Air Pollution Exposure in Relation to the Commute to School: A Bradford UK Case Study

Walking School Buses (WSBs) provide a safe alternative to being driven to school. Children benefit from the contribution the exercise provides towards their daily exercise target, it gives children practical experience with respect to road safety and it helps to relieve traffic congestion around the entrance to their school. Walking routes are designed largely based in road safety considerations, catchment need and the availability of parent support. However, little attention is given to the air pollution exposure experienced by children during their journey to school, despite the commuting microenvironment being an important contributor to a child’s daily air pollution exposure. This study aims to quantify the air pollution exposure experienced by children walking to school and those being driven by car. A school was chosen in Bradford, UK. Three adult participants carried out the journey to and from school, each carrying a P-Trak ultrafine particle (UFP) count monitor. One participant travelled the journey to school by car while the other two walked, each on opposite sides of the road for the majority of the journey. Data collection was carried out over a period of two weeks, for a total of five journeys to school in the morning and five on the way home at the end of the school day. Results of the study suggest that car commuters experience lower levels of air pollution dose due to lower exposure and reduced commute times. The largest reductions in exposure for pedestrians can be achieved by avoiding close proximity to traffic queuing up at intersections, and, where possible, walking on the side of the road opposite the traffic, especially during the morning commuting period. Major intersections should also be avoided as they were associated with peak exposures. Steps to ensure that the phasing of lights is optimised to minimise pedestrian waiting time would also help reduce exposure. If possible, busy roads should be avoided altogether. By the careful design of WSB routes, taking into account air pollution, children will be able to experience the benefits that walking to school brings while minimizing their air pollution exposure during their commute to and from school

Clinical and Genetic Features of Choroideremia in Childhood.

PURPOSE: To review the functional and anatomic characteristics of choroideremia in the pediatric population, aiming to describe the earliest features of the disease and to identify biomarkers useful for monitoring disease progression. DESIGN: Retrospective case series. PARTICIPANTS: Children diagnosed with choroideremia at a single institution. METHODS: Patients were identified using an electronic patient record system. Case notes and retinal imaging (color fundus photography [CFP], spectral-domain [SD] optical coherence tomography [OCT], and fundus autofluorescence [FAF]) then were reviewed. The results of genetic testing also were recorded. MAIN OUTCOME MEASURES: Presenting symptoms, visual acuity, fundus changes (CFP, SD OCT, FAF), and CHM sequencing results. RESULTS: Twenty-nine patients were identified with a mean age at referral of 9 years (range, 3-16 years). CHM mutations were identified in 15 of 19 patients tested. Nyctalopia was the predominant symptom (66%). Five of 29 patients were asymptomatic at presentation. At the final follow-up visit (mean age, 16 years; range, 7-26 years), most maintained excellent visual acuity (mean, 0.98±0.13 decimalized Snellen acuity). The first sign of retinopathy was widespread pigment clumping at the level of the retinal pigment epithelium (RPE). This later evolved to chorioretinal atrophy, most marked in the mid-peripheral retina. Peripapillary atrophy also was an early feature and was progressive in nature. Three different zones of FAF change were visible. Persistence of the inner retinal layers, detected by SD OCT, was visible at presentation in 15 of 27 patients. Subfoveal choroidal thickness decreased with age, whereas central retinal thickness increased over a similar interval. Four patients in whom visual acuity decreased over the follow-up period recorded a reduction in central retinal thickness. CONCLUSIONS: Progressive structural changes occur at a time when central visual function is maintained. Pigmentary changes at the level of the RPE occur early in the disease course. Peripapillary chorioretinal atrophy, central retinal thickness, and subfoveal choroidal thickness are likely to be valuable in monitoring disease progression and should be considered as potential biomarkers in future therapeutic trials

Macular dystrophies: clinical and imaging features, molecular genetics and therapeutic options

Macular dystrophies (MDs) consist of a heterogeneous group of disorders that are characterised by bilateral symmetrical central visual loss. Advances in genetic testing over the last decade have led to improved knowledge of the underlying molecular basis. The developments in high-resolution multimodal retinal imaging have also transformed our ability to make accurate and more timely diagnoses and more sensitive quantitative assessment of disease progression, and allowed the design of optimised clinical trial endpoints for novel therapeutic interventions. The aim of this review was to provide an update on MDs, including Stargardt disease, Best disease, X-linked r etinoschisis, pattern dystrophy, Sorsby fundus dystrophy and autosomal dominant drusen. It highlights the range of innovations in retinal imaging, genotype–phenotype and structure– function associations, animal models of disease and the multiple treatment strategies that are currently in clinical trial or planned in the near future, which are anticipated to lead to significant changes in the management of patients with MDs

