The Sleep Quality- and Myopia-Linked PDE11A-Y727C Variant Impacts Neural Physiology by Reducing Catalytic Activity and Altering Subcellular Compartmentalization of the Enzyme.

Recently, a Y727C variant in the dual-specific 3',5'-cyclic nucleotide phosphodiesterase 11A (PDE11A-Y727C) was linked to increased sleep quality and reduced myopia risk in humans. Given the well-established role that the PDE11 substrates cAMP and cGMP play in eye physiology and sleep, we determined if (1) PDE11A protein is expressed in the retina or other eye segments in mice, (2) PDE11A-Y7272C affects catalytic activity and/or subcellular compartmentalization more so than the nearby suicide-associated PDE11A-M878V variant, and (3) Pde11a deletion alters eye growth or sleep quality in male and female mice. Western blots show distinct protein expression of PDE11A4, but not PDE11A1-3, in eyes of Pde11a WT, but not KO mice, that vary by eye segment and age. In HT22 and COS-1 cells, PDE11A4-Y727C reduces PDE11A4 catalytic activity far more than PDE11A4-M878V, with both variants reducing PDE11A4-cAMP more so than PDE11A4-cGMP activity. Despite this, Pde11a deletion does not alter age-related changes in retinal or lens thickness or axial length, nor vitreous or anterior chamber depth. Further, Pde11a deletion only minimally changes refractive error and sleep quality. That said, both variants also dramatically alter the subcellular compartmentalization of human and mouse PDE11A4, an effect occurring independently of dephosphorylating PDE11A4-S117/S124 or phosphorylating PDE11A4-S162. Rather, re-compartmentalization of PDE11A4-Y727C is due to the loss of the tyrosine changing how PDE11A4 is packaged/repackaged via the trans-Golgi network. Therefore, the protective impact of the Y727C variant may reflect a gain-of-function (e.g., PDE11A4 displacing another PDE) that warrants further investigation in the context of reversing/preventing sleep disturbances or myopia.

The sleep quality- and myopia-linked PDE11A-Y727C variant impacts neural physiology by reducing catalytic activity and altering subcellular compartmentalization of the enzyme.

Recently, a Y727C variant in the dual-specific 3',5'-cyclic nucleotide phosphodiesterase 11A (PDE11A-Y727C) was linked to increased sleep quality and reduced myopia risk in humans. Given the well-established role that the PDE11 substrates cAMP and cGMP play in eye physiology and sleep, we determined if 1) PDE11A protein is expressed in the retina or other eye segments in mouse, 2) PDE11A-Y7272C affects catalytic activity and/or subcellular compartmentalization more so than the nearby suicide-associated PDE11A-M878V variant, and 3) Pde11a deletion alters eye growth or sleep quality in male and female mice. Western blots show distinct protein expression of PDE11A4, but not PDE11A1-3, in eyes of Pde11a WT-but not KO mice-that vary by eye segment and age. In HT22 and COS-1 cells, PDE11A4-Y727C reduces PDE11A4 catalytic activity far more than PDE11A4-M878V, with both variants reducing PDE11A4-cAMP more so than PDE11A4-cGMP activity. Despite this, Pde11a deletion does not alter age-related changes in retinal or lens thickness, axial length, nor vitreous or anterior chamber depth. Further, Pde11a deletion only minimally changes refractive error and sleep quality. That said, both variants also dramatically alter the subcellular compartmentalization of human and mouse PDE11A4, an effect occurring independently of dephosphorylating PDE11A4-S117/S124 or phosphorylating PDE11A4-S162. Rather, re-compartmentalization of PDE11A4-Y727C is due to the loss of the tyrosine changing how PDE11A4 is packaged/repackaged via the trans-Golgi network. Therefore, the protective impact of the Y727C variant may reflect a gain-of-function (e.g., PDE11A4 displacing another PDE) that warrants further investigation in the context of reversing/preventing sleep disturbances or myopia.

Diabetic Retinopathy Screening at the Point of Care (DR SPOC): detecting undiagnosed and vision-threatening retinopathy by integrating portable technologies within existing services.

