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AimsTo characterise differential pathogeneses of diabetic macular oedema (DMO) using ultra-widefield fluorescein angiography (UWFA) and evaluate responses to anti-vascular endothelial growth factor (anti-VEGF) therapy.MethodsNinety-nine eyes (73 consecutive patients) with anti-VEGF naïve DMO underwent UWFA and optical coherence tomography, of which 60 with central retinal thickness (CRT) >400 μm received monthly intravitreal ranibizumab injections. Best-corrected visual acuity (BCVA) and CRT were measured at baseline and after three injections.ResultsAfter excluding tractional factors, DMO was categorised into three types based on UWFA: (A) microaneurysm driven (49%), (B) peripheral ischaemia (37%) and (C) neovascularisation (15%). While all three types showed similar mean CRT (p=0.257), types B and C were associated with more diffuse oedema, which extended beyond the 6.0 mm central macula (p=0.0034). Following anti-VEGF treatment, all three types showed improvement in CRT and BCVA, which reached statistical significance for types A and B. A positive correlation was found between the Peripheral Ischaemia Index and improvement in CRT (slope=2.09, R2=0.1169, p=0.0151) but not BCVA (slope=−0.00037, R2=0.001149, p=0.8152).ConclusionsUWFA facilitates the detection of peripheral ischaemia, which is associated with a significant proportion of DMO. While this group of DMO responded well to anti-VEGF therapy, it remains to be determined whether addressing the peripheral ischaemia may reduce recurrence.

Introduction: Low gestational birth weight is associated with increased incidence of retinopathy of prematurity (ROP). In recent years, intravitreal injection of anti-vascular endothelial growth factor (VEGF) has become more prevalent for ROP. Despite the demonstrated effectiveness following anti-VEGF injection, recurrence of ROP has been reported. A standardized treatment protocol for recurrent ROP following anti-VEGF monotherapy is still lacking, particularly for extremely low birth weight infants. This study reviews possible treatments for recurrent ROP and associated challenges. Case Presentation: We report a very low birth weight infant (500 g) with a recurrence of ROP after the initial intravitreal bevacizumab (IVB) injection, who was successfully treated with a repeat injection at a later date. No retinal detachment or recurrence was observed after a long-term follow-up of 36 months. Conclusion: This case report highlights the complexity of managing ROP, particularly for recurrent ROP in very low birth weight infants. Premature infants with extremely low birth weight may benefit from a repeat injection of anti-VEGF after the initial IVB to treat the recurrence.

Background Osteosarcoma is the most common malignant bone tumor in children. Survival remains poor among histologically poor responders, and there is a need to identify them at diagnosis to avoid delivering ineffective therapy. Genetic variation contributes to a wide range of response and toxicity related to chemotherapy. The aim of this study is to use sequencing of blood cells to identify germline haplotypes strongly associated with drug resistance in osteosarcoma patients. Methods We used sequencing data from two patient datasets, from Inova Hospital and the NCI TARGET. We explored the effect of mutation hotspots, in the form of haplotypes, associated with relapse outcome. We then mapped the single nucleotide polymorphisms (SNPs) in these haplotypes to genes and pathways. We also performed a targeted analysis of mutations in Drug Metabolizing Enzymes and Transporter (DMET) genes associated with tumor necrosis and survival. Results We found intronic and intergenic hotspot regions from 26 genes common to both the TARGET and INOVA datasets significantly associated with relapse outcome. Among significant results were mutations in genes belonging to AKR enzyme family, cell-cell adhesion biological process and the PI3K pathways; as well as variants in SLC22 family associated with both tumor necrosis and overall survival. The SNPs from our results were confirmed using Sanger sequencing. Our results included known as well as novel SNPs and haplotypes in genes associated with drug resistance. Conclusion We show that combining next generation sequencing data from multiple datasets and defined clinical data can better identify relevant pathway associations and clinically actionable variants, as well as provide insights into drug response mechanisms.

Purpose To present the detailed retinal phenotype of patients with Leber Congenital Amaurosis/Early-Onset Severe Retinal Dystrophy (LCA/EOSRD) caused by sequence variants in four genes, either not (n = 1) or very rarely (n = 3) previously associated with the disease. Methods Retrospective case series of LCA/EOSRD from four pedigrees. Chart review of clinical notes, multimodal retinal imaging, electrophysiology, and molecular genetic testing at a single tertiary referral center (Moorfields Eye Hospital, London, UK). Results The mean age of presentation was 3 months of age, with disease onset in the first year of life in all cases. Molecular genetic testing revealed the following disease-causing variants: PRPF8 (heterozygous c.5804G > A), PRPH2 (homozygous c.620_627delinsTA, novel variant), RP1 (homozygous c.4147_4151delGGATT, novel variant) and RPGR (heterozygous c.1894_1897delGACA). PRPF8, PRPH2, and RP1 variants have very rarely been reported, either as unique cases or case reports, with limited clinical data presented. RPGR variants have not previously been associated with LCA/EOSRD. Clinical history and detailed retinal imaging are presented. Conclusions The reported cases extend the phenotypic spectrum of PRPF8- , PRPH2-, RP1- , and RPGR- associated disease, and the genotypic spectrum of LCA/EOSRD. The study highlights the importance of retinal and functional phenotyping, and the importance of specific genetic diagnosis to potential future therapy.

