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BackgroundHarsh environments surrounding fetuses and children can induce cellular damage in the developing brain, increasing the risk of intellectual disability and other neurodevelopmental disorders such as schizophrenia. However, the mechanisms by which early damage leads to disease manifestation in later life remain largely unknown. Previously, we demonstrated that the activation of heat shock (HS) signaling can be utilized as a unique reporter to label the cells that undergo specific molecular/cellular changes upon exposure to environmental insults throughout the body. Since the activation of HS signaling is an acute and transient event, this approach was not intended for long-term tracing of affected cells after the activation has diminished. In the present study, we generated new reporter transgenic mouse lines as a novel tool to achieve systemic and long-term tracking of affected cells and their progeny.MethodsThe reporter transgenic mouse system was designed so that the activation of HS signaling through HS response element (HSE) drives flippase (FLPo)-flippase recognition target (FRT) recombination-mediated permanent expression of the red fluorescent protein (RFP), tdTomato. With a priority on consistent and efficient assessment of the reporter system, we focused on intraperitoneal (i.p.) injection models of high-dose, short prenatal exposure to alcohol (ethanol) and sodium arsenite (ethanol at 4.0 g/kg/day and sodium arsenite at 5.0 mg/kg/day, at embryonic day (E) 12 and 13). Long-term reporter expression was examined in the brain of reporter mice that were prenatally exposed to these insults. Electrophysiological properties were compared between RFP+and RFP−cortical neurons in animals prenatally exposed to arsenite.ResultsWe detected RFP+neurons and glia in the brains of postnatal mice that had been prenatally exposed to alcohol or sodium arsenite. In animals prenatally exposed to sodium arsenite, we also detected reduced excitability in RFP+cortical neurons.ConclusionThe reporter transgenic mice allowed us to trace the cells that once responded to prenatal environmental stress and the progeny derived from these cells long after the exposure in postnatal animals. Tracing of these cells indicates that the impact of prenatal exposure on neural progenitor cells can lead to functional abnormalities in their progeny cells in the postnatal brain. Further studies using more clinically relevant exposure models are warranted to explore this mechanism.

Background: Stroke-induced ischemia affects both cortex and underlying white matter. Dalfampridine extended release tablets (D-ER) enhance action potential conduction in demyelinated axons, which may positively affect post-stroke recovery. Objective: Based on promising preliminary data, we compared efficacy of D-ER administered at 7.5 mg or 10 mg with placebo on post-stroke ambulation. Primary study outcome (response) was a ≥20% increase on the 2-minute walk test (2 MinWT) at 12 weeks after first drug administration. Methods: This was a multicenter, randomized, placebo-controlled, 3-arm, parallel-group, safety and efficacy trial. After obtaining baseline measures of 2 MinWT, Walk-12, and Timed Up and Go, subjects entered a 2-week, single-blind placebo run-in period and were randomized 1:1:1 to receive 7.5 mg D-ER, 10 mg D-ER, or placebo, dosed twice-daily for 12 weeks. Follow-up evaluations occurred at weeks 14 and 16 when subjects were off study drug. Results: The study was terminated early with 377 of planned 540 patients enrolled, due to no treatment effect. At week 12, mean increase in distances walked in 2 minutes were similar among the 3 study groups (14.9±40.0 feet; 19.4±39.6 feet; and 20.4±38.3 feet for placebo, 7.5 mg D-ER, and 10 mg D-ER, respectively). The proportion of subjects who showed ≥20% improvement on 2 MinWT at week 12 was 13.5%, 14.0%, and 19.0%, for placebo, 7.5 mg D-ER, and 10 mg D-ER, respectively; these were nonsignificant changes from baseline for all groups. Conclusions: D-ER at either a 7.5-mg or 10-mg dose did not significantly increase performance on the 2 MinWT in stroke survivors with gait impairment, although this study was terminated early before full enrollment. (Clinical Trial # NCT02271217).

Marketization of higher education has emerged as a global trend in many countries, and in the UK, students are now paying among the highest tuition fees globally. Marketization is synonymous with p...

