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Animal populations are often comprised of both foraging specialists and generalists. For instance, some individuals show higher foraging site fidelity (spatial specialization) than others. Such individual differences in degree of specialization can persist over time‐scales of months or even years in long‐lived animals, but the mechanisms leading to these different individual strategies are not fully understood. There is accumulating evidence that individual variation in foraging behaviour is shaped by animal personality traits, such as boldness. Despite this, the potential for boldness to drive differences in the degree of specialization is unknown. In this study, we used novel object tests to measure boldness in black‐legged kittiwakes (Rissa tridactyla) breeding at four colonies in Svalbard and deployed GPS loggers to examine their at‐sea foraging behaviour. We estimated the repeatability of foraging trips and used a hidden Markov model to identify locations of foraging sites in order to quantify individual foraging site fidelity. Across the breeding season, bolder birds were more repeatable than shy individuals in the distance and range of their foraging trips, and during the incubation period (but not chick rearing), bolder individuals were more site‐faithful. Birds exhibited these differences while showing high spatial similarity in foraging areas, indicating that site selection was not driven by personality‐dependent spatial partitioning. We instead suggest that a relationship between boldness and site fidelity may be driven by differences in behavioural flexibility between bold and shy individuals. Together, these results provide a potential mechanism by which widely reported individual differences in foraging specialization may emerge.

There is an urgent need for an effective tuberculosis (TB) vaccine. Heterologous prime-boost regimens induce potent cellular immunity. MVA85A is a candidate TB vaccine. This phase I clinical trial was designed to evaluate whether alternating aerosol and intradermal vaccination routes would boost cellular immunity to the Mycobacterium tuberculosis antigen 85A (Ag85A). Between December 2013 and January 2016, 36 bacille Calmette-Guérin-vaccinated, healthy UK adults were randomised equally between 3 groups to receive 2 MVA85A vaccinations 1 month apart using either heterologous (Group 1, aerosol-intradermal; Group 2, intradermal-aerosol) or homologous (Group 3, intradermal-intradermal) immunisation. Bronchoscopy and bronchoalveolar lavage (BAL) were performed 7 days post-vaccination. Adverse events (AEs) and peripheral blood were collected for 6 months post-vaccination. The laboratory and bronchoscopy teams were blinded to treatment allocation. One participant was withdrawn and was replaced. Participants were aged 21-42 years, and 28/37 were female. In a per protocol analysis, aerosol delivery of MVA85A as a priming immunisation was well tolerated and highly immunogenic. Most AEs were mild local injection site reactions following intradermal vaccination. Transient systemic AEs occurred following vaccination by both routes and were most frequently mild. All respiratory AEs following primary aerosol MVA85A (Group 1) were mild. Boosting an intradermal MVA85A prime with an aerosolised MVA85A boost 1 month later (Group 2) resulted in transient moderate/severe respiratory and systemic AEs. There were no serious adverse events and no bronchoscopy-related complications. Only the intradermal-aerosol vaccination regimen (Group 2) resulted in modest, significant boosting of the cell-mediated immune response to Ag85A (p = 0.027; 95% CI: 28 to 630 spot forming cells per 1 × 106 peripheral blood mononuclear cells). All 3 regimens induced systemic cellular immune responses to the modified vaccinia virus Ankara (MVA) vector. Serum antibodies to Ag85A and MVA were only induced after intradermal vaccination. Aerosolised MVA85A induced significantly higher levels of Ag85A lung mucosal CD4+ and CD8+ T cell cytokines compared to intradermal vaccination. Boosting with aerosol-inhaled MVA85A enhanced the intradermal primed responses in Group 2. The magnitude of BAL MVA-specific CD4+ T cell responses was lower than the Ag85A-specific responses. A limitation of the study is that while the intradermal-aerosol regimen induced the most potent cellular Ag85A immune responses, we did not boost the last 3 participants in this group because of the AE profile. Timing of bronchoscopies aimed to capture peak mucosal response; however, peak responses may have occurred outside of this time frame. To our knowledge, this is the first human randomised clinical trial to explore heterologous prime-boost regimes using aerosol and systemic routes of administration of a virally vectored vaccine. In this trial, the aerosol prime-intradermal boost regime was well tolerated, but intradermal prime-aerosol boost resulted in transient but significant respiratory AEs. Aerosol vaccination induced potent cellular Ag85A-specific mucosal and systemic immune responses. Whilst the implications of inducing potent mucosal and systemic immunity for protection are unclear, these findings are of relevance for the development of aerosolised vaccines for TB and other respiratory and mucosal pathogens. ClinicalTrials.gov NCT01954563.

