Nick Tyler

Effect of Gene Therapy on Visual Function in Leber's Congenital Amaurosis

Early-onset, severe retinal dystrophy caused by mutations in the gene encoding retinal pigment epithelium-specific 65-kD protein (RPE65) is associated with poor vision at birth and complete loss of vision in early adulthood. We administered to three young adult patients subretinal injections of recombinant adeno-associated virus vector 2/2 expressing RPE65 complementary DNA (cDNA) under the control of a human RPE65 promoter. There were no serious adverse events. There was no clinically significant change in visual acuity or in peripheral visual fields on Goldmann perimetry in any of the three patients. We detected no change in retinal responses on electroretinography. One patient had significant improvement in visual function on microperimetry and on dark-adapted perimetry. This patient also showed improvement in a subjective test of visual mobility. These findings provide support for further clinical studies of this experimental approach in other patients with mutant RPE65. (ClinicalTrials.gov number, NCT00643747 [ClinicalTrials.gov].).

Long-term effect of gene therapy on Leber's congenital amaurosis.

BACKGROUND Mutations in RPE65 cause Lebers congenital amaurosis, a progressive retinal degenerative disease that severely impairs sight in children. Gene therapy can result in modest improvements in night vision, but knowledge of its efficacy in humans is limited. METHODS We performed a phase 1-2 open-label trial involving 12 participants to evaluate the safety and efficacy of gene therapy with a recombinant adeno-associated virus 2/2 (rAAV2/2) vector carrying the RPE65 complementary DNA, and measured visual function over the course of 3 years. Four participants were administered a lower dose of the vector, and 8 were administered a higher dose. In a parallel study in dogs, we investigated the relationship among vector dose, visual function, and electroretinography (ERG) findings. RESULTS Improvements in retinal sensitivity were evident, to varying extents, in six participants for up to 3 years, peaking at 6 to 12 months after treatment and then declining. No associated improvement in retinal function was detected by means of ERG. Three participants had intraocular inflammation, and two had clinically significant deterioration of visual acuity. The reduction in central retinal thickness varied among participants. In dogs, RPE65 gene therapy with the same vector at lower doses improved vision-guided behavior, but only higher doses resulted in improvements in retinal function that were detectable with the use of ERG. CONCLUSIONS Gene therapy with rAAV2/2 RPE65 vector improved retinal sensitivity, albeit modestly and temporarily. Comparison with the results obtained in the dog model indicates that there is a species difference in the amount of RPE65 required to drive the visual cycle and that the demand for RPE65 in affected persons was not met to the extent required for a durable, robust effect. (Funded by the National Institute for Health Research and others; ClinicalTrials.gov number, NCT00643747.).

Predicting the walking speed of pedestrians on stairs

Abstract In this paper, we propose a framework in which the behaviour of a pedestrian is predicted based on the characteristics of both the pedestrian and the facility the pedestrian uses. As an example of its application, we develop a model to predict the walking speed of a pedestrian on stairs. We examine the physiology and biomechanics of walking on stairs, and then develop a model that predicts walking speed based on the weight and leg extensor power of the pedestrian, and the gradient of the stairs. The model was calibrated by experiment and validated by observations. The proposed framework establishes the importance of bridging the two types of characteristics: those of a pedestrian and those of the facility the pedestrian uses. Also, the developed walking speed model is useful for simulating how the design of stairs affects pedestrian circulation.

Effect of passenger-bus-traffic interactions on bus stop operations

ABSTRACT Buses are the unrecognized champions of public transport in modern cities around the world. However, the bus system is usually bedevilled by poor design that has resulted from poor understanding of how a bus system actually works. This article examines the impacts of the interactions between buses, passengers and traffic on delays and capacity at bus stops. First, issues like the stages of bus stop operations, causes of delays, and the interaction between bus frequency and stop delays are analysed. This suggests the necessity of microscopic simulation to study stops operations. An illustration of the sort of understanding that can be achieved by means of simulation experiments regarding arrival patterns of buses and passengers, boarding times, difficulties for leaving the stop and vehicle capacity is shown. Results indicate that it is important not to underestimate the real situation found at bus stops, as designing for ideal conditions will be insufficient if the reality is different. Application of these results shows that dramatic improvements can be made to the performance of the bus system as a result of a better understanding of its operation leading to simple changes in the design of infrastructure.

Influence of Platform Height, Door Width, and Fare Collection on Bus Dwell Time: Laboratory Evidence for Santiago de Chile

Dwell time is the time that a public transport vehicle remains stopped while transferring passengers. Dwell time depends on the number of boarding and alighting passengers plus other characteristics, such as platform height, door width, fare collection method, internal layout of the vehicle, and occupancy of the vehicle. Traditionally, dwell time has been described as a linear function of the number of passengers boarding and alighting. In this paper, results are presented of dwell time parameters obtained from real-scale experiments made at the Pedestrian Accessibility and Movement Environment Laboratory, University College London. Three variables were controlled: platform height (0, 150, and 300 mm), door width (800 and 1,600 mm), and fare collection method (prepayment outside the vehicle and payment with an electronic card at the entrance of the vehicle). For each value of the variables mentioned above, between 15 and 20 runs were recorded on videotape with four cameras and different views. In total, 300 records of boarding and alighting processes were obtained. Some results indicate that door width has more influence than platform height. For example, it was found that a wider door can reduce the average alighting time by almost 40%, regardless of platform height, and can reduce the average boarding time by 20%. However, for the same door width, a lower platform reduces the average alighting time by only 1% to 9%. More results and analysis are reported in this paper.

