Omalizumab for the Treatment of Multiple Food Allergies.

BACKGROUND: Food allergies are common and are associated with substantial morbidity; the only approved treatment is oral immunotherapy for peanut allergy. METHODS: In this trial, we assessed whether omalizumab, a monoclonal anti-IgE antibody, would be effective and safe as monotherapy in patients with multiple food allergies. Persons 1 to 55 years of age who were allergic to peanuts and at least two other trial-specified foods (cashew, milk, egg, walnut, wheat, and hazelnut) were screened. Inclusion required a reaction to a food challenge of 100 mg or less of peanut protein and 300 mg or less of the two other foods. Participants were randomly assigned, in a 2:1 ratio, to receive omalizumab or placebo administered subcutaneously (with the dose based on weight and IgE levels) every 2 to 4 weeks for 16 to 20 weeks, after which the challenges were repeated. The primary end point was ingestion of peanut protein in a single dose of 600 mg or more without dose-limiting symptoms. The three key secondary end points were the consumption of cashew, of milk, and of egg in single doses of at least 1000 mg each without dose-limiting symptoms. The first 60 participants (59 of whom were children or adolescents) who completed this first stage were enrolled in a 24-week open-label extension. RESULTS: Of the 462 persons who were screened, 180 underwent randomization. The analysis population consisted of the 177 children and adolescents (1 to 17 years of age). A total of 79 of the 118 participants (67%) receiving omalizumab met the primary end-point criteria, as compared with 4 of the 59 participants (7%) receiving placebo (P<0.001). Results for the key secondary end points were consistent with those of the primary end point (cashew, 41% vs. 3%; milk, 66% vs. 10%; egg, 67% vs. 0%; P<0.001 for all comparisons). Safety end points did not differ between the groups, aside from more injection-site reactions in the omalizumab group. CONCLUSIONS: In persons as young as 1 year of age with multiple food allergies, omalizumab treatment for 16 weeks was superior to placebo in increasing the reaction threshold for peanut and other common food allergens. (Funded by the National Institute of Allergy and Infectious Diseases and others; ClinicalTrials.gov number, NCT03881696.).

Disaster aid? Mapping historical responses to volcanic eruptions from 1800-2000 in the English-speaking Eastern Caribbean: their role in creating vulnerabilities.

This paper uses volcanic eruptions on the Caribbean islands of Montserrat and Saint Vincent to explore the role that British colonial rule in the past and near past (1800-2000) has played in response to and recovery from hazardous events, and in turn, the influence that the nature of the hazards has on these responses. It shows that systemic vulnerabilities to natural hazards have been created by inadequate aid responses and longer-term chronic problems and demonstrates that hazard impacts are compounded by them. Vulnerabilities could be reduced by analysing integrated hazard impacts to generate mitigative measures across hazards and identify actions that more closely match timescales of political decision-making. Incorporating local knowledge and experience into risk analysis will enable the most effective use of aid resources, ahead of emergencies. Finally, coupling aid for long-term development with emergency response would improve outcomes and adaptation to longer-term vulnerabilities in immediate rebuilding and short-term recovery.

IgE-mediated regulation of IL-10 and type I IFN enhances rhinovirus-induced Th2 differentiation by primary human monocytes.

Rhinovirus (RV) infections are linked to the development and exacerbation of allergic diseases including allergic asthma. IgE, another contributor to atopic disease pathogenesis, has been shown to regulate DC antiviral functions and influence T cell priming by monocytes. We previously demonstrated that IgE-mediated stimulation of monocytes alters multiple cellular functions including cytokine secretion, phagocytosis, and influenza-induced Th1 development. In this study, we investigate the effects of IgE-mediated stimulation on monocyte-driven, RV-induced T cell development utilizing primary human monocyte-T cell co-cultures. We demonstrate that IgE crosslinking of RV-exposed monocytes enhances monocyte-driven Th2 differentiation. This increase in RV-induced Th2 development was regulated by IgE-mediated inhibition of virus-induced type I IFN and induction of IL-10. These findings suggest an additional mechanism by which two clinically significant risk factors for allergic disease exacerbations-IgE-mediated stimulation and rhinovirus infection-may synergistically promote Th2 differentiation and allergic inflammation.

Meteorological Controls on Local and Regional Volcanic Ash Dispersal.

