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"Bush, Andrew"
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Evaluating Severe Therapy-Resistant Asthma in Children: Diagnostic and Therapeutic Strategies
Introduction: Worldwide, asthma is the most common non-communicable respiratory disease and causes considerable morbidity and mortality. Most people with asthma can be treated effectively with low-dose medications if these are taken correctly and regularly. Around 10% of people with asthma have an uncontrolled form of the disease or can only achieve control with high-dose medications, incurring disproportionately high health care costs. Areas Covered: PubMed and personal archives were searched for relevant articles on the definition, management and pharmacotherapy of severe asthma. The WHO classification of severe asthma and the treatment levels encompassed in the definition are discussed. Most children and young people referred for consideration of ‘beyond-guidelines therapy’ can in fact be managed on standard treatment after a multi-disciplinary team assessment focusing on ensuring correct basic management, and these steps are described in detail. Options for those with true therapy-resistant asthma are described. These include monoclonal antibodies, most of which target type 2 inflammation. Expert Opinion: Getting the basics right is still the most important aspect of asthma care. For those with severe, therapy-resistant asthma, an increasing number of life-transforming monoclonals have been developed, but there is still little understanding of, and a paucity of treatment options for, non-eosinophilic asthma.
Journal Article
current refugial rainforests of Sundaland are unrepresentative of their biogeographic past and highly vulnerable to disturbance
Understanding the historical dynamics of forest communities is a critical element for accurate prediction of their response to future change. Here, we examine evergreen rainforest distribution in the Sunda Shelf region at the last glacial maximum (LGM), using a spatially explicit model incorporating geographic, paleoclimatic, and geologic evidence. Results indicate that at the LGM, Sundaland rainforests covered a substantially larger area than currently present. Extrapolation of the model over the past million years demonstrates that the current \"island archipelago\" setting in Sundaland is extremely unusual given the majority of its history and the dramatic biogeographic transitions caused by global deglaciation were rapid and brief. Compared with dominant glacial conditions, lowland forests were probably reduced from approximately 1.3 to 0.8 x 10⁶ km² while upland forests were probably reduced by half, from approximately 2.0 to 1.0 x 10⁵ km². Coastal mangrove and swamp forests experienced the most dramatic change during deglaciations, going through a complete and major biogeographic relocation. The Sundaland forest dynamics of fragmentation and contraction and subsequent expansion, driven by glacial cycles, occur in the opposite phase as those in the northern hemisphere and equatorial Africa, indicating that Sundaland evergreen rainforest communities are currently in a refugial stage. Widespread human-mediated reduction and conversion of these forests in their refugial stage, when most species are passing through significant population bottlenecks, strongly emphasizes the urgency of conservation and management efforts. Further research into the natural process of fragmentation and contraction during deglaciation is necessary to understand the long-term effect of human activity on forest species.
Journal Article
Risk factors and early origins of chronic obstructive pulmonary disease
Chronic obstructive pulmonary disease is mainly a smoking-related disorder and affects millions of people worldwide, with a large effect on individual patients and society as a whole. Although the disease becomes clinically apparent around the age of 40–50 years, its origins can begin very early in life. Different risk factors in very early life—ie, in utero and during early childhood—drive the development of clinically apparent chronic obstructive pulmonary disease in later life. In discussions of which risk factors drive chronic obstructive pulmonary disease, it is important to realise that the disease is very heterogeneous and at present is largely diagnosed by lung function only. In this Review, we will discuss the evidence for risk factors for the various phenotypes of chronic obstructive pulmonary disease during different stages of life.