Capabilities and Radicalism: Engineering Accessibility in the 21st century

Abstract Engineering bridges the gap between, on the one hand, that mix of philosophy and politics that we call policy and, on the other, the physical implementation of the means to put policy into practice. Starting with a brief outline of the nature of accessibility, why it is important and how in some cases a person might be disabled by a lack of accessibility, this article – based on the authors Inaugural Lecture given at University College London in February 2005 – turns to consider how a persons needs challenge their capabilities (i.e. what they can do) and considers a radical approach to understanding peoples capabilities in the implementation process. Next, the formation of policy intentions in order to permit, encourage and implement the engineering of appropriate solutions is discussed and conclusions drawn about how this affects work in the transport domain. Perhaps we need to look at the world in a different way before we can make it a better place.

Microscopic simulation of pedestrians in accessibility evaluation

Evaluation of accessibility is of increasing importance to the design of the public realm – including both the built and moving environments and particularly the interface between them. This is of particular relevance to people who are living on the ‘margins of accessibility’, for example, elderly or disabled people. This paper discusses the interactions between a person, the environment and the activities they wish to pursue, and proposes a model that incorporates the concept of ‘capabilities’. The paper then describes how the systematization of these concepts could be tested by incorporating them in a microscopic simulation model of pedestrian activity. A worked example is used to demonstrate how the conceptual approach could yield consistent results under these circumstances. The paper concludes that the conceptual model provides a good basis for the evaluation of accessibility and that the microscopic simulation model incorporating these characteristics would be a useful way of testing pedestrian–environment interactions.

A micro-level approach to measuring the accessibility of footways for wheelchair users using the Capability Model

There are a growing number of people with mobility impairments who use wheelchairs to get around the built environment. This number is likely to increase in the future due to an increasingly ageing population combined with advances in medical technology which help to overcome some of the barriers to access that have hitherto prevented people from leading as full a life as they would have liked. Footways form an integral part of the transport network and therefore it is essential they can be accessed by all people. Currently, however, there is no well-defined method to measure the accessibility of footways for wheelchair users. One aspect of a footway is the crossfall – the transverse gradient designed to facilitate surface water drainage – which adds to a wheelchair users difficulty when progressing along the footway. This paper first reviews previous research on measuring the effect of crossfalls on wheelchair accessibility, highlighting the need for a new approach. It then proposes the Capability Model as a starting point for this new approach. The model is updated and populated with an initial capability set chosen to measure footway accessibility across footways with three different crossfall gradients (0%, 2.5% and 4%). The focus is on the physical work provided by the user to the wheelchair in order to keep it travelling in a straight line. It is shown that in order to travel in a straight line when a footway is flat only a single principal capability is required: the ability to produce sufficient force over the required distance to overcome the inertia and rolling resistance and keep the wheelchair moving at the chosen velocity. When a positive crossfall gradient is introduced a second capability is required: the ability to apply different levels of force to the left and right sides of the wheelchair. It is concluded that it is possible to measure these two capabilities and these provide a good insight into the effect of crossfalls on footway accessibility for wheelchair users.

Analysis of recent trends in bus and coach safety in Britain

Abstract We examine in detail trends from 1966 to 1990 and the fitting of statistical models to assess whether significant changes have taken place in casualty rates since local bus deregulation in 1986. The major source of data is the ‘Stats 19’ collated from police reports by the Department of Transport. The evidence indicates that no significant change in casualty rates for bus and coach occupants (defined as those killed or seriously injured) has occurred since local bus deregulation, although the previous trend of reduction in fatality rates has not been maintained. International comparisons have been made between Britain and a sample of other West European countries. Britain appears to have a higher occupant fatality rate. However, other countries′ data do not always include casualties to bus and coach occupants other than those in which vehicular collisions occur. Better comparative data is available for accidents involving buses and coaches with other road users, notably for Britain and Germany. These suggest that such accidents tend to reflect the national pattern of road casualty rates — for example, Germany has a higher level of collisions between buses and coaches, and other road vehicles, while Britain has a relatively high incidence of casualties involving pedestrians. Differences in accident rates between Britain and other European countries and the extent to which they reflect real differences, as distinct from those due to differences in recording of data, are evaluated, along with policy implications.

Bidirectional collision-avoidance behaviour of pedestrians on stairs

Microscopic observations were performed in order to examine bidirectional collision-avoidance behaviour of pedestrians on stairs. Results suggest that characteristics of collision avoidance on stairs are different from those in a busy flat space. On stairs, pedestrians tended to detour at the beginning of a flight to avoid collision with another pedestrian already on the stairs. The authors call this lane collision avoidance. The side preference of pedestrians on stairs and the handedness of two-lane flows were explored. On dextral staircases, most pedestrians chose the right-hand side for collision avoidance, whereas in sinistral staircases, pedestrians did not necessarily choose the right-hand side. Investigation of the relative position of one pedestrian to another leading pedestrian showed that following pedestrians tended to shift laterally in relation to a leading pedestrian when the ‘front-back’ interpersonal distance between them was small. The obtained knowledge is useful for the development of pedestrian simulations.