Purpose We aimed to evaluate the long-term natural history of polypoidal choroidal vasculopathy (PCV) in untreated patients. Methods This is a retrospective observational case series. Patients with symptomatic PCV who did not receive any treatment for at least 12 months were included from the records of three ophthalmic clinics in Asia. The medical records and imaging data were reviewed. Visual outcomes at month 12 and at last follow-up were analyzed. The influence of demographics and presenting features on visual outcome was analyzed. Results A total of 32 eyes (32 patients) were included in this analysis. The mean follow-up was 59.9 months (range, 18–119 months), the mean age was 65.7 years and 21 (65.6 %) patients were male. The mean presenting logMAR visual acuity was 0.79 (Standard deviation [SD] 0.49). The center of the fovea was involved by the PCV complex in 25 eyes (78.1 %). The mean greatest linear dimension (GLD) of the PCV complex was 2584 μm (SD 880). Twenty-three eyes (71.9 %) had a cluster-of-grapes configuration on indocyanine green angiography. Leakage of fluorescein angiography was present in 29 eyes (90.6 %). The mean logMAR vision deteriorated from 0.79 at baseline to 0.88 at month 12 ( p  = 0.11), and further to 1.14 ( p  = 0.003) at the last follow-up. The proportion of eyes that improved, remained unchanged and worsened was 21.9 %, 31.3 % and 46.9 %, respectively, at month 12; and 28.1 %, 9.4 % and 62.5 %, respectively, at last follow-up. The proportion of eyes with logMAR vision worse than 1.0 was 28.1 % at presentation, and increased to 31.3 % at month 12 and further to 53.1 % at last follow-up. Reasons for poor vision were due to retinal, subretinal or vitreous hemorrhage, and retinal pigment epithelium (RPE) atrophy and scarring. None of the presenting features were found to significantly influence visual outcome. Conclusions Half of eyes presenting with symptomatic PCV had a relatively benign course without treatment and some even had vision improvement. However, in the remaining eyes, vision deteriorated significantly, mainly due to hemorrhage and scarring. There may be subtypes of PCV with divergent natural history.

Background Vitreo-macular interface (VMI) disorders, including epiretinal membrane (ERM) diagnosed on optical coherence tomography (OCT), form a significant proportion of elective referrals to vitreoretinal (VR) surgeons. An in-person visit to a clinician involves travelling, waiting, investigations then an interaction with the surgeon, which entails many inefficiencies in a large institution. We report the pilot studies of a VR virtual service where these patients can be more efficiently reviewed, investigated, listed for surgery or discharged. Methods This was a prospective observational study comparing the outcomes of a virtual assessment to standard face-to-face clinics. All patients included were referred from optometry practices for ERM diagnosed on macula OCT. A first pilot study comprised 79 patients, who attended a diagnostics centre staffed with ophthalmic-trained technicians. A short history, visual acuity and ocular pressures were recorded. Widefield colour photographs and macular OCT images were acquired. Cases were asynchronously reviewed by trained ophthalmologists and senior nurses within the week, and following a telephone consultation with the patient, a virtual management plan was documented. All patients attended 1 week later for a face-to-face appointment, following which, virtual and face-to-face management plans were compared. A second pilot comprised 65 patients, through the same pathway, to examine consistency. A post-hoc analysis was carried out to identify the cohort of patients who would be suitable for a virtual management decision without a telephone consultation. Results ERMs comprised 35% of overall elective referrals in this study. In Pilot 1, 42% were virtually assessed for discharge, with high concordance with face-to-face outcomes (positive predictive value = 89%). There were 3 cases of missed retinal tears, and 1 OCT misdiagnosis. In the second pilot, 43% were discharged virtually, with higher concordant discharge rates (positive predictive value = 93%). There were no missed peripheral pathology and no misdiagnoses in this pilot. Conclusions Our virtual model demonstrates a safe and effective way of managing and discharging patients without a face-to-face clinic. This is especially suitable for low-risk conditions such as ERMs, which comprise a large proportion of referrals.

