Clinical outcomes of a treat and extend regimen with intravitreal aflibercept injections in patients with diabetic macular edema: Experience in clinical practice

Introduction: Treat-and-extend (T&E) and prore nata (PRN; ‘as needed’) regimens of intravitreal anti-vascular endothelial growth factor(VEGF) treatment have been found to reducethe injection burden on patients and improvethe cost effectiveness of the treatment of macular edema. The aim of this study was to assessthe effectiveness of a T&E regimen of aflibercept, in a clinical setting, in patients with diabetic macular edema (DME) who were either intravitreal anti-VEGF therapy naive or withminimal exposure to anti-VEGF (B 6 treatments) in the previous 12 months.Methods: This prospective, single arm, open labelstudy recruited patients with DME (macularthickness of C 300 lm) and best-corrected visualacuity (BCVA) between 28-78 ETDRS letters. Participants received five loading doses of intravitrealaflibercept at 4-weekly intervals. BCVA measurements and macular optical coherence tomographywere performed at each visit. If no disease activitywas detected, treatment intervals were increased by2 weeks to a maximum of 12 weeks. Outcomemeasures included: changes in BCVA and retinalanatomical measures (central foveal thickness[CFT] and central macular volume within 6 mm ofthe fovea [CSVol]) between baseline and 2 years,patient treatment intervals; and adverse events.Results: Of the 36 patients who providedinformed consent to participate in the studyand were screened, 26 patients (eyes) were eligible to participate in the study. After regressionanalysis, adjustment for repeated measures, andsignificant covariates, the mean BCVA increasedby 3.8 letters (95% confidence interval [CI] 1.1,6.4) and the CFT and CSVol decreased by127.2 lm (95% CI 91.7, 162.5) and 1.6 mm3 (95% CI 1.2, 2.0), respectively, over the courseof the study. In the second year, 16 of the 25patients still participating had their treatmentintervals extended to 12 weeks. There was noevidence of any new adverse events that wouldrequire changes to the aflibercept safety profile.Conclusion: For the majority of patients presenting with DME, a T&E regimen of afliberceptin the first 2 years of therapy is a practical alternative to PRN treatment with regular review

Current state and future prospects of artificial intelligence in ophthalmology: a review

Artificial intelligence (AI) has emerged as a major frontier in computer science research. Although AI has broad application across many medical fields, it will have particular utility in ophthalmology and will dramatically change the diagnostic and treatment pathways for many eye conditions such as corneal ectasias, glaucoma, age-related macular degeneration and diabetic retinopathy. However, given that AI has primarily been driven as a computer science, its concepts and terminology are unfamiliar to many medical professionals. Important key terms such as machine learning and deep learning are often misunderstood and incorrectly used interchangeably. This article presents an overview of AI and new developments relevant to ophthalmology

Expansion of human mesenchymal stem/stromal cells (hMSCs) in bioreactors using microcarriers: lessons learnt and what the future holds

Human mesenchymal stem/stromal cells (hMSCs) present a key therapeutic cellular intervention for use in cell and gene therapy (CGT) applications due to their immunomodulatory properties and multi-differentiation capability. Some of the indications where hMSCs have demonstrated pre-clinical or clinical efficacy to improve outcomes are cartilage repair, acute myocardial infarction, graft versus host disease, Crohn’s disease and arthritis. The current engineering challenge is to produce hMSCs at an affordable price and at a commercially-relevant scale whilst minimising process variability and manual, human operations. By employing bioreactors and microcarriers (due to the adherent nature of hMSCs), it is expected that production costs would decrease due to improved process monitoring and control leading to better consistency and process efficiency, and enabling economies of scale. This approach will result in off the shelf (allogeneic) hMSC-based products becoming more accessible and affordable. Importantly, cell quality, including potency, must be maintained during the bioreactor manufacturing process. This review aims to examine the various factors to be considered when developing a hMSC manufacturing process using microcarriers and bioreactors and their potential impact on the final product. As concluding remarks, gaps in the current literature and potential future areas of research are also discussed

