Context. The assembly history experienced by the Milky Way is currently being unveiled thanks to the data provided by the Gaia mission. It is likely that the globular cluster system of our Galaxy has ...followed a similarly intricate formation path. Aims. To constrain this formation path, we explore the link between the globular clusters and the known merging events that the Milky Way has experienced. Methods. To this end, we combined the kinematic information provided by Gaia for almost all Galactic clusters, with the largest sample of cluster ages available after carefully correcting for systematic errors. To identify clusters with a common origin we analysed their dynamical properties, particularly in the space of integrals of motion. Results. We find that about 40% of the clusters likely formed in situ. A similarly large fraction, 35%, appear to be possibly associated to known merger events, in particular to Gaia-Enceladus (19%), the Sagittarius dwarf galaxy (5%), the progenitor of the Helmi streams (6%), and to the Sequoia galaxy (5%), although some uncertainty remains due to the degree of overlap in their dynamical characteristics. Of the remaining clusters, 16% are tentatively associated to a group with high binding energy, while the rest are all on loosely bound orbits and likely have a more heterogeneous origin. The resulting age–metallicity relations are remarkably tight and differ in their detailed properties depending on the progenitor, providing further confidence on the associations made. Conclusions. We provide a table listing the likely associations. Improved kinematic data by future Gaia data releases and especially a larger, systematic error-free sample of cluster ages would help to further solidify our conclusions.
Nebulization of antimicrobial drugs such as tobramycin and colistin is a cornerstone in the treatment of patients with cystic fibrosis (CF) infected with Pseudomonas aeruginosa. However, nebulization ...has a high treatment burden. The Twincer.sup.TM is a dry powder inhaler specifically developed for the inhalation of antibiotics such as colistin. The aim of this study was to compare patient outcomes and experience with colistin dry powder by the Twincer with nebulization of colistin or tobramycin in adult CF patients in a real-life setting. This was a retrospective study from 01-01-2015 until 01-07-2018. Effectiveness was evaluated by comparing FEV.sub.1 decline and exacerbation rate during a mean of 4.1 years of nebulization therapy prior to the initiation of the Twincer against the same values during a mean of 1.7 years of treatment with the Twincer. Twenty-one patients were evaluated, of whom twelve could be included in the effectiveness analysis, with a total of twenty patient years. Of all patients 71.4% preferred therapy with the Twincer over nebulization. Twincer use resulted in high treatment adherence with an average adherence rate of 92.5%. There was no significant difference in annual decline in FEV.sub.1 %pred prior to and after start changing from nebulization to the use of the Twincer powder inhaler (median decline -1.56 -5.57-5.31 and 1.35 -8.45-6.36) respectively, p = 0.45 (linear mixed effect model)). No significant difference was found in the number of intravenous or combined total intravenous and oral antibiotic courses during Twincer therapy compared to when using nebulization (1.68 and 2.49 courses during Twincer therapy versus 1.51 and 2.94 courses during nebulization, p = 0.88 and p = 0.63). Colistin dry powder inhalation with the Twincer is a more patient friendly alternative to nebulization, and we did not observe significant differences in the clinical outcome, regarding lung function and exacerbation rates.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
Biologic Therapies for Severe Asthma Brusselle, Guy G; Koppelman, Gerard H
The New England journal of medicine,
01/2022, Letnik:
386, Številka:
2
Journal Article
Recenzirano
Odprti dostop
Patients with severe asthma are at increased risk for a decreased quality of life, fixed airway obstruction, hospitalization, and death. Biologics may be required to reduce the disease burden. This ...review discusses the mechanisms, efficacy, and safety of biologics for severe asthma.
Data from a controlled trial of asthma treatment that enrolled patients in the first decade of life were combined with follow-up data to provide novel information on the growth and decline in lung ...function in the first three decades of life in patients with asthma.
In persons without lung disease, forced expiratory volume in 1 second (FEV
1
) reaches its maximal level in late adolescence or early adulthood and remains stable for several years, a period known as the plateau of lung function, before gradually declining thereafter (Figure 1).
1
Under the construct described by Speizer and Tager,
1
the pattern of FEV
1
growth and decline in childhood and early adulthood is an important determinant of lung function in later adulthood; both reduced growth resulting in a low maximal level of lung function and early decline are associated with the subsequent development of chronic airflow . . .