INTRODUCTION: The aim of this study was to determine the prevalence of diabetic retinopathy (DR) in a low socioeconomic region of a high-income country, as well as determine the diagnostic utility of point-of-care screening for high-risk populations in tertiary care settings. RESEARCH DESIGN AND METHODS: This was a cross-sectional study of patients with diabetes attending foot ulcer or integrated care diabetes clinics at two Western Sydney hospitals (n=273). DR was assessed using portable, two-field, non-mydriatic fundus photography and combined electroretinogram/ pupillometry (ERG). With mydriatic photographs used as the reference standard, sensitivity and specificity of the devices were determined. Prevalence of DR and vision-threatening diabetic retinopathy (VTDR) were reported, with multivariate logistic regression used to identify predictors of DR. RESULTS: Among 273 patients, 39.6% had any DR, while 15.8% had VTDR, of whom 59.3% and 62.8% were previously undiagnosed, respectively. Non-mydriatic photography demonstrated 20.2% sensitivity and 99.5% specificity for any DR, with a 56.7% screening failure rate. Meanwhile, mydriatic photography produced high-quality images with a 7.6% failure rate. ERG demonstrated 72.5% sensitivity and 70.1% specificity, with a 15.0% failure rate. The RETeval ERG was noted to have an optimal DR cut-off score at 22. Multivariate logistic regression identified an eGFR of ≤29 mL/min/1.73 m2, HbA1c of ≥7.0%, pupil size of <4 mm diameter, diabetes duration of 5-24 years and RETeval score of ≥22 as strong predictors of DR. CONCLUSION: There is a high prevalence of vision-threatening and undiagnosed DR among patients attending high-risk tertiary clinics in Western Sydney. Point-of-care DR screening using portable, mydriatic photography demonstrates potential as a model of care which is easily accessible, targeted for high-risk populations and substantially enhances DR detection.

Panophthalmitis and Orbital Inflammation with Cavernous Sinus Thrombosis Following Cataract Surgery.

BACKGROUND: Panophthalmitis is a severe inflammation of the globe that can result as a rare complication of ophthalmic surgery. In severe cases, it may also be associated with orbital inflammation and cavernous sinus thrombosis. PURPOSE: This case demonstrates a rare and life-threatening post-operative complication of cataract surgery. We also hope to highlight the importance of considering the relevant risk factors associated with developing potential infections after cataract surgery, including the use of corneal sutures, high-risk behaviours such as excessive eye-rubbing, and non-compliance with appointments and post-operative medications. CASE REPORT: We report the case of a 35-year-old female with severe autism and developmental delay who developed panophthalmitis, orbital inflammation and cavernous sinus thrombosis 6 weeks post cataract surgery. The likely cause was corneal suture-related microbial keratitis, and the patient required enucleation due to sepsis. CONCLUSION: Post-surgical panophalmitis is a rapidly progressive disease that is not only sight- but life-threatening and demands urgent and intensive treatment. Consideration of early enucleation may be required to prevent deterioration in such patients.

Visual outcomes and late complications in paediatric orbital rhabdomyosarcoma.

BACKGROUND: Orbital rhabdomyosarcoma is a rare but important malignancy for an ophthalmologist. We aimed to review the management and outcome, including late orbital complications and visual acuity over 25 years from a specialist paediatric ophthalmology department. DESIGN: This was a retrospective longitudinal case series. PARTICIPANTS: All patients presenting to our institution between December 1989 and December 2014 with a histopathological diagnosis of rhabdomyosarcoma originating from (primary) or invading into the orbit (paranasal) were included. METHODS: The oncology and ophthalmology databases were cross referenced to identify patients. MAIN OUTCOME MEASURES: Baseline demographics, chemotherapy, surgical and radiation dose, visual acuity, ocular and systemic complications, local and distant recurrence and mortality were recorded for each patient. Outcomes were reported with descriptive statistics. RESULTS: Eighteen patients were included. Median age was 4.3 years (range 4 months to 16 years) with average follow-up of 9 years. The 5-year disease-specific survival was 100% for the orbital group and 25% for the paranasal group; 29% of the orbital group maintained vision better than 6/12 in their treated eye, and the overall globe conservation rate was 71%. The most common ocular complications were cataract and keratopathy in both the orbital and paranasal groups. Other ocular complications included orbital hypoplasia or fat atrophy, eyelid malposition and lacrimal duct stenosis. CONCLUSIONS: Ophthalmic late effects are seen in a significant proportion of patients with orbital rhabdomyosarcoma. There is excellent survival in these patients, and continued efforts should be made to reduce the late effects of therapy.

