Background IL-25 and IL-33 belong to distinct cytokine families, but experimental mouse studies suggest their immunologic functions in type 2 immunity are almost entirely overlapping. However, only ...polymorphisms in the IL-33 pathway ( IL1RL1 and IL33 ) have been significantly associated with asthma in large-cohort genome-wide association studies. Objective We sought to identify distinct pathways for IL-25 and IL-33 in the lung that might provide insight into their roles in asthma pathogenesis and potential for therapeutic intervention. Methods IL-25 receptor–deficient (Il17rb −/− ) , IL-33 receptor–deficient (ST2, Il1rl1−/− ), and double-deficient (Il17rb −/− Il1rl1 −/− ) mice were analyzed in models of allergic asthma. Microarrays, an ex vivo lung slice airway contraction model, and Il13+/eGFP mice were then used to identify specific effects of IL-25 and IL-33 administration. Results Comparison of IL-25 and IL-33 pathway–deficient mice demonstrates that IL-33 signaling plays a more important in vivo role in airways hyperreactivity than IL-25. Furthermore, methacholine-induced airway contraction ex vivo increases after treatment with IL-33 but not IL-25. This is dependent on expression of the IL-33 receptor and type 2 cytokines. Confocal studies with Il13+/eGFP mice show that IL-33 more potently induces expansion of IL-13–producing type 2 innate lymphoid cells, correlating with airway contraction. This predominance of IL-33 activity is enforced in vivo because IL-33 is more rapidly expressed and released in comparison with IL-25. Conclusion Our data demonstrate that IL-33 plays a critical role in the rapid induction of airway contraction by stimulating the prompt expansion of IL-13–producing type 2 innate lymphoid cells, whereas IL-25–induced responses are slower and less potent.
ABSTRACT
Chronic respiratory diseases are a major cause of morbidity and mortality. Asthma and chronic obstructive pulmonary disease (COPD) combined affect over 500 million people worldwide. While ...environmental factors are important in disease progression, asthma and COPD have long been known to be heritable with genetic components playing an important role in the risk of developing disease. Identification of genetic variation contributing to disease progression is important for a number of reasons including identification of risk alleles, understanding underlying disease mechanisms and development of novel therapies. Genome‐wide association studies (GWAS) have been successful in identifying many loci associated with lung function, COPD and asthma. In recent years, meta‐analyses and improved imputation have facilitated the growth of GWAS in terms of numbers of subjects and the number of single nucleotide polymorphisms (SNP) that can be interrogated. As a consequence, there has been a significant increase in the number of signals associated with asthma, COPD and lung function. SNP that have shown association with lung function reassuringly show a significant overlap with SNP associated with COPD giving a glimpse at pathways that may be involved in COPD mechanisms including genes in, for example, developmental pathways. In asthma, association signals are often in or near genes involved in both adaptive and innate immune response pathways, epithelial cell homeostasis and airway structural changes. The challenges now are translating these genetic signals into a new understanding of lung biology, understanding how variants impact health and disease and how they may provide opportunities for therapeutic intervention.
The subpolar North Atlantic is a key location for the Earth's climate system. In the Labrador Sea, intense winter air-sea heat exchange drives the formation of deep waters and the surface circulation ...of warm waters around the subpolar gyre. This process therefore has the ability to modulate the oceanic northward heat transport. Recent studies reveal decadal variability in the formation of Labrador Sea Water. Yet, crucially, its longer-term history and links with European climate remain limited. Here we present new decadally resolved marine proxy reconstructions, which suggest weakened Labrador Sea Water formation and gyre strength with similar timing to the centennial cold periods recorded in terrestrial climate archives and historical records over the last 3000 years. These new data support that subpolar North Atlantic circulation changes, likely forced by increased southward flow of Arctic waters, contributed to modulating the climate of Europe with important societal impacts as revealed in European history.
Outbreaks of emerging and zoonotic infections represent a substantial threat to human health and well-being. These outbreaks tend to be characterised by highly stochastic transmission dynamics with ...intense variation in transmission potential between cases. The negative binomial distribution is commonly used as a model for transmission in the early stages of an epidemic as it has a natural interpretation as the convolution of a Poisson contact process and a gamma-distributed infectivity. In this study we expand upon the negative binomial model by introducing a beta-Poisson mixture model in which infectious individuals make contacts at the points of a Poisson process and then transmit infection along these contacts with a beta-distributed probability. We show that the negative binomial distribution is a limit case of this model, as is the zero-inflated Poisson distribution obtained by combining a Poisson-distributed contact process with an additional failure probability. We assess the beta-Poisson model's applicability by fitting it to secondary case distributions (the distribution of the number of subsequent cases generated by a single case) estimated from outbreaks covering a range of pathogens and geographical settings. We find that while the beta-Poisson mixture can achieve a closer to fit to data than the negative binomial distribution, it is consistently outperformed by the negative binomial in terms of Akaike Information Criterion, making it a suboptimal choice on parsimonious grounds. The beta-Poisson performs similarly to the negative binomial model in its ability to capture features of the secondary case distribution such as overdispersion, prevalence of superspreaders, and the probability of a case generating zero subsequent cases. Despite this possible shortcoming, the beta-Poisson distribution may still be of interest in the context of intervention modelling since its structure allows for the simulation of measures which change contact structures while leaving individual-level infectivity unchanged, and vice-versa.
