Primary cosmic-ray elemental spectra have been measured with the balloon-borne Cosmic Ray Energetics And Mass (CREAM) experiment since 2004. The third CREAM payload (CREAM-III) flew for 29 days ...during the 2007-2008 Antarctic season. Energies of incident particles above 1 TeV are measured with a calorimeter. Individual elements are clearly separated with a charge resolution of ∼0.12 e (in charge units) and ∼0.14 e for protons and helium nuclei, respectively, using two layers of silicon charge detectors. The measured proton and helium energy spectra at the top of the atmosphere are harder than other existing measurements at a few tens of GeV. The relative abundance of protons to helium nuclei is 9.53 0.03 for the range of 1 TeV/n to 63 TeV/n. This ratio is considerably smaller than other measurements at a few tens of GeV/n. The spectra become softer above ∼20 TeV. However, our statistical uncertainties are large at these energies and more data are needed.
We introduce the antibody landscape, a method for the quantitative analysis of antibodymediated immunity to antigenically variable pathogens, achieved by accounting for antigenic variation among ...pathogen strains. We generated antibody landscapes to study immune profiles covering 43 years of influenza A/H3N2 virus evolution for 69 individuals monitored for infection over 6 years and for 225 individuals pre- and postvaccination. Upon infection and vaccination, titers increased broadly, including previously encountered viruses far beyond the extent of cross-reactivity observed after a primary infection. We explored implications for vaccination and found that the use of an antigenically advanced virus had the dual benefit of inducing antibodies against both advanced and previous antigenic clusters. These results indicate that preemptive vaccine updates may improve influenza vaccine efficacy in previously exposed individuals.
Many different bacterial species have the ability to cause an infection of the bovine mammary gland and the host response to these infections is what we recognize as mastitis. In this review we ...evaluate the pathogen specific response to the three main bacterial species causing bovine mastitis:
Escherichia coli,
Streptococcus uberis and
Staphylococcus aureus. In this paper we will review the bacterial growth patterns, host immune response and clinical response that results from the intramammary infections. Clear differences in bacterial growth pattern are shown between bacterial species. The dominant pattern in
E. coli infections is a short duration high bacteria count infection, in
S. aureus this is more commonly a persistent infection with relative low bacteria counts and in
S. uberis a long duration high bacteria count infection is often observed. The host immune response differs significantly depending on the invading bacterial species. The underlying reasons for the differences and the resulting host response are described. Finally we discuss the clinical response pattern for each of the three bacterial species. The largest contrast is between
E. coli and S. aureus where a larger proportion of
E. coli infections cause potentially severe clinical symptoms, whereas the majority of
S. aureus infections go clinically unnoticed.
The relevance of fully understanding the bovine host response to intramammary infection is discussed, some major gaps in our knowledge are highlighted and directions for future research are indicated.
The Wet Chemistry Laboratory on the Phoenix Mars Lander performed aqueous chemical analyses of martian soil from the polygon-patterned northern plains of the Vastitas Borealis. The solutions ...contained approximately 10 mM of dissolved salts with 0.4 to 0.6% perchlorate (ClO₄) by mass leached from each sample. The remaining anions included small concentrations of chloride, bicarbonate, and possibly sulfate. Cations were dominated by Mg²⁺ and Na⁺, with small contributions from K⁺ and Ca²⁺. A moderately alkaline pH of 7.7 ± 0.5 was measured, consistent with a carbonate-buffered solution. Samples analyzed from the surface and the excavated boundary of the approximately 5-centimeter-deep ice table showed no significant difference in soluble chemistry.
The aetiology of rheumatoid arthritis (RA), a prototype immune-mediated inflammatory disorder, is poorly understood. It is currently unknown whether the disease process starts in the synovium, the ...primary target of RA, or at other sites in the body.
To examine, in a prospective study, the presence of synovitis in people with an increased risk of developing RA.
Thirteen people without evidence of arthritis, who were positive for IgM rheumatoid factor and/or anticitrullinated protein antibodies, were included in the study. To evaluate synovial inflammatory changes, all participants underwent dynamic contrast-enhanced MRI and arthroscopic synovial biopsy sampling of a knee joint at inclusion. Results were compared with knee MRI data and synovial biopsy data of 6 and 10 healthy controls, respectively.