Aims. Several kinematic and chemical substructures have been recently found amongst Milky Way halo stars with retrograde motions. It is currently unclear how these various structures are related to ...each other. This Letter aims to shed light on this issue. Methods. We explore the retrograde halo with an augmented version of the Gaia DR2 RVS sample, extended with data from three large spectroscopic surveys, namely RAVE, APOGEE, and LAMOST. In this dataset, we identify several structures using the HDBSCAN clustering algorithm. We discuss their properties and possible links using all the available chemical and dynamical information. Results. In concordance with previous work, we find that stars with Fe/H < −1 have more retrograde motions than those with Fe/H > −1. The retrograde halo contains a mixture of debris from objects like Gaia-Enceladus, Sequoia, and even the chemically defined thick disc. We find that the Sequoia has a smaller range in orbital energies than previously suggested and is confined to high energy. Sequoia could be a small galaxy in itself, but since it overlaps both in integrals-of-motion space and chemical abundance space with the less bound debris of Gaia-Enceladus, its nature cannot yet be fully settled. In the low-energy part of the halo, we find evidence for at least one more distinct structure: Thamnos. Stars in Thamnos are on low-inclination, mildly eccentric retrograde orbits, moving at vϕ ≈ −150 km s−1, and are chemically distinct from the other structures. Conclusions. Even with the excellent Gaia DR2 data, piecing together all the fragments found in the retrograde halo remains challenging. At this point, we are very much in need of large datasets with high-quality high-resolution spectra and tailored high-resolution hydrodynamical simulations of galaxy mergers.
The assembly of our Galaxy can be reconstructed using the motions and chemistry of individual stars
. Chemo-dynamical studies of the stellar halo near the Sun have indicated the presence of multiple ...components
, such as streams
and clumps
, as well as correlations between the stars' chemical abundances and orbital parameters
. Recently, analyses of two large stellar surveys
revealed the presence of a well populated elemental abundance sequence
, two distinct sequences in the colour-magnitude diagram
and a prominent, slightly retrograde kinematic structure
in the halo near the Sun, which may trace an important accretion event experienced by the Galaxy
. However, the link between these observations and their implications for Galactic history is not well understood. Here we report an analysis of the kinematics, chemistry, age and spatial distribution of stars that are mainly linked to two major Galactic components: the thick disk and the stellar halo. We demonstrate that the inner halo is dominated by debris from an object that at infall was slightly more massive than the Small Magellanic Cloud, and which we refer to as Gaia-Enceladus. The stars that originate in Gaia-Enceladus cover nearly the full sky, and their motions reveal the presence of streams and slightly retrograde and elongated trajectories. With an estimated mass ratio of four to one, the merger of the Milky Way with Gaia-Enceladus must have led to the dynamical heating of the precursor of the Galactic thick disk, thus contributing to the formation of this component approximately ten billion years ago. These findings are in line with the results of galaxy formation simulations, which predict that the inner stellar halo should be dominated by debris from only a few massive progenitors
.
The extent to which genetic risk factors are shared between childhood-onset (COA) and adult-onset (AOA) asthma has not been estimated. On the basis of data from the UK Biobank study (n = 447,628), we ...found that the variance in disease liability explained by common variants is higher for COA (onset at ages between 0 and 19 years; h2g = 25.6%) than for AOA (onset at ages between 20 and 60 years; h2g = 10.6%). The genetic correlation (rg) between COA and AOA was 0.67. Variation in age of onset among COA-affected individuals had a low heritability (h2g = 5%), which we confirmed in independent studies and also among AOA-affected individuals. To identify subtype-specific genetic associations, we performed a genome-wide association study (GWAS) in the UK Biobank for COA (13,962 affected individuals) and a separate GWAS for AOA (26,582 affected individuals) by using a common set of 300,671 controls for both studies. We identified 123 independent associations for COA and 56 for AOA (37 overlapped); of these, 98 and 34, respectively, were reproducible in an independent study (n = 262,767). Collectively, 28 associations were not previously reported. For 96 COA-associated variants, including five variants that represent COA-specific risk factors, the risk allele was more common in COA- than in AOA-affected individuals. Conversely, we identified three variants that are stronger risk factors for AOA. Variants associated with obesity and smoking had a stronger contribution to the risk of AOA than to the risk of COA. Lastly, we identified 109 likely target genes of the associated variants, primarily on the basis of correlated expression quantitative trait loci (up to n = 31,684). GWAS informed by age of onset can identify subtype-specific risk variants, which can help us understand differences in pathophysiology between COA and AOA and so can be informative for drug development.