The asynchronous relationship between millennial-scale temperature changes over Greenland and Antarctica during the last glacial period has led to the notion of a bipolar seesaw which acts to ...redistribute heat depending on the state of meridional overturning circulation within the Atlantic Ocean. Here we present new records from the South Atlantic that show rapid changes during the last deglaciation that were instantaneous (within dating uncertainty) and of opposite sign to those observed in the North Atlantic. Our results demonstrate a direct link between the abrupt changes associated with variations in the Atlantic meridional overturning circulation and the more gradual adjustments characteristic of the Southern Ocean. These results emphasize the importance of the Southern Ocean for the development and transmission of millennial-scale climate variability and highlight its role in deglacial climate change and the associated rise in atmospheric carbon dioxide.
The Atlantic meridional overturning circulation (AMOC) is a system of ocean currents that has an essential role in Earth's climate, redistributing heat and influencing the carbon cycle
. The AMOC has ...been shown to be weakening in recent years
; this decline may reflect decadal-scale variability in convection in the Labrador Sea, but short observational datasets preclude a longer-term perspective on the modern state and variability of Labrador Sea convection and the AMOC
. Here we provide several lines of palaeo-oceanographic evidence that Labrador Sea deep convection and the AMOC have been anomalously weak over the past 150 years or so (since the end of the Little Ice Age, LIA, approximately AD 1850) compared with the preceding 1,500 years. Our palaeoclimate reconstructions indicate that the transition occurred either as a predominantly abrupt shift towards the end of the LIA, or as a more gradual, continued decline over the past 150 years; this ambiguity probably arises from non-AMOC influences on the various proxies or from the different sensitivities of these proxies to individual components of the AMOC. We suggest that enhanced freshwater fluxes from the Arctic and Nordic seas towards the end of the LIA-sourced from melting glaciers and thickened sea ice that developed earlier in the LIA-weakened Labrador Sea convection and the AMOC. The lack of a subsequent recovery may have resulted from hysteresis or from twentieth-century melting of the Greenland Ice Sheet
. Our results suggest that recent decadal variability in Labrador Sea convection and the AMOC has occurred during an atypical, weak background state. Future work should aim to constrain the roles of internal climate variability and early anthropogenic forcing in the AMOC weakening described here.
Antivirals, such as molnupiravir, and SARS-CoV-2 neutralising monoclonal antibodies (nMAbs), such as sotrovimab, reduced the risk of hospitalisation and death in clinical trials of high-risk ...non-hospitalised patients with Covid-19. However, the real-world benefits of these drugs are unclear.
To evaluate the characteristics and outcomes of high-risk patients referred for outpatient antiviral or nMAb treatment for symptomatic Covid-19.
The records of patients referred to a large UK Covid Medicines Delivery Unit (CMDU) over nine weeks (December 2021-February 2022) were reviewed. Data were collected on demographics, referral indications, vaccination, deprivation, treatment, complications, hospital admission, and mortality.
1820 patients were referred to the CMDU, with 604 (33.2%) suitable for further assessment. 169 patients received sotrovimab, 80 patients received molnupiravir, 70 patients declined treatment, and 266 were ineligible for treatment because of resolving symptoms. There were trends towards higher proportions of female and white patients, lower deprivation scores, and malignancy- or transplant-related indications in the groups receiving treatment compared with untreated patients. Covid-19-related hospitalisations occurred in 1.2% of the treated group and 3.0% of the untreated group indicating a potential treatment effect, however Covid-related hospitalisations were lower than reported in the original clinical trials (2.2% compared with 7-10%).
The referral pathways for outpatient treatment of Covid-19 are inefficient, and the UK system may not be serving all groups equitably. Hospitalisation with Covid-19 was rare regardless of treatment. Ongoing service evaluation is required to ensure efficient use of resources for the outpatient management of Covid-19.
Since the election of Narendra Modi’s Bharatiya Janata Party (BJP)-led government in May 2014, India’s approach to East Asia has changed, principally in response to pressures exerted by China. The ...Modi government inherited an East Asia strategy that combined a push for greater diplomatic and economic linkages with the region, an effort to improve Sino-Indian relations through a mix of engagement and deterrence, and a strengthening of security ties with the United States (US) and its allies. During its first three years in office, this paper argues that the Modi government stuck with this approach but attempted to pursue it more energetically as well as to assert India’s interests more clearly and forcefully in interactions with Beijing. After the Doklam standoff in 2017, however, India was pushed to assume a more clearly competitive stance, despite concerns about the reliability of Donald J. Trump’s new administration in Washington, China’s growing belligerence towards India and the rest of the region, and the impact of COVID-19. This stance entails both internal and external balancing, and a push for greater economic self-reliance that implies some decoupling from China, but which also has implications for India’s relations with other countries in East Asia.
Legionnaires' disease, a form of pneumonia which can be fatal, is transmitted via the inhalation of water droplets containing Legionella bacteria. These droplets can be dispersed in the atmosphere ...several kilometers from their source. The most common such sources are contaminated water within cooling towers and other air-conditioning systems but other sources such as ornamental fountains and spa pools have also caused outbreaks of the disease in the past. There is an obvious need to locate and eliminate any such sources as quickly as possible. Here a maximum likelihood model estimating the source of an outbreak from case location data has been developed and implemented. Unlike previous models, the average dose exposure sub-model is formulated using a atmospheric dispersion model. How the uncertainty in inferred parameters can be estimated is discussed. The model is applied to the 2012 Edinburgh Legionnaires' disease outbreak.
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