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

The All-Data-Based Evolutionary Hypothesis of Ciliated Protists with a Revised Classification of the Phylum Ciliophora (Eukaryota, Alveolata)

This work is licensed under a Creative Commons Attribution 4.0 International License. The images or other third party material in this article are included in the article's Creative Commons license, unless indicated otherwise in the credit line; if the material is not included under the Creative Commons license, users will need to obtain permission from the license holder to reproduce the material. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/ The file attached is the published version of the article

De novo mutations in SMCHD1 cause Bosma arhinia microphthalmia syndrome and abrogate nasal development

Bosma arhinia microphthalmia syndrome (BAMS) is an extremely rare and striking condition characterized by complete absence of the nose with or without ocular defects. We report here that missense mutations in the epigenetic regulator SMCHD1 mapping to the extended ATPase domain of the encoded protein cause BAMS in all 14 cases studied. All mutations were de novo where parental DNA was available. Biochemical tests and in vivo assays in Xenopus laevis embryos suggest that these mutations may behave as gain-of-function alleles. This finding is in contrast to the loss-of-function mutations in SMCHD1 that have been associated with facioscapulohumeral muscular dystrophy (FSHD) type 2. Our results establish SMCHD1 as a key player in nasal development and provide biochemical insight into its enzymatic function that may be exploited for development of therapeutics for FSHD

Risk of selection bias in randomised trials

Background: Selection bias occurs when recruiters selectively enrol patients into the trial based on what the next treatment allocation is likely to be. This can occur even if appropriate allocation concealment is used if recruiters can guess the next treatment assignment with some degree of accuracy. This typically occurs in unblinded trials when restricted randomisation is implemented to force the number of patients in each arm or within each centre to be the same. Several methods to reduce the risk of selection bias have been suggested; however, it is unclear how often these techniques are used in practice. Methods: We performed a review of published trials which were not blinded to assess whether they utilised methods for reducing the risk of selection bias. We assessed the following techniques: (a) blinding of recruiters; (b) use of simple randomisation; (c) avoidance of stratification by site when restricted randomisation is used; (d) avoidance of permuted blocks if stratification by site is used; and (e) incorporation of prognostic covariates into the randomisation procedure when restricted randomisation is used. We included parallel group, individually randomised phase III trials published in four general medical journals (BMJ, Journal of the American Medical Association, The Lancet, and New England Journal of Medicine) in 2010. Results: We identified 152 eligible trials. Most trials (98%) provided no information on whether recruiters were blind to previous treatment allocations. Only 3% of trials used simple randomisation; 63% used some form of restricted randomisation, and 35% did not state the method of randomisation. Overall, 44% of trials were stratified by site of recruitment; 27% were not, and 29% did not report this information. Most trials that did stratify by site of recruitment used permuted blocks (58%), and only 15% reported using random block sizes. Many trials that used restricted randomisation also included prognostic covariates in the randomisation procedure (56%). Conclusions: The risk of selection bias could not be ascertained for most trials due to poor reporting. Many trials which did provide details on the randomisation procedure were at risk of selection bias due to a poorly chosen randomisation methods. Techniques to reduce the risk of selection bias should be more widely implemented

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

Solving Nonlinear Parabolic Equations by a Strongly Implicit Finite-Difference Scheme

We discuss the numerical solution of nonlinear parabolic partial differential equations, exhibiting finite speed of propagation, via a strongly implicit finite-difference scheme with formal truncation error $\mathcal{O}\left[(\Delta x)^2 + (\Delta t)^2 \right]$. Our application of interest is the spreading of viscous gravity currents in the study of which these type of differential equations arise. Viscous gravity currents are low Reynolds number (viscous forces dominate inertial forces) flow phenomena in which a dense, viscous fluid displaces a lighter (usually immiscible) fluid. The fluids may be confined by the sidewalls of a channel or propagate in an unconfined two-dimensional (or axisymmetric three-dimensional) geometry. Under the lubrication approximation, the mathematical description of the spreading of these fluids reduces to solving the so-called thin-film equation for the current's shape $h(x,t)$. To solve such nonlinear parabolic equations we propose a finite-difference scheme based on the Crank--Nicolson idea. We implement the scheme for problems involving a single spatial coordinate (i.e., two-dimensional, axisymmetric or spherically-symmetric three-dimensional currents) on an equispaced but staggered grid. We benchmark the scheme against analytical solutions and highlight its strong numerical stability by specifically considering the spreading of non-Newtonian power-law fluids in a variable-width confined channel-like geometry (a "Hele-Shaw cell") subject to a given mass conservation/balance constraint. We show that this constraint can be implemented by re-expressing it as nonlinear flux boundary conditions on the domain's endpoints. Then, we show numerically that the scheme achieves its full second-order accuracy in space and time. We also highlight through numerical simulations how the proposed scheme accurately respects the mass conservation/balance constraint.Comment: 36 pages, 9 figures, Springer book class; v2 includes improvements and corrections; to appear as a contribution in "Applied Wave Mathematics II

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