Importance: Occupational therapists are the primary clinicians tasked with management of the more affected upper extremity (UE) after stroke. However, there is a paucity of efficacious, easy-to-use, inexpensive interventions to increase poststroke UE function. Objective: To compare the effect of a multimodal mental practice (MMMP) regimen with a repetitive task practice (RTP)–only regimen on paretic UE functional limitation. Design: Secondary analysis of randomized controlled pilot study data. Setting: Outpatient clinical rehabilitation laboratory. Participants: Eighteen chronic stroke survivors exhibiting moderate, stable UE impairment. Intervention: Participants administered RTP only participated in 45-min, one-on-one occupational therapy sessions 3 times per week for 10 wk; participants administered MMMP completed time-matched UE training sessions consisting of action observation, RTP, and mental practice, delivered in 15-min increments. Outcomes and Measures: The Action Research Arm Test, the UE section of the Fugl-Meyer Scale, and the Hand subscale of the Stroke Impact Scale (Version 3.0) were administered 1 wk before and 1 wk after intervention. Results: The MMMP group exhibited significantly larger (p < .01) increases on all three outcome measures compared with the RTP group and surpassed minimal clinically important difference standards for all three UE outcome measures. Conclusions and Relevance: Because of the time-matched duration of MMMP and RTP, findings suggest that MMMP may be just as feasible as RTP to implement in clinical settings. Efforts to replicate results of this study in a large-scale trial are warranted. What This Article Adds: This study shows the efficacy of an easy-to-use protocol that significantly increased affected arm function even years after stroke.

Coccidioidomycosis is a fungal disease endemic to the southwestern United States, Mexico, and Central and South America. Prevalence rates are increasing steadily, and new endemic areas of Coccidioides are emerging. Standard treatment is often administered for months to decades, and intolerance to medications and treatment failures are common. No new treatments for coccidioidomycosis have been approved in the United States in nearly 40 years. On 5 August 2020, the US Food and Drug Administration convened experts in coccidioidomycosis from academia, industry, patient groups, and other government agencies to discuss the disease landscape and strategies to facilitate product development for treatment of coccidioidomycosis. This article summarizes the key topics concerning drug development for coccidioidomycosis presented by speakers and panelists during the workshop, such as unmet need, trial designs, endpoints, incentives, research and development support, and collaborations to facilitate antifungal drug development.

Purpose This paper aims to examine the development of research on ageing and demography and the implications for the study of tourism. It examines the demographic time bomb created by an ageing population and the implications of complex health conditions, such as dementia, for the visitor economy. Practical measures are identified with an example of a “call to action” for small to medium-sized tourism businesses. Design/methodology/approach This review is based on existing knowledge of ageing and draws upon a historical timeline that stretches from the nineteenth century to 2100. Findings The impact of complex health conditions such as dementia will pose major challenges for the visitor economy and will require behavioural change within existing business practices to accommodate the needs of people with dementia and their carers. Research limitations/implications Major changes in business practices and the development of more holistic views of accessibility will be needed to accommodate an ageing population in 2100. Some of the initial changes businesses can make are outlined in a “call to action” leaflet extract. Practical implications Businesses will need to focus more on customer care practices to ensure that they can accommodate the complex needs of people with dementia and their carers as they continue to pursue the tourism and leisure activities that they have grown accustomed to. Social implications Businesses will need to become more fully engaged with new agendas on accessibility, inclusivity and good business practice that raise significant ethical, financial and legal issues for the way they do business in the future. Originality/value The paper sets out an overarching grand societal challenge around ageing that is now confronting many countries worldwide. As part of that agenda, this paper raises the issue of hidden conditions such as dementia. The paper seeks to stimulate a wider debate for researchers and policymakers going forward, framed around the following questions which arise from the paper: How is dementia understood as a hidden condition in the visitor economy? To what extent is there awareness and action in the visitor economy sector? What can the visitor economy sector do to address issues of inclusivity and dementia?

