation of hos1 circadian clock defects and suggest that HOS1 may indirectly affect cold signaling through disruption of the circadian clock.

Network balance via CRY signalling controls the Arabidopsis circadian clock over ambient temperatures.

Circadian clocks exhibit 'temperature compensation', meaning that they show only small changes in period over a broad temperature range. Several clock genes have been implicated in the temperature-dependent control of period in Arabidopsis. We show that blue light is essential for this, suggesting that the effects of light and temperature interact or converge upon common targets in the circadian clock. Our data demonstrate that two cryptochrome photoreceptors differentially control circadian period and sustain rhythmicity across the physiological temperature range. In order to test the hypothesis that the targets of light regulation are sufficient to mediate temperature compensation, we constructed a temperature-compensated clock model by adding passive temperature effects into only the light-sensitive processes in the model. Remarkably, this model was not only capable of full temperature compensation and consistent with mRNA profiles across a temperature range, but also predicted the temperature-dependent change in the level of LATE ELONGATED HYPOCOTYL, a key clock protein. Our analysis provides a systems-level understanding of period control in the plant circadian oscillator.

Retrospective analysis of the natural history and management of serpiginous choroiditis in Australia and New Zealand.

BACKGROUND: To examine the prevalence of serpiginous choroidopathy in a predominantly Caucasian community, to examine associations between serpiginous choroiditis and other systemic diseases, and to report on the effect of immunosuppression on the long-term course of serpiginous choroiditis. DESIGN: Retrospective cohort study with patients from tertiary care centres and private practices. PARTICIPANTS: 18 patients, mean age 48 years at baseline. One patient was seen only once. Median follow-up was 69 months (5.8 years, range 0.4-29.7 years). METHODS: Patients were identified using the Australian and New Zealand Ophthalmic Surveillance Unit. A chart analysis was performed for all patients. Three treatment groups were identified: no treatment, prednisolone monotherapy, or combination of prednisolone and immunosuppression. Negative binomial regression was used to calculate incidence rate ratios for patient relapse. MAIN OUTCOME MEASURES: Patient demographics, clinical features, associated systemic diseases, treatments administered and dates of relapse. RESULTS: The disease prevalence in Australia and New Zealand is 1 case per 1.5 million people. Five cases (28%) had a positive QuantiFERON. A total of 32 relapses were observed: 14 while receiving no treatment, 11 on prednisolone and 7 on combination therapy. Compared with the no treatment group, the incidence rate ratio for prednisolone monotherapy and combination therapy was 1.29 and 2.92, respectively (95% confidence interval 0.40-4.14 and 0.96-8.88). CONCLUSION: Although the confidence intervals indicate that the difference in incidence rate ratios are not significant, these results suggest that there is a group of patients who have a benign course without long-term immunosuppression or corticosteroid treatment.

Intravitreal Injection Rates for Neovascular Age-Related Macular Degeneration in Australia During the 2020 COVID-19 Lockdowns.

PURPOSE: We investigate the impact of COVID-19 and lockdowns on anti-vascular endothelial growth factor (anti-VEGF) treatment for neovascular age-related macular degeneration (AMD) in Victoria (Australian state with highest burden of COVID-19 in 2020) and Australia, by examining anti-VEGF prescriptions supplied for AMD treatment between 2018 and 2020. METHODS: We performed a retrospective, population-based analysis of aflibercept and ranibizumab prescriptions supplied for the treatment of AMD in Victoria and Australia between 1 January 2018 and 31 December 2020, as recorded by the Pharmaceutical Benefits Scheme (PBS) and Repatriation PBS, the Australian Government program subsidising medication costs for Australian residents and veterans. Poisson models and univariate regression were used to descriptively examine trends in monthly anti-VEGF prescription rates with time and changes in monthly prescription rates (prescription rate ratios [RR]). RESULTS: In 2020, anti-VEGF AMD prescription rates in Victoria decreased by 18% during the nationwide lockdown between March and May (RR 0.82, 95% CI: 0.80-0.85, p < .001), and by 24% during the Victorian-specific lockdown between July and October (RR 0.76, 95% CI: 0.73-0.78, p < .001). In Australia, prescription rates tended to decrease between January and October 2020, reducing by 25% (RR 0.75, 95% CI: 0.74-0.77, p < .001) between these months, including between March and April (RR 0.94, 95% CI: 0.92-0.95, p < .001) but not April and May (RR 1.10, 95% CI: 1.09-1.12, p < .001). CONCLUSION: In 2020, anti-VEGF prescriptions for AMD treatment decreased modestly in Victoria during both lockdowns and in Australia during the year. Decreases may represent reduced treatment because of COVID-19, including public health orders, patients' self-limiting care, and ophthalmologists treating-and-extending to maximum intervals.