MRI findings evaluated by measurement of maximal enhancement, rate of enhancement, synovial volume and enhancement shape curve distribution were similar between the autoantibody-positive subjects and the healthy controls. Consistent with these findings, all but one autoantibody-positive subject showed very low scores for phenotypic markers, adhesion molecules and vascularity, all in the same range as those in normal controls. The one person with higher scores had patellofemoral joint space narrowing.
Subclinical inflammation of the synovium does not coincide with the appearance of serum autoantibodies during the pre-RA stage. Thus, systemic autoimmunity precedes the development of synovitis, suggesting that a 'second hit' is involved. This study supports the rationale for exploring preventive strategies aimed at interfering with the humoral immune response before synovial inflammation develops.
Abstract
The Cosmic Ray Energetics And Mass for the International Space Station (ISS-CREAM) experiment successfully recorded data for 539 days from 2017 August to 2019 February. We report the energy ...spectrum of cosmic-ray protons from the ISS-CREAM experiment at energies from 1.60 × 10
3
to 6.55 × 10
5
GeV. The measured spectrum deviates from a single power law. A smoothly broken power-law fit to the data, including statistical and systematic uncertainties, shows the spectral index change at 9.0 × 10
3
GeV from 2.57 ± 0.03 to 2.82 ± 0.02 with a significance of greater than 3
σ
. This bump-like structure is consistent with a spectral softening recently reported by the balloon-borne CREAM, DAMPE, and NUCLEON, but ISS-CREAM extends measurements to higher energies.
Governments have agreed to expand the global protected area network from 13% to 17% of the world's land surface by 2020 (Aichi target 11) and to prevent the further loss of known threatened species ...(Aichi target 12). These targets are interdependent, as protected areas can stem biodiversity loss when strategically located and effectively managed. However, the global protected area estate is currently biased toward locations that are cheap to protect and away from important areas for biodiversity. Here we use data on the distribution of protected areas and threatened terrestrial birds, mammals, and amphibians to assess current and possible future coverage of these species under the convention. We discover that 17% of the 4,118 threatened vertebrates are not found in a single protected area and that fully 85% are not adequately covered (i.e., to a level consistent with their likely persistence). Using systematic conservation planning, we show that expanding protected areas to reach 17% coverage by protecting the cheapest land, even if ecoregionally representative, would increase the number of threatened vertebrates covered by only 6%. However, the nonlinear relationship between the cost of acquiring land and species coverage means that fivefold more threatened vertebrates could be adequately covered for only 1.5 times the cost of the cheapest solution, if cost efficiency and threatened vertebrates are both incorporated into protected area decision making. These results are robust to known errors in the vertebrate range maps. The Convention on Biological Diversity targets may stimulate major expansion of the global protected area estate. If this expansion is to secure a future for imperiled species, new protected areas must be sited more strategically than is presently the case.
Higher plasma leucine, isoleucine and valine (BCAA) concentrations are associated with diabetes, obesity and insulin resistance (IR). Here, we evaluated the effects of 6-weeks very-low calorie diet ...(VLCD) upon fasting BCAA in overweight (OW) non-diabetic men, to explore associations between circulating BCAA and IR, before and after a weight loss intervention. Fasting plasma BCAAs were quantified in an OW (n = 26; BMI 32.4 ± 3 kg/m
; mean age 44 ± 9 y) and a normal-weight (NW) group (n = 26; BMI 24 ± 3.1 kg/m
; mean age 32 ± 12.3 y). Ten of the OW group (BMI 32.2 ± 4 kg/m
; 46 ± 8 y) then underwent 6-weeks of VLCD (600-800 kcal/day). Fasting plasma BCAA (gas chromatography-mass spectrometry), insulin sensitivity (HOMA-IR) and body-composition (DXA) were assessed before and after VLCD. Total BCAA were higher in OW individuals (sum leucine/isoleucine/valine: 457 ± 85 µM) compared to NW control individuals (365 ± 78 µM, p < 0.001). Despite significant weight loss (baseline 103.9 ± 12.3 to 93 ± 9.6 kg and BMI 32.2 ± 4 to 28.9 ± 3.6 kg/m
), no changes were observed in BCAAs after 6-weeks of VLCD. Moreover, although VLCD resulted in a significant reduction in HOMA-IR (baseline 1.19 ± 0.62 to 0.51 ± 0.21 post-VLCD; p < 0.001), Pearson's r revealed no relationships between BCAA and HOMA-IR, either before (leucine R
: 2.49e-005, p = 0.98; isoleucine R
: 1.211-e006, p = 0.9; valine R
: 0.004, p = 0.85) or after VLCD (leucine R
: 0.003, p = 0.86; isoleucine R
: 0.006, p = 0.82; valine R
: 0.002, p = 0.65). Plasma BCAA are higher in OW compared to NW individuals. However, while 6-weeks VLCD reduced body weight and IR in OW individuals, this was not associated with reductions in BCAA. This suggests that studies demonstrating links between BCAA and insulin resistance in OW individuals, are complex and are not normalised by simply losing weight.