Volcanic ash has the capacity to impact human health, livestock, crops and infrastructure, including international air traffic. For recent major eruptions, information on the volcanic ash plume has been combined with relatively coarse-resolution meteorological model output to provide simulations of regional ash dispersal, with reasonable success on the scale of hundreds of kilometres. However, to predict and mitigate these impacts locally, significant improvements in modelling capability are required. Here, we present results from a dynamic meteorological-ash-dispersion model configured with sufficient resolution to represent local topographic and convectively-forced flows. We focus on an archetypal volcanic setting, Soufrière, St Vincent, and use the exceptional historical records of the 1902 and 1979 eruptions to challenge our simulations. We find that the evolution and characteristics of ash deposition on St Vincent and nearby islands can be accurately simulated when the wind shear associated with the trade wind inversion and topographically-forced flows are represented. The wind shear plays a primary role and topographic flows a secondary role on ash distribution on local to regional scales. We propose a new explanation for the downwind ash deposition maxima, commonly observed in volcanic eruptions, as resulting from the detailed forcing of mesoscale meteorology on the ash plume.

Volcanogenic Pseudo-Fossils from the ∼3.48 Ga Dresser Formation, Pilbara, Western Australia.

The ∼3.48 billion-year-old Dresser Formation, Pilbara Craton, Western Australia, is a key geological unit for the study of Earth's earliest life and the habitats it occupied. Here, we describe a new suite of spheroidal to lenticular microstructures that morphologically resemble some previously reported Archean microfossils. Correlative microscopy shows that these objects have a size distribution, wall ultrastructure, and chemistry that are incompatible with a microfossil origin and instead are interpreted as pyritized and silicified fragments of vesicular volcanic glass. Organic kerogenous material is associated with much of the altered volcanic glass; variable quantities of organic carbon line or fill the insides of some individual vesicles, while relatively large, tufted organic-rich laminae envelop multiple vesicles. The microstructures reported herein constitute a new type of abiogenic artifact (pseudo-fossil) that must be considered when evaluating potential signs of early life on Earth or elsewhere. In the sample studied here, where hundreds of these microstructures are present, the combined evidence permits a relatively straightforward interpretation as vesicular volcanic glass. However, reworked, isolated, and silicified microstructures of this type may prove particularly problematic in early or extraterrestrial life studies since they adsorb carbon onto their surfaces and are readily pyritized, mimicking a common preservation mechanism for bona fide microfossils. In those cases, nanoscale analysis of wall ultrastructure would be required to firmly exclude a biological origin. Key Words: Microfossils-Pseudo-fossils-Volcanic vesicles-Archean life-Pilbara Craton-Dresser Formation. Astrobiology 18, 539-555.

A pulse of mid-Pleistocene rift volcanism in Ethiopia at the dawn of modern humans.

The Ethiopian Rift Valley hosts the longest record of human co-existence with volcanoes on Earth, however, current understanding of the magnitude and timing of large explosive eruptions in this region is poor. Detailed records of volcanism are essential for interpreting the palaeoenvironments occupied by our hominin ancestors; and also for evaluating the volcanic hazards posed to the 10 million people currently living within this active rift zone. Here we use new geochronological evidence to suggest that a 200 km-long segment of rift experienced a major pulse of explosive volcanic activity between 320 and 170 ka. During this period, at least four distinct volcanic centres underwent large-volume (>10 km3) caldera-forming eruptions, and eruptive fluxes were elevated five times above the average eruption rate for the past 700 ka. We propose that such pulses of episodic silicic volcanism would have drastically remodelled landscapes and ecosystems occupied by early hominin populations.

IgE cross-linking critically impairs human monocyte function by blocking phagocytosis.

BACKGROUND: IgE cross-linking triggers many cellular processes that drive allergic disease. While the role of IgE in mediating allergic responses is best described on basophils and mast cells, expression of the high-affinity IgE receptor on other innate immune cells, including monocytes, suggests that it may affect the function of these cells in allergic environments. OBJECTIVE: To determine the effect of IgE cross-linking on the function of human monocytes. METHODS: Monocytes purified from healthy donor blood samples were cultured for 4 to 96 hours with media alone, a cross-linking anti-IgE antibody or control IgG. Surface CD14 and CD64 expression and secreted cytokine concentrations were determined. Monocyte function was determined by assessing (1) phagocytosis of Escherichia coli or apoptotic HEp2 cells and (2) killing of intracellular E coli. Select experiments were performed on monocytes obtained from participants with elevated versus normal serum IgE concentrations. RESULTS: IgE cross-linking on monocytes increased CD14 expression and induced secretion of TNF-α, IL-6, and autoregulatory IL-10. These effects were greatest in individuals with elevated serum IgE concentrations. In contrast, IgE cross-linking reduced CD64 expression and significantly impaired phagocytic function without disrupting the capacity of monocytes to kill bacteria. CONCLUSIONS: IgE cross-linking drives monocyte proinflammatory processes and autoregulatory IL-10 in a serum IgE-dependent manner. In contrast, monocyte phagocytic function is critically impaired by IgE cross-linking. Our findings suggest that IgE cross-linking on monocytes may contribute to allergic disease by both enhancing detrimental inflammatory responses and concomitantly crippling phagocytosis, a primary mechanism used by these cells to resolve inflammation.

