Strategies for improving early detection and diagnosis of neovascular age-related macular degeneration

Treatment of the neovascular form of age-related macular degeneration (AMD) has been revolutionized by the introduction of such agents as ranibizumab, bevacizumab, and aflibercept. As a result, the incidence of legal blindness occurring secondary to AMD has fallen dramatically in recent years in many countries. While these agents have undoubtedly been successful in reducing visual impairment and blindness, patients with neovascular AMD typically lose some vision over time, and often lose the ability to read, drive, or perform other important activities of daily living. Efforts are therefore under way to develop strategies that allow for earlier detection and treatment of this disease. In this review, we begin by providing an overview of the rationale for, and the benefits of, early detection and treatment of neovascular AMD. To achieve this, we begin by providing an overview of the pathophysiology and natural history of choroidal neovascularization, before reviewing the evidence from both clinical trials and "real-world" outcome studies. We continue by highlighting an area that is often overlooked: the importance of patient education and awareness for early AMD detection. We conclude the review by reviewing an array of both established and emerging technologies for early detection of choroidal neovascularization, ranging from Amsler chart testing, to hyperacuity testing, to advanced imaging techniques, such as optical coherence tomography

Automated Analysis of Vitreous Inflammation Using Spectral-Domain Optical Coherence Tomography

Purpose: To develop an automated method for quantifying vitreous signal intensity on optical coherence tomography (OCT), with particular application for use in the assessment of vitreous inflammation. Methods: This retrospective, observational case-control series comprised 30 patients (30 eyes), with vitreous haze secondary to intermediate, posterior, or panuveitis; 12 patients (12 eyes) with uveitis without evidence of vitreous haze; and 18 patients (18 eyes) without intraocular inflammation or vitreoretinal disease. The presence and severity of vitreous haze was classified according to the National Eye Institute system; other inflammatory indices and clinical parameters were also documented. Spectral-domain OCT images were analyzed using custom VITreous ANalysis software (termed 'VITAN'), which is fully automated and avoids the need for manual segmentation. Results: VITAN performed accurate segmentation in all scans. Automated measurements of the vitreous:retinal pigment epithelium (RPE) signal ratio showed a moderate correlation with clinical vitreous haze scores (r ¼ 0.585, P , 0.001), comparable to that reported using manual segmentation in our previous study (r ¼ 0.566, P ¼ 0.0001). The novel parameter of vitreous:RPE textural ratio showed a marginally stronger correlation (r ¼ 0.604, P , 0.001) with clinical vitreous haze scores than the Vitreous:RPE signal ratio. Conclusions: The custom OCT image analysis software (VITAN) allows rapid and automated measurement of vitreous parameters, that is comparable to our previously reported vitreous:RPE index, and correlates with clinically measured disease activity. Such OCT-based indices may provide the much needed objective markers of vitreous activity, which may be used in both clinical assessment, and as outcome measures in clinical trials for intermediate, posterior, and panuveitis. Translational Relevance: We describe a rapid automated method for quantifying vitreous signal intensity on optical coherence tomography (OCT) and show that this correlates with clinical assessment of vitreous inflammation. Such OCT-based indices may provide the much needed objective markers of vitreous activity, which may be used both in routine clinical assessment, and as outcome measures in clinical trials for intermediate, posterior, and panuveitis

Evaluation of objective vitritis grading method using optical coherence tomography: influence of phakic status and previous vitrectomy

PURPOSE: To evaluate a proposed method for objective measurement of vitreous inflammation using a spectral. domain optical coherence tomography (SD OCT) device in a large cohort of uveitis eyes, including pseudophakic eyes and vitrectomized eyes. DESIGN: Retrospective, observational cohort study. METHODS: One hundred five uveitis eyes (105 patients) with different vitreous haze score grades according to standardized protocols and corresponding SD OCT images (Cirrus HD-OCT; Carl Zeiss Meditec, Dublin, California, USA) were included. Clinical data recorded included phakic status, previous vitreoretinal surgery, and anterior chamber (AC) cells and flare. SD OCT images were analyzed using custom software that provided absolute measurements of vitreous (VIT) and retinal pigment epithelium (RPE) signal intensities, which were compared to generate a relative optical density ratio with arbitrary units (VIT/RPE-relative intensity) and compared to VHS. RESULTS: VIT/RPE-relative intensity showed a significant positive correlation with vitreous haze score (r = 0.535, P <.001) that remained significant after adjusting for factors governing media clarity, such as AC cells, AC flare, and phakic status (R-2-adjusted = 0.424, P <.001). Significant differences were also observed between the different vitreous haze score groups (P <.001). Preliminary observation did not observe differences in VIT/RPE-relative intensity values between phakic and pseudophakic eyes (0.3522 vs 0.3577, P =.48) and between nonvitrectomized and vitrectomized eyes (0.3540 vs 0.3580, P = .52), overall and respectively for each vitreous haze score subgroup. CONCLUSIONS: VIT/RPE-relative intensity values provide objective measurements of vitreous inflammation employing an SD OCT device. Phakic status and previous vitrectomy su

