Immune-Mediated Retinal Vasculitis in Posterior Uveitis and Experimental Models: The Leukotriene (LT)B4-VEGF Axis

Retinal vascular diseases have distinct, complex and multifactorial pathogeneses yet share several key pathophysiological aspects including inflammation, vascular permeability and neovascularisation. In non-infectious posterior uveitis (NIU), retinal vasculitis involves vessel leakage leading to retinal enlargement, exudation, and macular oedema. Neovascularisation is not a common feature in NIU, however, detection of the major angiogenic factor—vascular endothelial growth factor A (VEGF-A)—in intraocular fluids in animal models of uveitis may be an indication for a role for this cytokine in a highly inflammatory condition. Suppression of VEGF-A by directly targeting the leukotriene B4 (LTB4) receptor (BLT1) pathway indicates a connection between leukotrienes (LTs), which have prominent roles in initiating and propagating inflammatory responses, and VEGF-A in retinal inflammatory diseases. Further research is needed to understand how LTs interact with intraocular cytokines in retinal inflammatory diseases to guide the development of novel therapeutic approaches targeting both inflammatory mediator pathways

WHO essential medicines for children 2011-2019: age-appropriateness of enteral formulations

INTRODUCTION: The WHO Essential Medicine List for children (EMLc) is used for promoting access to medicines. The age-appropriateness of enteral (oral and rectal) formulations for children depend on their adaptability/flexibility to allow age-related or weight-related doses to be administered/prescribed and the child's ability to swallow, as appropriate. There is scant information on the age-appropriateness of essential enteral medicines for children. OBJECTIVE: To evaluate the age-appropriateness of enteral essential medicines. MATERIALS AND METHODS: Age-appropriateness of all enteral formulations indicated and recommended in the EMLc 3rd to 7th (2011-2019) editions were determined by assessing swallowability and/or dose adaptability for children under 12 years, stratified into five age groups. RESULTS: Enteral formulations in the EMLc were more age-appropriate for older children aged 6-11 years than for younger children. In the 3rd edition, for older children, 77%, n=342, of formulations were age-appropriate. For younger children, age-appropriateness decreased with age group: 34% in those aged 3-5 years, 30% in those aged 1-2 years, 22% among those aged 28 days to 11 months and 15% in those aged 0-27 days. Overall, similar proportions were found for the 7th edition. In contrast, the majority of medicines in the 7th list were age-appropriate in targeted diseases like HIV and tuberculosis. CONCLUSION: Most recommended enteral essential medicines in EMLc 2011 and 2019 were not age-appropriate for children <6 years. Medicines which are not age-appropriate must be manipulated before administration, leading to potential issues of safety and efficacy. Evaluation of the age-appropriateness of formulations for medicines to be included in EMLc could improve access to better medicines for children in the future

Accuracy of Intravenous and Enteral Preparations Involving Small Volumes for Paediatric Use: A Review

Background: Children often need to be administered very small volumes of medicines that are authorised for use in adults. Neonatal drug delivery is particularly challenging and doses are often immeasurable with the equipment currently available. Aim: To summarise research to date on the accuracy of intravenous and enteral medicine preparation requiring small volumes (<0.1mL), with a focus on paediatric use and to identify areas for further work. Method: Twenty-three publications were identified for the narrative review via: Web of Science (1950-2016), Cumulative Index to Nursing and Allied Health Literature (1976-2016), Excerpta Medica Database (1974-2016) and International Pharmaceutical Abstracts (1970-2016) searches. Nine additional papers were identified through backward citation tracking and a further 17 were included from the personal knowledge of the review team. Results: Measurement of volumes (<0.1mL), for enteral and intravenous dosing, account for 25% of medicine manipulations within paediatric hospitals. Inaccuracies are described throughout the literature with dose administration errors attributed to technique, calculation, dilution and problems associated with equipment. Whilst standardised concentrations for intravenous infusion and drug concentrations which avoid measurement of small volumes would ameliorate problems, further work is needed to establish accurate methods for handling small volumes during the administration of medicines to children and risk minimisation strategies to support staff involved are also necessary. Conclusion: This review has revealed a paucity of information on the clinical outcomes from problems in measuring small volumes for children and highlighted the need for further work to eliminate this source of inaccurate dosing and potential for medication error