Phenotype and genotype of 197 British patients with McArdle disease: An observational single-centre study

McArdle disease is caused by recessive mutations in PYGM gene. The condition is considered to cause a “pure” muscle phenotype with symptoms including exercise intolerance, inability to perform isometric activities, contracture, and acute rhabdomyolysis leading to acute renal failure. This is a retrospective observational study aiming to describe phenotypic and genotypic features of a large cohort of patients with McArdle disease between 2011 and 2019. Data relating to genotype and phenotype, including frequency of rhabdomyolysis, fixed muscle weakness, gout and comorbidities, inclusive of retinal disease (pattern retinal dystrophy) and thyroid disease, were collected. Data from 197 patients are presented. Seven previously unpublished PYGM mutations are described. Exercise intolerance (100%) and episodic rhabdomyolysis (75.6%) were the most common symptoms. Fixed muscle weakness was present in 82 (41.6%) subjects. Unexpectedly, ptosis was observed in 28 patients (14.2%). Hyperuricaemia was a common finding present in 88 subjects (44.7%), complicated by gout in 25% of cases. Thyroid dysfunction was described in 30 subjects (15.2%), and in 3 cases, papillary thyroid cancer was observed. Pattern retinal dystrophy was detected in 15 out of the 41 subjects that underwent an ophthalmic assessment (36.6%). In addition to fixed muscle weakness, ptosis was a relatively common finding. Surprisingly, dysfunction of thyroid and retinal abnormalities were relatively frequent comorbidities. Further studies are needed to better clarify this association, although our finding may have important implication for patient management

Assessment of allelopathic potential of selected medicinal plants of Pakistan

Inula falconeri, Inula koelzii, Lactuca dissecta and Anthemis nobilis were collected from Himalaya and Hindukush ranges of Pakistan and their allelopathic effect was studied through Sandwich and Homogenated Sandwich methods. The study also aimed at analyzing whether method andconcentration can affect the overall results. The results showed that method has no significant value; however, concentration of leaf leachates has highly significant value for exploring the inhibition or stimulation pattern of the plant species

Advanced diagnostic genetic testing in inherited retinal disease: experience from a single tertiary referral centre in the UK National Health Service

In 2013, as part of our genetic investigation of patients with inherited retinal disease, we utilized multigene panel testing of 105 genes known to cause retinal disease in our patient cohorts. This test was performed in a UK National Health Service (NHS) accredited laboratory. The results of all multigene panel tests requested between 1.4.13 and 31.8.14 were retrospectively reviewed. All patients had been previously seen at Moorfields Eye Hospital, London, UK and diagnosed with an inherited retinal dystrophy after clinical examination and detailed retinal imaging. The results were categorized into three groups: (i) Testing helped establish a certain molecular diagnosis in 45 out of 115 (39%). Variants in USH2A (n = 6) and RP1 (n = 4) were most common. (ii) Definitive conclusions could not be drawn from molecular testing alone in 13 out of 115 (11%) as either insufficient pathogenic variants were discovered or those identified were not consistent with the phenotype. (iii) Testing did not identify any pathogenic variants responsible for the phenotype in 57 out of 115 (50%). Multigene panel testing performed in an NHS setting has enabled a molecular diagnosis to be confidently made in 40% of cases. Novel variants accounted for 38% of all identified variants. Detailed retinal phenotyping helped the interpretation of specific variants. Additional care needs to be taken when assessing polymorphisms in genes that have been infrequently associated with disease, as historical techniques were not as rigorous as contemporary ones. Future iterations of sequencing are likely to offer higher sensitivity, testing a broader range of genes, more rapidly and at a reduced cost

Spatial distribution of metabolites in the retina and its relevance to studies of metabolic retinal disorders