Determinants of non-attendance at face-to-face and telemedicine ophthalmic consultations

BACKGROUND/AIMS: Evaluation of telemedicine care models has highlighted its potential for exacerbating healthcare inequalities. This study seeks to identify and characterise factors associated with non-attendance across face-to-face and telemedicine outpatient appointments. METHODS: A retrospective cohort study at a tertiary-level ophthalmic institution in the UK, between 1 January 2019 and 31 October 2021. Logistic regression modelled non-attendance against sociodemographic, clinical and operational exposure variables for all new patient registrations across five delivery modes: asynchronous, synchronous telephone, synchronous audiovisual and face to face prior to the pandemic and face to face during the pandemic. RESULTS: A total of 85 924 patients (median age 55 years, 54.4% female) were newly registered. Non-attendance differed significantly by delivery mode: (9.0% face to face prepandemic, 10.5% face to face during the pandemic, 11.7% asynchronous and 7.8%, synchronous during pandemic). Male sex, greater levels of deprivation, a previously cancelled appointment and not self-reporting ethnicity were strongly associated with non-attendance across all delivery modes. Individuals identifying as black ethnicity had worse attendance in synchronous audiovisual clinics (adjusted OR 4.24, 95% CI 1.59 to 11.28) but not asynchronous. Those not self-reporting their ethnicity were from more deprived backgrounds, had worse broadband access and had significantly higher non-attendance across all modes (all p<0.001). CONCLUSION: Persistent non-attendance among underserved populations attending telemedicine appointments highlights the challenge digital transformation faces for reducing healthcare inequalities. Implementation of new programmes should be accompanied by investigation into the differential health outcomes of vulnerable populations

Intravenous indocyanine green dye is insufficient for robust immune cell labelling in the human retina

It is not currently possible to reliably visualise and track immune cells in the human central nervous system or eye. Previous work demonstrated that indocyanine green (ICG) dye could label immune cells and be imaged after a delay during disease in the mouse retina. We report a pilot study investigating if ICG can similarly label immune cells within the human retina. Twelve adult participants receiving ICG angiography as part of routine standard of care were recruited. Baseline retinal images were obtained prior to ICG administration then repeated over a period ranging from 2 hours to 9 days. Matched peripheral blood samples were obtained to examine systemic immune cell labelling and activation from ICG by flow cytometry with human macrophage cultures as positive controls. Differences between the delayed near infrared ICG imaging and 488 nm autofluorescence was observed across pathologies, likely arising from the retinal pigment epithelium (RPE). Only one subject demonstrated ICG signal on peripheral blood myeloid cells and only three distinct cell-sized signals appeared over time within the retina of three participants. No significant increase in immune cell activation markers were detected after ICG administration. ICG accumulated in the endosomes of macrophage cultures and was detectable above a minimum concentration, suggesting cell labelling is possible. ICG can label RPE and may be used as an additional biomarker for RPE health across a range of retinal disorders. Standard clinical doses of intravenous ICG do not lead to robust immune cell labelling in human blood or retina and further optimisation in dose and route are required

Clinical Validation of an Ultra High-Throughput Spiral Microfluidics for the Detection and Enrichment of Viable Circulating Tumor Cells

Background: Circulating tumor cells (CTCs) are cancer cells that can be isolated via liquid biopsy from blood and can be phenotypically and genetically characterized to provide critical information for guiding cancer treatment. Current analysis of CTCs is hindered by the throughput, selectivity and specificity of devices or assays used in CTC detection and isolation. Methodology/Principal Findings: Here, we enriched and characterized putative CTCs from blood samples of patients with both advanced stage metastatic breast and lung cancers using a novel multiplexed spiral microfluidic chip. This system detected putative CTCs under high sensitivity (100%, n = 56) (Breast cancer samples: 12–1275 CTCs/ml; Lung cancer samples: 10–1535 CTCs/ml) rapidly from clinically relevant blood volumes (7.5 ml under 5 min). Blood samples were completely separated into plasma, CTCs and PBMCs components and each fraction were characterized with immunophenotyping (Pan-cytokeratin/CD45, CD44/CD24, EpCAM), fluorescence in-situ hybridization (FISH) (EML4-ALK) or targeted somatic mutation analysis. We used an ultra-sensitive mass spectrometry based system to highlight the presence of an EGFR-activating mutation in both isolated CTCs and plasma cell-free DNA (cf-DNA), and demonstrate concordance with the original tumor-biopsy samples. Conclusions/Significance: We have clinically validated our multiplexed microfluidic chip for the ultra high-throughput, low-cost and label-free enrichment of CTCs. Retrieved cells were unlabeled and viable, enabling potential propagation and real-time downstream analysis using next generation sequencing (NGS) or proteomic analysis.Singapore-MIT Alliance for Research and Technolog