Journal Article
Kids, Difficult Asthma and Fungus
Fungi have many potential roles in paediatric asthma, predominantly by being a source of allergens (severe asthma with fungal sensitization, SAFS), and also directly damaging the epithelial barrier and underlying tissue by releasing proteolytic enzymes (fungal bronchitis). The umbrella term ‘fungal asthma’ is proposed for these manifestations. Allergic bronchopulmonary aspergillosis (ABPA) is not a feature of childhood asthma, for unclear reasons. Diagnostic criteria for SAFS are based on sensitivity to fungal allergen(s) demonstrated either by skin prick test or specific IgE. In children, there are no exclusion criteria on total IgE levels or IgG precipitins because of the rarity of ABPA. Diagnostic criteria for fungal bronchitis are much less well established. Data in adults and children suggest SAFS is associated with worse asthma control and greater susceptibility to asthma attacks than non-sensitized patients. The data on whether anti-fungal therapy is beneficial are conflicting. The pathophysiology of SAFS is unclear, but the epithelial alarmin interleukin-33 is implicated. However, whether individual fungi have different pathobiologies is unclear. There are many unanswered questions needing further research, including how fungi interact with other allergens, bacteria, and viruses, and what optimal therapy should be, including whether anti-neutrophilic strategies, such as macrolides, should be used. Considerable further research is needed to unravel the complex roles of different fungi in severe asthma.
Journal Article
Variability of Arctic Sea Ice Based on Quantile Regression and the Teleconnection with Large-Scale Climate Patterns
Under global warming, Arctic sea ice has declined significantly in recent decades, with years of extremely low sea ice occurring more frequently. Recent studies suggest that teleconnections with large-scale climate patterns could induce the observed extreme sea ice loss. In this study, a probabilistic analysis of Arctic sea ice was conducted using quantile regression analysis with covariates, including time and climate indices. From temporal trends at quantile levels from 0.01 to 0.99, Arctic sea ice shows statistically significant decreases over all quantile levels, although of different magnitudes at different quantiles. At the representative extreme quantile levels of the 5th and 95th percentiles, the Arctic Oscillation (AO), the North Atlantic Oscillation (NAO), and the Pacific–North American pattern (PNA) have more significant influence on Arctic sea ice than El Niño–Southern Oscillation (ENSO), the Pacific decadal oscillation (PDO), and the Atlantic multidecadal oscillation (AMO). Positive AO as well as positive NAO contribute to low winter sea ice, and a positive PNA contributes to low summer Arctic sea ice. If, in addition to these conditions, there is concurrently positive AMO and PDO, the sea ice decrease is amplified. Teleconnections between Arctic sea ice and the climate patterns were demonstrated through a composite analysis of the climate variables. The anomalously strong anticyclonic circulation during the years of positive AO, NAO, and PNA promotes more sea ice export through Fram Strait, resulting in excessive sea ice loss. The probabilistic analyses of the teleconnections between the Arctic sea ice and climate patterns confirm the crucial role that the climate patterns and their combinations play in overall sea ice reduction, but particularly for the low and high quantiles of sea ice concentration.
Journal Article
Significance of Cloud Microphysics and Cumulus Parameterization Schemes in Simulating an Extreme Flood-Producing Precipitation Event in the Central Himalaya
Between 11 and 14 August 2017, the southern belt of the central Himalaya experienced extreme precipitation, with some stations recording more than 500 mm of accumulated rainfall, which resulted in widespread, devastating flooding. Precipitation was concentrated over the sub-Himalaya, and the established forecasting systems failed to predict the event. In this study, we evaluate the performance of six cloud microphysics schemes in the Weather Research and Forecasting (WRF) model forced with the advanced ERA5 dataset. We also examine the importance of the cumulus scheme in WRF at 3 km horizontal grid spacing in highly convective events like this. Six WRF simulations, each with one of the six different microphysics schemes with the Kain–Fritsch cumulus scheme turned off, all fail to reproduce the spatial variability of accumulated precipitation during this devastating flood-producing precipitation event. In contrast, the simulations exhibit greatly improved performance with the cumulus scheme turned on. In this study, the cumulus scheme helps to initiate convection, after which grid-scale precipitation becomes dominant. Amongst the different simulations, the WRF simulation using the Morrison microphysics scheme with the cumulus turned on displayed the best performance, with the smallest normalized root mean square error (NRMSE) of 0.25 and percentage bias (PBIAS) of −6.99%. The analysis of cloud microphysics using the two best-performing simulations reveals that the event is strongly convective, and it is essential to keep the cumulus scheme on for such convective events and capture all the precipitation characteristics showing that in regions of extreme topography, the cumulus scheme is still necessary even down to the grid spacing of at least 3 km.