Persons with mild stroke experience motor and cognitive impairments that negatively affect their health and quality of life. To address these deficits, it is essential for clinicians and researchers to precisely identify mild stroke survivors. Despite the fact that half of all strokes are categorized as mild, no standards exist on what constitutes a "mild" stroke. The purpose of this study is to summarize the current classification of mild stroke using a mapping review approach. Strategies to categorize "mild stroke" severity were explored in 188 papers indexed in the PubMed database. The results indicate that there was substantial variability in the procedures and scoring criteria used to determine mild stroke. To identify persons with mild stroke, researchers have largely applied assessment instruments developed to inform acute stroke care (eg, National Institutes of Health Stroke Scale, Modified Rankin Scale, Barthel Index). Unfortunately, these approaches demonstrate floor effects and fail to detect the long-term disabling impairments that often limit the outcomes of mild stroke survivors. Additional research is warranted to suggest an evidence-based mild stroke categorization strategy that enhances diagnosis, treatment, and referral decisions to the benefit of mild stroke survivors.

Ageing and dementia are major societal challenges affecting many countries, with around 46.8 million people worldwide estimated to be living with dementia. These estimates suggest that the worldwide population of people living with dementia will double every 20 years to reach 131.5 million by 2050. Recognition that dementia is a significant challenge for the travel and tourism sector is starting to develop. This paper contributes to this emerging agenda on ageing and dementia focusing on the accessibility needs of this group through a two-stage research study that demonstrates the practical needs and leadership challenges this poses for the tourism sector. Using the UK as an exemplar of dementia-readiness, the study examines Destination Management Organisation (DMO) website provision of advice for people with dementia and their carers. It then reports the findings of a survey DMO managers attitudes towards creating dementia-friendly destinations.

Domain-specific endpoints are assessments that correspond to the output of individual neural systems and are useful for capturing treatment effects on specific behaviors. By contrast, global endpoints combine several attributes into a single score and are useful for capturing broad treatment effects in a summary way. While global endpoints have become the de facto mechanism required to define benefit in stroke trials, they also have important limitations, some of which might be addressed by simultaneously measuring domain-specific endpoints. Substantial opportunity remains to identify quantifiable patient benefit that would otherwise not be captured by global endpoints. Potential advantages of incorporating domain-specific endpoints in acute stroke trials are discussed, such as increased granularity of measurement, improved understanding of how therapies affect the brain between acute treatment and day 90, and optimized therapeutic translation. Potential disadvantages are also considered, including time and cost of administering domain-specific endpoints, as well as statistical implications. Domain-specific endpoints and global endpoints are not mutually exclusive, and both capture clinical benefits to patients. Incorporating a broader set of outcome assessments in stroke trials, including both global and domain-specific endpoints, is warranted.

The application of marketing and advertising principles in tourism is largely undertaken by the private sector, seeking to communicate and sell their products and services to tourists. Destinations are often seen by the tourist as the outwardly facing element of a tourism service or product, being a place where their consumption occurs. Tourist destinations are a mix of tourism products, experiences and other intangible items promoted to consumers. The destination is often referred to as an amalgam of the six A’s: available packages, accessibility, attractions, amenities, activities and ancillary services and in the most developed destinations, a public/public–private or private sector organization may be responsible for the coordination, planning and promotion of the destination. A central feature of any destination marketing strategy will be the formulation of a destination product. In some cases, a destination may find that competitive forces have caused it to begin to decline.

This chapter discusses the role of the government and other agencies in the facilitation and development of tourism. It mainly focuses on the reasons for public sector involvement in tourism, the activities of the sector and the mechanisms through which public sector objectives in tourism are achieved. The public sector plays a very significant role in facilitating, controlling and/or providing the context for tourism development. The public sector operates at a number of different geographic levels in tourism, including: Supra-national organizations, International organizations, National governments, Government-funded agencies and Local authorities. Public sector interest in tourism stretches across all of these organizational and geographic dimensions. There are 32 local authorities across Scotland, and the role that they play in tourism is of crucial importance to ensuring that visitors have a satisfying and rewarding experience in the area. The traditional rationale for public sector activity in tourism is to generate economic benefits, although in the new millennium a much wider rationale exists.