Leukotriene B4 (LTB4) and its receptor in Experimental Autoimmune Uveitis (EAU) and in human retinal tissues: clinical severity and LTB4-dependence of retinal Th17 cells

Nomacopan, a drug originally derived from tick saliva, has dual functions of sequestering leukotriene B4 (LTB4) and inhibiting complement component 5 (C5) activation. It was demonstrated that nomacopan provides therapeutic benefit in experimental autoimmune uveitis (EAU). The longer-acting forms of nomacopan were more efficacious in mouse EAU models and the long-acting variant that inhibited only LTB4 was at least as effective as the long-acting variant that inhibited both C5 and LTB4, preventing structural damage to the retina and a significant reduction of effector Th17 cells and inflammatory macrophages. Increased levels of LTB4 and C5a (produced upon C5 activation) were detected during disease progression. Retinal activated lymphocytes were shown to express LTB4 receptors (R) in vitro and in inflamed draining lymph nodes (dLN). Levels of LTB4R-expressing retinal active/inflammatory macrophages were also increased. Within the dLN CD4+T cell population, 30% expressed LTB4R+ following activation in vitro, while retinal infiltrating cells expressed LTB4R and C5aR. Validation of expression of those receptors in human uveitis and healthy tissues suggests that infiltrating cells could be targeted by inhibitors of the LTB4-BLT1 pathway as a novel therapeutic approach. In conclusion, this study provides novel data on intraocular LTB4 and C5a in EAU, their associated receptor expression by retinal infiltrating cells in mouse and human tissues and in attenuating EAU via the dual inhibitor nomacopan

Development and inter-rater reliability of the Liverpool adverse drug reaction causality assessment tool.

To develop and test a new adverse drug reaction (ADR) causality assessment tool (CAT)

Adverse drug reactions and off-label and unlicensed medicines in children: a nested case control study of inpatients in a pediatric hospital

Off-label and unlicensed (OLUL) prescribing has been prevalent in pediatric practice. Using data from a prospective cohort study of adverse drug reactions (ADRs) among pediatric inpatients, we aimed to test the hypothesis that OLUL status is a risk factor for ADRs

Use of the complement inhibitor Coversin to treat HSCT-associated TMA

Finding an inherited complement abnormality in HSCT-associated TMA provides a rationale for the use of a complement inhibitor.Alternative complement inhibitors such as Coversin should be considered in patients who are resistant to eculizumab

Incidence, characteristics and risk factors of adverse drug reactions in hospitalized children - a prospective observational cohort study of 6,601 admissions

Adverse drug reactions (ADRs) are an important cause of harm in children. Current data are incomplete due to methodological differences between studies: only half of all studies provide drug data, incidence rates vary (0.6% to 16.8%) and very few studies provide data on causality, severity and risk factors of pediatric ADRs. We aimed to determine the incidence of ADRs in hospitalized children, to characterize these ADRs in terms of type, drug etiology, causality and severity and to identify risk factors

Quantum optical memory protocols in atomic ensembles

We review a series of quantum memory protocols designed to store the quantum information carried by light into atomic ensembles. In particular, we show how a simple semiclassical formalism allows to gain insight into various memory protocols and to highlight strong analogies between them. These analogies naturally lead to a classification of light storage protocols into two categories, namely photon echo and slow-light memories. We focus on the storage and retrieval dynamics as a key step to map the optical information into the atomic excitation. We finally review various criteria adapted for both continuous variables and photon-counting measurement techniques to certify the quantum nature of these memory protocols

An epigraphene platform for coherent 1D nanoelectronics

Exceptional edge state ballistic transport, first observed in graphene nanoribbons grown on the sidewalls of trenches etched in electronics grade silicon carbide even at room temperature, is shown here to manifest in micron scale epigraphene structures that are conventionally patterned on single crystal silicon carbide substrates. Electronic transport is dominated by a single electronic mode, in which electrons travel large distances without scattering, much like photons in an optical fiber. In addition, robust quantum coherence, non-local transport, and a ground state with half a conductance quantum are also observed. These properties are explained in terms of a ballistic edge state that is pinned at zero energy. The epigraphene platform allows interconnected nanostructures to be patterned, using standard microelectronics methods, to produce phase coherent 1D ballistic networks. This discovery is unique, providing the first feasible route to large scale quantum coherent graphene nanoelectronics, and a possible inroad towards quantum computing