Journal Article
Ecological selectivity of the emerging mass extinction in the oceans
To better predict the ecological and evolutionary effects of the emerging biodiversity crisis in the modern oceans, we compared the association between extinction threat and ecological traits in modern marine animals to associations observed during past extinction events using a database of 2497 marine vertebrate and mollusc genera. We find that extinction threat in the modern oceans is strongly associated with large body size, whereas past extinction events were either nonselective or preferentially removed smaller-bodied taxa. Pelagic animals were victimized more than benthic animals during previous mass extinctions but are not preferentially threatened in the modern ocean. The differential importance of large-bodied animals to ecosystem function portends greater future ecological disruption than that caused by similar levels of taxonomic loss in past mass extinction events.
Journal Article
Climate–Glacier Dynamics and Topographic Forcing in the Karakoram Himalaya: Concepts, Issues and Research Directions
Understanding climate-glacier dynamics in High Mountain Asia is of critical importance to address issues including water resources, sea-level rise, mountain geodynamics, natural hazards and ecosystem sustainability. The Karakoram Himalaya is arguably the least understood region, given its extreme topography, climate-system coupling, and advancing and surge-type glaciers that exhibit complex flow patterns. Glacier fluctuations in the Karakoram Himalaya are highly variable in space and time because of numerous controlling factors, including the westerlies, the Indian summer monsoon, various teleconnections, topographic effects, glacier debris-cover characteristics, glacier dynamics, and geological conditions. The influence of the integrative coupling of forcing factors, however, has not been adequately assessed for characterizing the glaciers in the Karakoram Himalaya. Given the scarcity of in-situ data and the difficulty of conducting fieldwork on these glaciers, recent research has focused on utilizing remote sensing, geospatial technologies, and scientific modeling to obtain baseline information about the state of glaciers in the region. This review summarizes our current knowledge of glaciers, climate-glacier interaction, and topographic forcing in the Karakoram Himalaya, and demonstrates the complexities in mountain geodynamics that influence climate-glacier dynamics. Innovative analysis is also presented in support of our review and discussion.
Journal Article
Management of severe asthma in children
Children who are referred to specialist care with asthma that does not respond to treatment (problematic severe asthma) are a heterogeneous group, with substantial morbidity. The evidence base for management is sparse, and is mostly based on data from studies in children with mild and moderate asthma and on extrapolation of data from studies in adults with severe asthma. In many children with severe asthma, the diagnosis is wrong or adherence to treatment is poor. The first step is a detailed diagnostic assessment to exclude an alternative diagnosis (“not asthma at all”), followed by a multidisciplinary approach to exclude comorbidities (“asthma plus”) and to assess whether the child has difficult asthma (improves when the basic management needs, such as adherence and inhaler technique, are corrected) or true, therapy-resistant asthma (still symptomatic even when the basic management needs are resolved). In particular, environmental causes of secondary steroid resistance should be identified. An individualised treatment plan should be devised depending on the clinical and pathophysiological characterisation. Licensed therapeutic approaches include high-dose inhaled steroids, the Symbicort maintenance and reliever (SMART) regimen (with budesonide and formoterol fumarate), and anti-IgE therapy. Unlicensed treatments include methotrexate, azathioprine, ciclosporin, and subcutaneous terbutaline infusions. Paediatric data are needed on cytokine-specific monoclonal antibody therapies and bronchial thermoplasty. However, despite the interest in innovative approaches, getting the basics right in children with apparently severe asthma will remain the foundation of management for the foreseeable future.
Journal Article