This chapter considers the diverse range of intermediaries in the travel and tourism industry and the challenge of technology for the travel agency sector. It discusses issue associated with regulating the tour-operator sector together with the impact of large integrated operators and the effects of consolidation and concentration in the tourism sector. Retailing tourism products to consumers is a key element in the production, selling and distribution of tourism services, where different organizations link the supply to the source of demand. The European statistics agency Eurostat produces a report – Tourism Trips of Europeans in which it outlines the travel behaviour of over 500 million Europeans and which illustrates the scale and volume as well as activities they undertake. Tour operators have the ability to purchase services and elements of the tourism experience from other principals or suppliers at significant discounts by buying in bulk. New tourism is characterized by more experienced travellers who have a growing environmental concern.

This chapter discusses the importance of coastal areas for tourism, the nature of the coastal environment and the challenges for future management. The relationship between coastal areas and tourism is as old as tourism itself. Early tourists favoured seaside locations and made journeys to fashionable resorts to bathe in seawater to take advantage of its alleged curative powers. The meeting of land and sea creates biologically and geologically diverse environments as well as attractive and unique landscapes which may form the basis for tourism. Holderness is an area of coastline in East Yorkshire, stretching around 50 km from Flamborough Head to Spurn Point, with thriving tourist locations such as Bridlington, Hornsea and Withernsea. The significance of tourism has reinforced the importance of hard coastal engineering strategies to protect the amenity, including a 2 km concrete sea wall, designed to provide protection for the town, resort, attractions and the 7420 caravans.

This chapter presents an introduction to the study of tourism and the concepts with which students need to be acquainted, including the meaning of ‘tourism’ and what is meant by the terms ‘tourist’, ‘traveller’, ‘visitor’ and ‘excursionist’. It reviews some of the leading studies in the growing field of tourism studies to provide an overview of the evolution of tourism as an area of study, and issues related to tourism development in the wider environment of global change are recognized. Tourism is part of a global process of change and development which is no longer confined to the developed countries that traditionally provided the demand for world travel. Tourism is embraced as a subject for serious academic study, but it has not always been this way. The tourism is fraught by a number of problems which any student and researcher needs to be aware of. Some of the principal problems are: recognition, conceptualization, terminology, data sources, reductionism and rigour.

Throughout history people have travelled for many different reasons and so tourism is as old as human activity, although its development from antiquity highlights its critical link – that one had to have the means by which to consume tourism. Tourism is by no means a new phenomenon, with its historical origins in the ancient cultures of the Greek and Roman social elite. The historian’s analysis of tourism is dominated by two complementary and yet divergent themes: the development of tourism and its continuity as a phenomenon through time; this often runs parallel to and sometimes in opposition with the process of change, where tourism is constantly evolving and changing often due to innovation in transport or products. Pilgrimages in medieval Britain (brought to life for a modern audience by Chaucer’s Canterbury Tales) show that both the supply and demand for what might be loosely termed ‘tourism products and services’ were operating as far back as the fifteenth century.

The purpose of this chapter is to provide the reader with an appreciation of the many types of tourism supplier, providing key examples of organizations involved and the scale of operations together with some of the issues facing them, notably the management of tourism and strategy issues. It presents an introductory framework which introduces supply and different approaches used to explain its significance. M. T. Sinclair and M. Stabler indicate that supply issues can be classified and divided into three main categories: descriptions of the industry and its operation, management and marketing, the spatial development [the geographical development] and interactions which characterize the industry on a local, national and international scale and the effects which result from the development of the industry. The key aspects of tourism supply are: tour operators and intermediaries, attractions, accommodation, transportation and other tourist facilities and services. Within economic models of perfect competition, economists make a number of assumptions related to tourism issues.

According to D. Hall and S. J. Page, one of the fundamental questions tourism researchers consistently seek to answer is: why do tourists travel? And this simple proposition remains one of the principal challenges facing tourism research. As Cheng noted, the sharing economy has changed the nature of consumption as consumers may be both consumers and/or suppliers as opposed to the traditional model of organizations fulfilling the supply function. Understanding tourist motivation and decision-making is important for two main reasons: Planning considerations and Economic considerations. In basic terms, such a process involves a ‘purchase’, but in tourism the importance of experiencing a destination environment must be recognized where the tourist becomes a consumer of place or culture, and a purchaser of tourism products. The influential study that stimulated thinking in this area is B. Pine and J. Gilmore’s The Experience Economy, which suggested that this was the next stage in the evolution of a society from a service economy.