This review identified associations between illness perception and health outcomes of patients with a medical diagnosis included in the Hospital Readmissions Reduction Program. Inclusion criteria were English language, use of quantitative methodology, health outcomes specified, and identifiable effect size and statistical significance of the relationship. Most of the 31 studies in this review showed that favorable illness perception has been associated with better health outcomes, while unfavorable illness perception has been associated with worse outcomes. A multifaceted approach might include behavioral, clinical, educational, and psychosocial components to improve one’s illness perception through educative, cognitive-behavioral, or psychodynamic counseling.

Intradermal MVA85A, a candidate vaccine against tuberculosis, induces high amounts of Ag85A-specific CD4 T cells in adults who have already received the BCG vaccine, but aerosol delivery of this vaccine might offer immunological and logistical advantages. We did a phase 1 double-blind trial to compare the safety and immunogenicity of aerosol-administered and intradermally administered MVA85A In this phase 1, double-blind, proof-of-concept trial, 24 eligible BCG-vaccinated healthy UK adults were randomly allocated (1:1) by sequentially numbered, sealed, opaque envelopes into two groups: aerosol MVA85A and intradermal saline placebo or intradermal MVA85A and aerosol saline placebo. Participants, the bronchoscopist, and immunologists were masked to treatment assignment. The primary outcome was safety, assessed by the frequency and severity of vaccine-related local and systemic adverse events. The secondary outcome was immunogenicity assessed with laboratory markers of cell-mediated immunity in blood and bronchoalveolar lavage samples. Safety and immunogenicity were assessed for 24 weeks after vaccination. Immunogenicity to both insert Ag85A and vector modified vaccinia virus Ankara (MVA) was assessed by ex-vivo interferon-γ ELISpot and serum ELISAs. Since all participants were randomised and vaccinated according to protocol, our analyses were per protocol. This trial is registered with ClinicalTrials.gov, number NCT01497769. Both administration routes were well tolerated and immunogenic. Respiratory adverse events were rare and mild. Intradermal MVA85A was associated with expected mild local injection-site reactions. Systemic adverse events did not differ significantly between the two groups. Three participants in each group had no vaccine-related systemic adverse events; fatigue (11/24 [46%]) and headache (10/24 [42%]) were the most frequently reported symptoms. Ag85A-specific systemic responses were similar across groups. Ag85A-specific CD4 T cells were detected in bronchoalveolar lavage cells from both groups and responses were higher in the aerosol group than in the intradermal group. MVA-specific cellular responses were detected in both groups, whereas serum antibodies to MVA were only detectable after intradermal administration of the vaccine. Further clinical trials assessing the aerosol route of vaccine delivery are merited for tuberculosis and other respiratory pathogens. The Wellcome Trust and Oxford Radcliffe Hospitals Biomedical Research Centre.