Reduction in Herpes Zoster Antiviral Use Since the Introduction of the Live-Attenuated Zoster Vaccine on Australia's National Immunisation Program: A Population-Based Study from 1994 to 2019.

INTRODUCTION: Zostavax, the live-attenuated vaccine used to prevent herpes zoster (HZ), has been available to individuals aged 70 and 71-79 years (phased catch-up) via Australia's National Immunisation Program (NIP) since 2016. There are limited data characterising the incidence of HZ at the level of the Australian population. National prescription data for antivirals used to treat HZ may be used as a proxy for HZ incidence. We aimed to examine trends in antiviral prescriptions supplied for the treatment of HZ in Australia pre- and post-2016, and to assess whether Zostavax's inclusion on the NIP correlated with a reduction in HZ antiviral prescription rates. METHODS: Using the Australian Pharmaceutical Benefits Scheme and Repatriation Pharmaceutical Benefits Scheme prescribing data, we analysed antiviral prescriptions supplied for the treatment of HZ Australia-wide between 1994 and 2019. Annual prescription rates were calculated, and trends and changes in HZ antiviral use were explored descriptively and using Poisson models. RESULTS: HZ antiviral prescription rates increased 2.6-fold (160%) between 1995 and 2015 [25.4 (95% CI 25.2, 25.6) and 65.3 (95% CI 64.9, 65.6) prescriptions per 10,000 people, respectively], and then decreased 0.45-fold (55%) between 2016 and 2018 [60.9 (95% CI 60.6, 61.2) and 27.5 (95% CI 27.3, 27.9) prescriptions per 10,000 people, respectively]. The prescription rate for the antiviral famciclovir restricted specifically for treating HZ in immunocompromised individuals increased 8.5-fold (750%) between 2006 (year first listed) and 2019 [0.3 (95% CI 0.3, 0.3) and 2.5 (95% CI 2.4, 2.6) prescriptions per 10,000 people, respectively]. CONCLUSION: The introduction of the live-attenuated HZ vaccine on Australia's formal national vaccination program was associated with a reduction in HZ antiviral prescription rates within the Australian population. The data suggest that the introduction of Shingrix, the non-live subunit zoster vaccine, may also be associated with a similar reduction in HZ antiviral prescriptions used to treat the immunocompromised, as well as the general population, given its accepted greater efficacy over Zostavax.

Light inputs shape the Arabidopsis circadian system.

The circadian clock is a fundamental feature of eukaryotic gene regulation that is emerging as an exemplar genetic sub-network for systems biology. The circadian system in Arabidopsis plants is complex, in part due to its phototransduction pathways, which are themselves under circadian control. We therefore analysed two simpler experimental systems. Etiolated seedlings entrained by temperature cycles showed circadian rhythms in the expression of genes that are important for the clock mechanism, but only a restricted set of downstream target genes were rhythmic in microarray assays. Clock control of phototransduction pathways remained robust across a range of light inputs, despite the arrhythmic transcription of light-signalling genes. Circadian interactions with light signalling were then analysed using a single active photoreceptor. Phytochrome A (phyA) is expected to be the only active photoreceptor that can mediate far-red (FR) light input to the circadian clock. Surprisingly, rhythmic gene expression was profoundly altered under constant FR light, in a phyA-dependent manner, resulting in high expression of evening genes and low expression of morning genes. Dark intervals were required to allow high-amplitude rhythms across the transcriptome. Clock genes involved in this response were identified by mutant analysis, showing that the EARLY FLOWERING 4 gene is a likely target and mediator of the FR effects. Both experimental systems illustrate how profoundly the light input pathways affect the plant circadian clock, and provide strong experimental manipulations to understand critical steps in the plant clock mechanism.