Changing patterns in paediatric optic atrophy aetiology: 1979 to 2015.

BACKGROUND: To evaluate the aetiology of paediatric optic atrophy in an Australian population. DESIGN: Retrospective review of medical records was conducted at The Children's Hospital at Westmead, Sydney, Australia. PARTICIPANTS: Two hundred twenty-seven subjects <16 years who were diagnosed with optic atrophy on fundoscopic examination between 1979 and 2015 were included in the study. METHODS: Subjects were obtained from the hospital database, which codes diagnoses for all admissions, as well as the orthoptic department database, which codes diagnoses for ophthalmology department outpatients. MAIN OUTCOME MEASURES: The predominant cause for optic atrophy was assigned to each patient. Clinical presentation was defined as the principal reason for evaluation. Demographic data included gender, affected eye and age at diagnosis. Data on medical comorbidities (cerebral palsy, developmental delay, microcephaly and seizures) and ocular comorbidities (strabismus and nystagmus) were collected. RESULTS: The mean age at initial eye review was 4.7 ± 4.4 years. There was bilateral optic atrophy in 81.5% of cases. Unilateral optic atrophy was largely due to tumours. When analysing over the three time periods, (1979-1990, 1991-2003 and 2004-2015), perinatal events (3.0%, 22.7% and 22.6%) and neurodegenerative disease (3.0%, 14.9% and 15.1%) are slowly replacing tumours (39.4%, 24.8% and 15.1%) as the top causes for paediatric optic atrophy. The incidence of other causes has remained fairly stable over time, albeit an increase in idiopathic causes. CONCLUSIONS: There has been shift in the etiological profile of optic atrophy. Whilst tumours are still an important cause of paediatric optic atrophy for an Australian population, perinatal events and neurodegenerative disease are becoming more significant.

Intravitreal triamcinolone acetonide as adjunctive treatment with systemic therapy for uveitic macular edema.

PURPOSE: To report the outcome of a single intravitreal triamcinolone acetonide (IVTA) injection as an adjunctive treatment with systemic medication for refractory uveitic cystoid macular edema (CME). METHODS: This was a retrospective, noncomparative, interventional case series. Medical records of 25 patients (35 eyes) with quiescent uveitic CME who were treated with oral immunosuppressive therapy and underwent 4 mg/0.1 mL IVTA injection were reviewed. Data was collected 6 months post-injection and included details of uveitis, best-corrected visual acuity (BCVA), CME, systemic therapy required, and potential complications of IVTA injection. RESULTS: Thirty eyes (85%) responded with improvement in vision. The mean BCVA improvement was 0.33 (from 0.67 to 0.34 logarithm of the minimum angle of resolution; Snellen equivalent, between 2 and 3 lines) (p<0.001), at a mean time of 6.2 weeks (range 2-16). Resolution of CME was achieved in 31 (88%) of the treated eyes. Following initial response to IVTA, CME relapsed in 8 eyes (26%) after a mean time of 4.2 months (range 2.5-5.5). The dosage of oral corticosteroids and/or second-line immunosuppressive agents was able to be reduced or stopped in 22 patients, 29 of 35 eyes (82.8%). The most common adverse effect was increased intraocular pressure, in 17 (49%) of the treated eyes. Steroid-induced cataract was observed in 6 eyes (17%). CONCLUSIONS: Intravitreal triamcinolone acetonide appears to be an effective supplementary tool in the management of CME refractory to systemic immunosuppressive therapy. Retreatment might be required in some and may be associated with elevated intraocular pressure and cataract.