Long-term remission of myopic choroidal neovascular membrane after treatment with ranibizumab: a case report

<p>Abstract</p> <p>Introduction</p> <p>Myopia has become a big public health problem in certain parts of the world. Sight-threatening complications like choroidal neovascularisation membranes occur in up to 10% of pathological myopia, and natural history studies show a trend towards progressive visual loss. There are long-term financial and quality-of-life implications in this group of patients, and treatment strategies should aim for long-term preservation of vision.</p> <p>Case presentation</p> <p>A 56-year-old Caucasian woman presented with a best-corrected visual acuity of 6/6-1 in her right eye and 6/24 in her left. Fundal examination revealed pathological myopia in both eyes and an elevated lesion associated with pre-retinal haemorrhage in the left macula. Ocular coherence tomography and fundus fluorescein angiogram confirmed a subfoveal classic choroidal neovascularisation membrane. The patient decided to proceed with intravitreal ranibizumab (0.5 mg) therapy. One month after treatment, best-corrected visual acuity improved to 6/12 in her left eye, with complete resolution subretinal fluid on ocular coherence tomography. After three months, best-corrected visual acuity further improved to 6/9, which was maintained up to 16 months post-treatment.</p> <p>Conclusion</p> <p>We suggest intravitreal ranibizumab as an alternative treatment for long-term remission of myopic choroidal neovascular membrane. It also suggests that myopic choroidal neovascularisation membranes may require fewer treatments to achieve sustained remission. Furthermore, this could serve as a feasible long-term management option if used in conjunction with ocular coherence tomography.</p

Evaluating psychometric properties of the Emotional Eating Scale Adapted for Children and Adolescents (EES-C) in a clinical sample of children seeking treatment for obesity: a case for the unidimensional model.

BackgroundThe Emotional Eating Scale - Adapted for Children and Adolescents (EES-C) assesses children's urge to eat in response to experiences of negative affect. Prior psychometric studies have demonstrated the high reliability, concurrent validity, and test-retest reliability of theoretically defined subconstructs among non-clinical samples of children and adolescents who were primarily healthy weight; however, no psychometric studies exist investigating the EES-C among clinical samples of children with overweight/obesity (OW/OB). Furthermore, studies conducted in different contexts have suggested a discordant number of subconstructs of emotions related to eating. The purpose of this study was to evaluate the validity of the EES-C in a clinical sample of children seeking weight-loss treatment.MethodUsing a hierarchical bi-factor approach, we evaluated the validity of the EES-C to measure a single general construct, a set of two separate correlated subconstructs, or a hierarchical arrangement of two constructs, and determined reliability in a clinical sample of treatment-seeking children with OW/OB aged 8-12 years (N = 147, mean age = 10.4 years.; mean BMI z = 2.0; female = 66%; Hispanic = 32%, White and other = 68%).ResultsComparison of factor-extraction methods suggested a single primary construct underlying EES-C in this clinical sample. The bi-factor indices provided clear evidence that most of the reliable variance in the total score (90.8 for bi-factor model with three grouping factors and 95.2 for bi-factor model with five grouping factors) was attributed to the general construct. After adjusting for relationships with the primary construct, remaining correlations among sets of items did not suggest additional reliable constructs.ConclusionResults suggest that the primary interpretive emphasis of the EES-C among treatment-seeking children with overweight or obesity should be placed on a single general construct, not on the 3- or 5- subconstructs as was previously suggested

Biological, clinical and population relevance of 95 loci for blood lipids.

Plasma concentrations of total cholesterol, low-density lipoprotein cholesterol, high-density lipoprotein cholesterol and triglycerides are among the most important risk factors for coronary artery disease (CAD) and are targets for therapeutic intervention. We screened the genome for common variants associated with plasma lipids in &gt;100,000 individuals of European ancestry. Here we report 95 significantly associated loci (P &lt; 5 x 10(-8)), with 59 showing genome-wide significant association with lipid traits for the first time. The newly reported associations include single nucleotide polymorphisms (SNPs) near known lipid regulators (for example, CYP7A1, NPC1L1 and SCARB1) as well as in scores of loci not previously implicated in lipoprotein metabolism. The 95 loci contribute not only to normal variation in lipid traits but also to extreme lipid phenotypes and have an impact on lipid traits in three non-European populations (East Asians, South Asians and African Americans). Our results identify several novel loci associated with plasma lipids that are also associated with CAD. Finally, we validated three of the novel genes-GALNT2, PPP1R3B and TTC39B-with experiments in mouse models. Taken together, our findings provide the foundation to develop a broader biological understanding of lipoprotein metabolism and to identify new therapeutic opportunities for the prevention of CAD