The role of biopreservation in cell and gene therapy bioprocessing

Cell and gene-based therapies represent a novel therapeutic modality that has the potential to provide a treatment option for a range of medical conditions. There are, however, numerous processing and manufacturing challenges that must be addressed before such therapies are considered commercially and clinically viable. A significant challenge associated with the manufacture of such therapies is ensuring cell quality and the product’s critical quality attributes are retained throughout the entire bioprocess. Biopreservation is an important aspect of cell and gene-based therapy bioprocessing, which enables the development of cell banks. It increases process flexibility by providing a shelf-life to the product, enables the storage of intermediates and provides breakpoints within the process. In this article, we summarize the advances and challenges associated with biopreservation of cell and gene therapies

Design and development of a new ambr250® bioreactor vessel for improved cell and gene therapy applications

The emergence of cell and gene therapies has generated significant interest in their clinical and commercial potential. However, these therapies are prohibitively expensive to manufacture and can require extensive time for development due to our limited process knowledge and understanding. The automated ambr250® stirred-tank bioreactor platform provides an effective platform for high-throughput process development. However, the original dual pitched-blade 20 mm impeller and baffles proved sub-optimal for cell therapy candidates that require suspension of microcarriers (e.g. for the culture of adherent human mesenchymal stem cells) or other particles such as activating Dynabeads® (e.g. for the culture of human T-cells). We demonstrate the development of a new ambr250® stirred-tank bioreactor vessel which has been designed specifically to improve the suspension of microcarriers/beads and thereby improve the culture of such cellular systems. The new design is unbaffled and has a single, larger elephant ear impeller. We undertook a range of engineering and physical characterizations to determine which vessel and impeller configuration would be most suitable for suspension based on the minimum agitation speed (NJS) and associated specific power input (P/V)JS. A vessel (diameter, T, = 60 mm) without baffles and incorporating a single elephant ear impeller (diameter 30 mm and 45° pitch-blade angle) was selected as it had the lowest (P/V)JS and therefore potentially, based on Kolmogorov concepts, was the most flexible system. These experimentally-based conclusions were further validated firstly with computational fluid dynamic (CFD) simulations and secondly experimental studies involving the culture of both T-cells with Dynabeads® and hMSCs on microcarriers. The new ambr250® stirred-tank bioreactor successfully supported the culture of both cell types, with the T-cell culture demonstrating significant improvements compared to the original ambr250® and the hMSC-microcarrier culture gave significantly higher yields compared with spinner flask cultures. The new ambr250® bioreactor vessel design is an effective process development tool for cell and gene therapy candidates and potentially for autologous manufacture too

A Cross-Sectional Survey of Anesthetic Airway Equipment and Airway Management Practices in Uganda.

BACKGROUND: Anesthesia-related causes contribute to a significant proportion of perioperative deaths, especially in low and middle-income countries (LMICs). There is evidence that complications related to failed airway management are a significant contributor to perioperative morbidity and mortality. While existing data have highlighted the magnitude of airway management complications in LMICs, there are inadequate data to understand their root causes. This study aimed to pilot an airway management capacity tool that evaluates airway management resources, provider practices, and experiences with difficult airways in an attempt to better understand potential contributing factors to airway management challenges. METHODS: We developed a novel airway management capacity assessment tool through a nonsystematic review of existing literature on anesthesia and airway management in LMICs, internationally recognized difficult airway algorithms, minimum standards for equipment, the safe practice of anesthesia, and the essential medicines and health supplies list of Uganda. We distributed the survey tool during conferences and workshops, to anesthesia care providers from across the spectrum of surgical care facilities in Uganda. The data were analyzed using descriptive methods. RESULTS: Between May 2017 and May 2018, 89 of 93 surveys were returned (17% of anesthesia providers in the country) from all levels of health facilities that provide surgical services in Uganda. Equipment for routine airway management was available to all anesthesia providers surveyed, but with a limited range of sizes. Pediatric airway equipment was always available 54% of the time. There was limited availability of capnography (15%), video laryngoscopes (4%), cricothyroidotomy kits (6%), and fiber-optic bronchoscopes (7%). Twenty-one percent (18/87) of respondents reported experiencing a "can't intubate, can't ventilate" (CICV) scenario in the 12 months preceding the survey, while 63% (54/86) reported experiencing at least 1 CICV during their career. Eighty-five percent (74/87) of respondents reported witnessing a severe airway management complication during their career, with 21% (19/89) witnessing a death as a result of a CICV scenario. CONCLUSIONS: We have developed and implemented an airway management capacity tool that describes airway management practices in Uganda. Using this tool, we have identified significant gaps in access to airway management resources. Gaps identified by the survey, along with advocacy by the Association of Anesthesiologists of Uganda, in partnership with the Ugandan Ministry of Health, have led to some progress in closing these gaps. Expanding the availability of airway management resources further, providing more airway management training, and identifying opportunities to support skilled workforce expansion have the potential to improve perioperative safety in Uganda