Background: A pre-specified meta-analysis of individual patient data from the 52-week METREX and METREO trials, which investigated mepolizumab for chronic obstructive pulmonary disease (COPD) in patients with blood eosinophil counts [greater than or equal to] 150 cells/[micro]L (screening) or [greater than or equal to] 300 cells/[micro]L (prior year) and frequent exacerbations, enables more robust characterization of mepolizumab efficacy in COPD and exploration of the relationship between blood eosinophil count and treatment responses. Methods: In METREX (117106/NCT02105948) and METREO (117113/NCT02105961), randomized patients received mepolizumab or placebo added to existing inhaled corticosteroid (ICS)-based triple maintenance therapy. The annual rate of moderate/severe exacerbations (primary endpoint) was compared between subcutaneous (SC) mepolizumab 100 mg versus placebo (primary comparison of interest) and all doses (100 mg and 300 mg SC) versus placebo in patients with blood eosinophil counts [greater than or equal to] 150 cells/[micro]L at screening or [greater than or equal to] 300 cells/[micro]L in the prior year. Secondary/other endpoints included time to first moderate/severe exacerbation, exacerbations leading to emergency department visit/hospitalization and health-related quality of life (HRQoL). A predictive model of the relationship between screening blood eosinophil counts and exacerbation rates included data from all randomized patients. Results: In total, 1510 patients were randomized in METREX and METREO and 1136 patients were included in the pre-specified meta-analysis. From the meta-analysis, mepolizumab 100 mg SC significantly reduced annual moderate/severe exacerbation rates versus placebo by 18% (rate ratio: 0.82; 95% confidence interval: 0.71, 0.95; p=0.006) and delayed time to first moderate/ severe exacerbation (hazard ratio: 0.80 [0.68, 0.94]; p=0.006). Mepolizumab 100 mg SC versus placebo numerically reduced exacerbations leading to ED visits/hospitalization and improved HRQoL. A modelling approach demonstrated increasing efficacy for moderate/severe exacerbations with increasing screening blood eosinophil count; this relationship was more pronounced for exacerbations requiring oral corticosteroids (post hoc). The all-doses comparison had similar results. Conclusion: Mepolizumab reduces exacerbations in patients with eosinophil-associated COPD. Results suggest that blood eosinophil counts ([greater than or equal to] 150 cells/[micro]L at screening or [greater than or equal to] 300 cells/[micro]L in the prior year) allow for identification of patients with COPD who experience exacerbations while treated with maximal ICS-based triple maintenance therapy who are likely to benefit from mepolizumab. Keywords: mepolizumab, COPD, eosinophil, exacerbation

Tuberculosis vaccine development is hindered by the lack of validated immune correlates of protection. Exploring immune correlates of risk of disease and/or infection in prospective samples can inform this field. We investigate whether previously identified immune correlates of risk of TB disease also associate with increased risk of M.tb infection in BCG-vaccinated South African infants, who became infected with M.tb during 2-3 years of follow-up. M.tb infection is defined by conversion to positive reactivity in the QuantiFERON test. We demonstrate that inflammation and immune activation are associated with risk of M.tb infection. Ag85A-specific IgG is elevated in infants that were subsequently infected with M.tb , and this is coupled with upregulated gene expression of immunoglobulin-associated genes and type-I interferon. Plasma levels of IFN- α 2, TNF- α , CXCL10 (IP-10) and complement C2 are also higher in infants that were subsequently infected with M.tb . The identification of immune correlates of protection in humans would inform on the design and development of tuberculosis vaccine candidates. In this work, authors examine samples collected from South African infants, to determine whether the correlates of risk of tuberculosis disease, previously identified in this population, are also correlates of risk of M. tuberculosis infection.

Purpose of ReviewThoracic aortic aneurysms (TAA) have a strong heritable basis, and identification of a genetic etiology has important implications for patients with TAA and their relatives. This review provides an overview of Mendelian causes of TAA, discusses important considerations for genetic testing, and summarizes the impact a genetic diagnosis may have on a patient’s medical care.Recent FindingsThoracic aortic disease may be non-syndromic or seen as part of a genetic syndrome, such as Marfan syndrome, Loeys-Dietz syndrome, or vascular Ehlers-Danlos syndrome. Expanded access to genetic testing has revealed the wide and overlapping phenotypic spectrum of these conditions, highlighting the need for genetic testing to establish an accurate diagnosis. Important aspects of genetic evaluation include thorough phenotyping through family history and physical examination, selection of an appropriate genetic test driven by the patient’s phenotype, and careful interpretation of genetic test results. Improved understanding of the natural history of these conditions has led to tailored management recommendations, including gene-based recommendations for prophylactic surgical repair.SummaryIdentification of a genetic etiology allows for careful monitoring of disease progression, informs the timing of prophylactic surgical repair, and facilitates the identification of other at-risk relatives through cascade genetic testing.