Introduction: The primate retina has evolved regional specialisations for specific visual functions. The macula is specialised towards high acuity vision and is an area that contains an increased density of cone photoreceptors and signal processing neurons. Different regions in the retina display unique susceptibility to pathology, with many retinal diseases primarily affecting the macula. Objectives: To better understand the properties of different retinal areas we studied the differential distribution of metabolites across the retina. Methods: We conducted an untargeted metabolomics analysis on full-thickness punches from three different regions (macula, temporal peri-macula and periphery) of healthy primate retina. Results: Nearly half of all metabolites identified showed differential abundance in at least one comparison between the three regions. Furthermore, mapping metabolomics results from macula-specific eye diseases onto our region-specific metabolite distributions revealed differential abundance defining systemic metabolic dysregulations that were region specific. Conclusions: The unique metabolic phenotype of different retinal regions is likely due to the differential distribution of different cell types in these regions reflecting the specific metabolic requirements of each cell type. Our results may help to better understand the pathobiology of retinal diseases with region specificity

The Fundus Phenotype Associated With The p.Ala243Val BEST1 Mutation

PURPOSE: To describe a highly recognizable and reproducible retinal phenotype associated with a specific BEST1 mutation-p.Ala243Val. METHODS: Retrospective review of consecutive cases where genetic testing has identified p.Ala243Val BEST1 as the cause of disease. Electronic patient records were used to extract demographic, as well as functional and anatomical data. These data were compared with those observed with the most common BEST1 genotype, p.Arg218Cys. RESULTS: Eight individuals (six families) were identified with the p.Ala243Val BEST1 mutation and seven patients with the pathologic variant p.Arg218Cys. No patients with mutation of codon 243 knowingly had a family history of retinal disease, whereas all patients with the p.Arg218Cys variant did. The maculopathy was bilateral in all cases. The p.Ala243Val mutation was associated with a pattern dystrophy-type appearance, most visible with near-infrared reflectance and fundus autofluorescence imaging. This phenotype was never observed with any other genotype. This mutation was associated with an older median age of symptom onset (median = 42, interquartile range = 22) compared with those harboring the p.Arg218Cys mutation (median = 18, interquartile range = 12; Mann-Whitney U test; P 0.05). CONCLUSION: The mutation p.Ala243Val is associated with highly recognizable and reproducible pattern dystrophy-like phenotype. Patients develop symptoms at a later age and tend to have better preservation of electrooculogram amplitudes

Large-scale analysis of antigenic diversity of T-cell epitopes in dengue virus

BACKGROUND: Antigenic diversity in dengue virus strains has been studied, but large-scale and detailed systematic analyses have not been reported. In this study, we report a bioinformatics method for analyzing viral antigenic diversity in the context of T-cell mediated immune responses. We applied this method to study the relationship between short-peptide antigenic diversity and protein sequence diversity of dengue virus. We also studied the effects of sequence determinants on viral antigenic diversity. Short peptides, principally 9-mers were studied because they represent the predominant length of binding cores of T-cell epitopes, which are important for formulation of vaccines. RESULTS: Our analysis showed that the number of unique protein sequences required to represent complete antigenic diversity of short peptides in dengue virus is significantly smaller than that required to represent complete protein sequence diversity. Short-peptide antigenic diversity shows an asymptotic relationship to the number of unique protein sequences, indicating that for large sequence sets (~200) the addition of new protein sequences has marginal effect to increasing antigenic diversity. A near-linear relationship was observed between the extent of antigenic diversity and the length of protein sequences, suggesting that, for the practical purpose of vaccine development, antigenic diversity of short peptides from dengue virus can be represented by short regions of sequences (~<100 aa) within viral antigens that are specific targets of immune responses (such as T-cell epitopes specific to particular human leukocyte antigen alleles). CONCLUSION: This study provides evidence that there are limited numbers of antigenic combinations in protein sequence variants of a viral species and that short regions of the viral protein are sufficient to capture antigenic diversity of T-cell epitopes. The approach described herein has direct application to the analysis of other viruses, in particular those that show high diversity and/or rapid evolution, such as influenza A virus and human immunodeficiency virus (HIV)

A Unified Mathematical Modelling and Simulation for Cathodic Blistering Mechanism incorporating diffusion and fracture mechanics concepts

A novel mathematical model has been developed to understand the mechanism of blister initiation and propagation. The model employs a two-part theoretical approach encompassing the debondment of a coating film from the substrate, coupled with the design components incorporating diffusion and fracture mechanics, where the latter is derived from equi-biaxial tensile loading. Integrating the two components, a comprehensive mathematical design for the propagation of blister boundaries based on specific toughness functions and mode adjustment parameters has been developed. This approach provided a reliable and efficient prediction method for blister growth rate and mechanisms. The model provided a foundation for holistic design based on diffusion and mechanic components to enable better understanding of the debondment of thin elastic films bonded to a metallic substrate