Constraining timescales of focused magmatic accretion and extension in the Afar crust using lava geochronology.

As continental rift zones mature the tectonic and volcanic processes associated with crustal extension become confined to narrow magmatic rift zones, reminiscent of oceanic spreading ridges. The formation of these rift zones and the development of ocean-ridge type topography is a significant milestone in rift evolution as it signifies the localization of crustal extension and rift-related volcanism. Here we show that lavas, which erupted since ~200 ka along part of the on-land Red Sea rift system in Afar, Ethiopia, have a consistent age-progression from the rift axis outwards, indicating that axial dyke intrusion has been the primary mechanism of segment growth and that focused magmatic accretion and extension in the crust have remained stable here over this period. Our results suggest that as this rift segment has formed, in thinned and intruded continental crust, the time-averaged surface opening rate has closely approximated the total extension rate between Africa and Arabia.

A global health partnership's use of time-limited support to catalyze health practice change: the case of GAVI's Injection Safety Support.

This paper presents the findings of a study to assess the effectiveness and sustainability of a GAVI (Global Alliance of Vaccines and Immunization) sponsored, time-limited Injection Safety (INS) support. The support came in two forms: 1) in-kind, in the form of AD syringes and safety boxes, and 2) in cash, for those countries that already had a secure, multi-year source of AD syringes and safety boxes, but proposed to use INS support to strengthen their injection safety activities. In total, GAVI gave INS support for a three-year period to 58 countries: 46 with commodities and 12 with cash support. To identify variables that might be associated with financial sustainability, frequencies and cross-tabulations were run against various programmatic and socio-economic variables in the 58 countries. All but two of the 46 commodity-recipient countries were able to replace and sustain the use of AD syringes and safety boxes after the end of their GAVI INS support despite the fact that standard disposable syringes are less costly than ADs (10-15 percent differential). In addition, all 12 cash-recipient countries continued to use AD syringes and safety boxes in their immunization programs in the years following GAVI INS assistance. At the same time, countries were often not prepared for the increased waste management requirements associated with the use of the syringes, suggesting the importance of anticipating challenges with the introduction of new technologies. The sustained use of AD syringes in countries receiving injection safety support from GAVI, in a majority of cases through government financing, following the completion of three years of time-limited support, represents an early indication of how GHPs can contribute to improved health outcomes in immunization safety in the world's poorest countries in a sustainable way.

Middle Paleolithic assemblages from the Indian subcontinent before and after the Toba super-eruption.

The Youngest Toba Tuff (YTT) eruption, which occurred in Indonesia 74,000 years ago, is one of Earth's largest known volcanic events. The effect of the YTT eruption on existing populations of humans, and accordingly on the course of human evolution, is debated. Here we associate the YTT with archaeological assemblages at Jwalapuram, in the Jurreru River valley of southern India. Broad continuity of Middle Paleolithic technology across the YTT event suggests that hominins persisted regionally across this major eruptive event.

The use of tree-rings and foliage as an archive of volcanogenic cation deposition.

Tree cores (Pinus nigra ssp. laricio) and leaves (Castanea sativa) from the flanks of Mount Etna, Sicily were analysed by ICP-MS to investigate whether volcanogenic cations within plant material provide an archive of a volcano's temporal and spatial depositional influence. There is significant compositional variability both within and between trees, but no systematic dendrochemical correlation with periods of effusive, explosive or increased degassing activity. Dendrochemistry does not provide a record of persistent but fluctuating volcanic activity. Foliar levels of bioaccumulated cations correspond to modelled plume transport patterns, and map short-term volcanic fumigation. Around the flanks of the volcano foliar variation is greater for volatile cations (Cs, Cd, Pb) than for lithophilic cations (Ba, Sr), consistent with trace-metal supply from volcanic aerosol during quiescent periods.

A family of microporous materials formed by Sn(IV) phosphonate nanoparticles.

Reaction of Sn(IV) with phosphonic acids results in the formation of tin phosphonates with a spherical morphology arising from the aggregation of nanosized individual particles. Under high magnification, the spheres are shown to be porous with surface areas of 200-515 m2/g, depending on the type of phosphonic acid and the synthesis conditions used. The pores are largely micro in nature but also somewhat dependent on the type of phosphonic acid utilized in the preparation. Both aliphatic and aromatic organic phosphonates form these spherical aggregates. Functional groups, such as amino and carboxyl, may be introduced as part of the phosphonic acid or subsequently by further reaction, leading to a large family of naturally formed nanoparticles with accompanying microporosity.