MVA85A and AERAS-402 are two clinically advanced viral vectored TB vaccine candidates expressing Mycobacterium tuberculosis antigens designed to boost BCG-induced immunity. Clinical trials with candidate malaria vaccines have demonstrated that adenoviral vector based priming immunisation, followed by MVA vector boost, induced high levels of immunity. We present the safety and immunogenicity results of the first clinical trial to evaluate this immunisation strategy in TB. In this phase 1, open-label trial, 40 healthy previously BCG-vaccinated participants were enrolled into three treatment groups and vaccinated with 1 or 2 doses of AERAS-402 followed by MVA85A; or 3 doses of AERAS-402. Most related adverse events (AEs) were mild and there were no vaccine related serious AEs. Boosting AERAS-402 with MVA85A significantly increased Ag85A-specific T-cell responses from day of vaccination. Two priming doses of AERAS-402 followed by MVA85A boost, resulted in a significantly higher AUC post-peak Ag85A response compared to three doses of AERAS-402 and historical data with MVA85A vaccination alone. The frequency of CD8+ T-cells producing IFN-γ, TNF-α and IL-2 was highest in the group receiving two priming doses of AERAS-402 followed by MVA85A. Vaccination with AERAS-402 followed by MVA85A was safe and increased the durability of antigen specific T-cell responses and the frequency and polyfunctionality of CD8+ T-cells, which may be important in protection against TB. Further clinical trials with adenoviral prime-MVA85A boost regimens are merited to optimise vaccination intervals, dose and route of immunisation and to evaluate this strategy in the target population in TB high burden countries. ClinicalTrials.gov NCT01683773.

Vaccines to protect against tuberculosis (TB) are urgently needed. We performed a case–control analysis to identify immune correlates of TB disease risk in Bacille Calmette–Guerin (BCG) immunized infants from the MVA85A efficacy trial. Among 53 TB case infants and 205 matched controls, the frequency of activated HLA-DR + CD4 + T cells associates with increased TB disease risk (OR=1.828, 95% CI=1.25–2.68, P =0.002, FDR=0.04, conditional logistic regression). In an independent study of Mycobacterium tuberculosis -infected adolescents, activated HLA-DR + CD4 + T cells also associate with increased TB disease risk (OR=1.387, 95% CI=1.068–1.801, P =0.014, conditional logistic regression). In infants, BCG-specific T cells secreting IFN-γ associate with reduced risk of TB (OR=0.502, 95% CI=0.29–0.86, P =0.013, FDR=0.14). The causes and impact of T-cell activation on disease risk should be considered when designing and testing TB vaccine candidates for these populations. BCG vaccine confers only partial protection against tuberculosis. Here the authors show that the risk of tuberculosis infection and progression to disease in BCG-immunized children positively correlates with the frequency of activated HLA-DR + CD4 + T cells.

Tidewater glacier fronts can represent important foraging areas for Arctic predators. Their ecological importance is likely to change in a warmer Arctic. Their profitability and use by consumers are expected to vary in time, but the underlying mechanisms driving such variation remain poorly known. The subglacial plume, originating from meltwater discharge, is responsible for the entrainment and transport of zooplankton to the surface, making them more readily available for surface-feeding seabirds. Both discharge and zooplankton abundance are known to fluctuate in time and are thus expected to modulate the foraging profitability of glacier fronts. This study tested the predictions that annual use of glacier fronts by black-legged kittiwakes Rissa tridactyla is positively related to the average glacier discharge and prey biomass in the fjord. To do this, we combined a multiyear dataset of environmental drivers and GPS tracks of birds in Kongsfjorden, Svalbard. Our results confirmed the interannual variation in the use of glacier fronts by kittiwakes; however, contrary to our predictions, these variations were negatively correlated to both glacier discharge and zooplankton abundance. These apparent negative relationships likely reflect non-linear effects and complex interactions between local and regional environmental factors that affect the relative profitability of glacier fronts as foraging areas. Despite their high spatial predictability, glacier fronts may not offer consistent foraging opportunities for marine predators over time.