Summary
Background
Atopic dermatitis is a chronic inflammatory skin disease that may require systemic therapy. Ciclosporin A (CsA) is a widely used, potent immunosuppressant but it is not effective ...in all patients with atopic dermatitis, and side‐effects limit its use. Dupilumab, a fully human anti‐interleukin 4 receptor‐alpha monoclonal antibody, inhibits signaling of IL‐4 and IL‐13, key drivers of Type 2/Th2‐mediated inflammation, and is approved in the U.S.A. and the European Union for the treatment of inadequately‐controlled moderate‐to‐severe atopic dermatitis in adults.
Objectives
To evaluate efficacy and safety of dupilumab with concomitant topical corticosteroids (TCS) in adults with atopic dermatitis with inadequate response to/intolerance of CsA, or for whom CsA treatment was medically inadvisable.
Methods
In this 16‐week, double‐blind, randomized, placebo‐controlled, phase III trial, patients were randomized 1 : 1 : 1 to subcutaneous dupilumab 300 mg weekly (qw) or every 2 weeks (q2w) or placebo. All received concomitant medium‐potency TCS from Week −2 through Week 16; dosage could be tapered if lesions cleared, or stopped for adverse reactions to TCS.
Results
In total, 390 patients were screened, 325 were randomized, and 318 completed the trial. Treatment groups had similar baseline characteristics. Significantly more patients in the dupilumab qw + TCS and q2w + TCS groups achieved ≥ 75% improvement from baseline in the Eczema Area and Severity Index at Week 16 vs. the placebo + TCS group (primary end point) (59·1% and 62·6% vs. 29·6%, respectively; P < 0·001 vs. placebo + TCS, both doses). Other clinical outcomes and atopic dermatitis symptoms were significantly improved in the dupilumab qw + TCS and q2w + TCS groups, including pruritus, pain, sleep disturbance, symptoms of anxiety and depression, and quality of life (QoL). Treatment groups had similar overall rates of adverse events (qw + TCS, q2w + TCS and placebo + TCS groups: 69·1%, 72·0% and 69·4%, respectively) and serious adverse events (1·8%, 1·9% and 1·9%, respectively). Conjunctivitis was more frequent with dupilumab + TCS; skin infections were more frequent with placebo + TCS.
Conclusions
Dupilumab + TCS significantly improved signs and symptoms of atopic dermatitis and QoL in adults with a history of inadequate response to/intolerance of CsA, or for whom CsA treatment was medically inadvisable. No new safety signals were identified.
What's already known about this topic?
Patients with atopic dermatitis that is inadequately controlled with topical therapy have few systemic treatment options.
Ciclosporin A (CsA) is a systemic immunosuppressant approved for atopic dermatitis in most European countries and Japan, but not all patients respond, and side‐effects limit its use.
Dupilumab (monoclonal antibody against interleukin‐4 receptor‐alpha) with/without topical corticosteroids (TCS) is approved in the U.S.A. and the European Union for the treatment of adults with inadequately‐controlled moderate‐to‐severe atopic dermatitis.
What does this study add?
In this 16‐week trial in adults with atopic dermatitis and history of inadequate response or intolerance to CsA, or for whom CsA treatment was medically inadvisable, dupilumab administered weekly or every 2 weeks with concomitant TCS significantly improved signs and symptoms and quality of life, with no new safety signals.
These data support the use of dupilumab in this difficult‐to‐treat population.
Linked Editorial: Schmitt. Br J Dermatol 2018; 178:992–993.
Linked Letter: Thyssen. Br J Dermatol 2018; 178:1220.
Plain language summary available online
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