Molecular aspects of eye development and regeneration in the Australian redclaw crayfish, Cherax quadricarinatus

The compound eye evolved over 500 million years ago and enables mosaic vision in most arthropod species. The molecular regulation of the development of the compound eye has been primarily studied in the fruit fly Drosophila melanogaster. However, due to the nature of holometabolous insects halting growth after their terminal metamorphosis into the adult form, they lack the capacity to regenerate. Crustaceans, unlike holometabolous insects, continue to grow during adulthood, achieved through regular shedding of their exoskeleton, in a cyclic process known as molting. This therefore offers crustaceans as a highly suitable model to study ocular regeneration in the adult arthropod eye. We have assessed the regenerative capacity of the retinal section of the Cherax quadricarinatus (red-claw crayfish) eye, following ablation and successive post-metamorphic molts. This work then provides a transcriptomic description of the outer, pigmented retinal tissue (the ommatidia and lamina ganglionaris) and the basal, non-pigmented neuroendocrine ocular tissue (the X-organ Sinus Gland complex, hemiellipsoid body and optic nerve). Using comparative analysis, we identified all the transcripts in the C. quadricarinatus ocular transcriptome that are known to function in compound eye development in D. melanogaster. Differentially and uniquely transcribed genes of the retina are described, suggesting proposed mechanisms that may regulate ocular regeneration in decapod Crustacea. This research exemplifies the application C. quadricarinatus holds as an optimal model to study the regulation of ocular regeneration. Further in-depth transcriptomic analyses are now required, sampled throughout the regeneration process to better define the regulatory mechanism

Time spent outdoors in childhood is associated with reduced risk of myopia as an adult

Myopia (near-sightedness) is an important public health issue. Spending more time outdoors can prevent myopia but the long-term association between this exposure and myopia has not been well characterised. We investigated the relationship between time spent outdoors in childhood, adolescence and young adulthood and risk of myopia in young adulthood. The Kidskin Young Adult Myopia Study (KYAMS) was a follow-up of the Kidskin Study, a sun exposure-intervention study of 1776 children aged 6–12 years. Myopia status was assessed in 303 (17.6%) KYAMS participants (aged 25–30 years) and several subjective and objective measures of time spent outdoors were collected in childhood (8–12 years) and adulthood. Index measures of total, childhood and recent time spent outdoors were developed using confirmatory factor analysis. Logistic regression was used to assess the association between a 0.1-unit change in the time outdoor indices and risk of myopia after adjusting for sex, education, outdoor occupation, parental myopia, parental education, ancestry and Kidskin Study intervention group. Spending more time outdoors during childhood was associated with reduced risk of myopia in young adulthood (multivariable odds ratio [OR] 0.82, 95% confidence interval [CI] 0.69, 0.98). Spending more time outdoors in later adolescence and young adulthood was associated with reduced risk of late-onset myopia (≥ 15 years of age, multivariable OR 0.79, 95% CI 0.64, 0.98). Spending more time outdoors in both childhood and adolescence was associated with less myopia in young adulthood