Background The surgical management of patients with uncontrolled glaucoma and scleroderma is challenging, as the hostile ocular surface poses a challenge to surgery. A serious complication is tube erosion, with the risk of subsequent endophthalmitis. Here, we present a novel technique of harvesting autologous tissue to successfully manage recurrent tube extrusion. Case presentation MG is a 60-year-old Arabic lady diagnosed with scleroderma, that was previously managed with systemic corticosteroids. She has chronic open angle glaucoma, with a failed left eye trabeculectomy, which was then managed by a Baerveldt tube (BVT) insertion. Eight months after this primary surgery, she developed an anterior uveitis. This was further complicated by conjunctival erosion, tube exposure, leak around the sclerostomy site and hypotony. The erosion was likely secondary to her tight eyelids as a result of her scleroderma. She was taken back to theatre for tube revision, with single layer amniotic membrane transplant (AMT) over the exposed area, but the tube was eroding again after 2 months. She eventually underwent tube extraction, pars plana tube plate stabilisation, pars plana vitrectomy (PPV), pars plana tube insertion, phacoemulsification and intra-ocular lens insertion, jointly with the vitreo-retinal surgeons and with high dose prednisolone cover both pre- and post-operatively. We harvested the capsule which had grown over the end plate of the original tube. We sutured this over the new tube, specifically over a single layer of tutoplast prior to conjunctival closure. Almost a year on, the pars plana tube remains in place with no complications. Conclusions This case highlights the role of a pars plana tube in cases of cicatricial disease, with the use autologous tissue instead of grafts wherever possible. In patients with systemic disease such as scleroderma, pre-operative immunosuppression helps to reduce the of erosion in difficult cases.

The Royal College of Ophthalmologists published key principles addressing the restoration of services.2 Central Middlesex Hospital (CMH) serves Brent, a predominantly Black, Asian and Minority Ethnic population with high morbidity and mortality risk from COVID-19.3 Many preprint articles suggested increased risk of hospitalisation, admission to the intensive care unit and death for people of Black and Asian ethnicity.4 Brent had 210.9 COVID-19 deaths per 100 000; the highest age-standardised rate in England and Wales during the first pandemic wave.5 In addition, the cataract complexity rate for patients operated at CMH is the highest in the country.6 Restarting elective surgery presented a major challenge for NHS London Trusts hit first by the pandemic with greatest impact. [...]the modified Medically Necessary Time-Sensitive (modified-MeNTS) score (table 1) to determine the risk of morbidity and mortality from COVID-19 infection,7 and third, the cataract complexity score,2 to establish surgical risk. Table 1 Modified MeNTS scoring system that systematically integrates factors associated with greater severity of COVID-19 illness and COVID-19 transmission risk to facilitate triage and decision-making for medically necessary, time-sensitive procedures (MeNTS) COVID risk score: modified MeNTS   0 1 2 Total Age <65 65–85 >85   Cardiovascular disease None Mild* Severe   Chronic obstructive pulmonary disease None Inhaler CPAP   Diabetes None Tablets Insulin   Immunocompromised None Moderate Severe   Anaesthetic Local Sedation GA   BAME Other South Asian Black   Exposure to COVID-19 positive in last 14 days No Possible Yes   Lives in nursing home No – Yes   Other (male sex, recent cancer therapy, high BMI, kidney or liver disease, severe dementia) None – Yes   Total   Low: 0–4 Moderate: 5–6 High: >6 Adapted from Prachand et al 2020,.7 *On medication only BAME, Black, Asian and Minority Ethnic; BMI, body mass index.

Background Age-related macular degeneration (AMD) is the leading cause of vision loss in elderly, Caucasian populations. There is strong evidence that mitochondrial dysfunction and oxidative stress play a role in the cell death found in AMD retinas. The purpose of this study was to examine the association of the Caucasian mitochondrial JTU haplogroup cluster with AMD. We also assessed for gender bias and additive risk with known high risk nuclear gene SNPs, ARMS2/LOC387715 (G > T; Ala69Ser, rs10490924) and CFH (T > C; Try402His, rs1061170). Methods Total DNA was isolated from 162 AMD subjects and 164 age-matched control subjects located in Los Angeles, California, USA. Polymerase chain reaction (PCR) and restriction enzyme digestion were used to identify the J, U, T, and H mitochondrial haplogroups and the ARMS2-rs10490924 and CFH-rs1061170 SNPs. PCR amplified products were sequenced to verify the nucleotide substitutions for the haplogroups and ARMS2 gene. Results The JTU haplogroup cluster occurred in 34% (55/162) of AMD subjects versus 15% (24/164) of normal (OR = 2.99; p = 0.0001). This association was slightly greater in males (OR = 3.98, p = 0.005) than the female population (OR = 3.02, p = 0.001). Assuming a dominant effect, the risk alleles for the ARMS2 (rs10490924; p = 0.00001) and CFH (rs1061170; p = 0.027) SNPs were significantly associated with total AMD populations. We found there was no additive risk for the ARMS2 (rs10490924) or CFH (rs1061170) SNPs on the JTU haplogroup background. Conclusions There is a strong association of the JTU haplogroup cluster with AMD. In our Southern California population, the ARMS2 (rs10490924) and CFH (rs1061170) genes were significantly but independently associated with AMD. SNPs defining the JTU mitochondrial haplogroup cluster may change the retinal bioenergetics and play a significant role in the pathogenesis of AMD.