Aims.
About 10 billion years ago the Milky Way merged with a massive satellite,
Gaia
-Enceladus. To gain insight into the properties of its debris we analyse in detail a suite of simulations that ...includes an experiment that produces a good match to the kinematics of nearby halo stars inferred from
Gaia
data.
Methods.
We compare the kinematic distributions of stellar particles in the simulations and study the distribution of debris in orbital angular momentum, eccentricity, and energy, and its relation to the mass loss history of the simulated satellite.
Results.
We confirm that
Gaia
-Enceladus probably fell in on a retrograde, 30° inclination orbit. We find that while 75% of the debris in our preferred simulation has high eccentricity (> 0.8), roughly 9% has eccentricity lower than 0.6. Star particles lost early have large retrograde motions, and a subset of these have low eccentricity. Such stars would be expected to have lower metallicities as they stem from the outskirts of the satellite, and hence naively they could be confused with debris associated with a separate system. These considerations seem to apply to some of the stars from the postulated Sequoia galaxy.
Conclusions.
When a massive disc galaxy undergoes a merger event, it leaves behind debris with a complex phase-space structure, a wide range of orbital properties, and a range of chemical abundances. Observationally, this results in substructures with very different properties, which can be misinterpreted as implying independent progeny. Detailed chemical abundances of large samples of stars and tailored hydrodynamical simulations are critical to resolving such conundrums.
Development of the gut-brain axis in early life may be disturbed by antibiotic use. It has been hypothesized that this disturbance may contribute to development of neurodevelopmental disorders, ...including autism spectrum disorder and attention-deficit hyperactivity disorder. We aimed to assess the association between antibiotic use in early life and the risk of developing attention-deficit hyperactivity disorder or autism spectrum disorder, while controlling for shared genetic and environmental factors in a discordant twin design.
We conducted a cohort study in twins (7-12 years; 25 781 twins) from the Netherlands Twin Register (NTR) and a replication study in the Childhood and Adolescent Twin Study in Sweden (CATSS; 7946 9-year-old twins). Antibiotic use was recorded before age 2 years. Attention-deficit hyperactivity disorder and autism spectrum disorder were parent-reported in the Netherlands Twin Register and register-based in the Childhood and Adolescent Twin Study in Sweden.
Early-life antibiotic use was associated with increased risk of attention-deficit hyperactivity disorder development pooled odds ratio (OR) 1.10, 95% confidence interval (CI) 1.02-1.17 and autism spectrum disorder (pooled OR 1.15, 95% CI 1.06-1.25) in a case-control design. When restricting to monozygotic twin pairs discordant for the outcome, associations disappeared for both disorders in both cohorts (attention-deficit hyperactivity disorder OR 0.90, 95% CI 0.48-1.69 and OR 0.80, 95% CI 0.37-1.76, and autism spectrum disorder OR 0.66, 95% CI 0.38-1.16 and OR 0.29, 95% CI 0.02-4.50, respectively).
Our findings suggest that the association between early-life antibiotic use and risk of attention-deficit hyperactivity and autism spectrum disorder may be confounded by shared familial environment and genetics.
Allergies to peanuts, tree nuts, and sesame seeds are among the most important food-related causes of anaphylaxis. Important clinical questions include: Why is there a variable occurrence of ...coallergy among these foods and Is this immunologically mediated? The clinical and immunologic data summarized here suggest an immunologic basis for these coallergies that is based on similarities among the 2S albumins. Data from component resolved diagnostics have highlighted the relationship between IgE binding to these allergens and the presence of IgE-mediated food allergy. Furthermore, in vitro and in vivo experiments provide strong evidence that the 2S albumins are the most important allergens in peanuts for inducing an allergic effector response. Although the 2S albumins are diverse, they have a common disulfide-linked core with similar physicochemical properties that make them prime candidates to explain much of the observed coallergy among peanuts, tree nuts, and sesame seeds. The well-established frequency of cashew and pistachio nut coallergy (64%-100%) highlights how the structural similarities among their 2S albumins may account for observed clinical cross-reactivity. A complete understanding of the physicochemical properties of the 2S albumins in peanuts, tree nuts, and sesame seeds will enhance our ability to diagnose, treat, and ultimately prevent these allergies.
PDF
