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Natural infections expose the immune system to escalating antigen and inflammation over days to weeks, whereas nonlive vaccines are single bolus events. We explored whether the immune system responds optimally to antigen kinetics most similar to replicating infections, rather than a bolus dose. Using HIV antigens, we found that administering a given total dose of antigen and adjuvant over 1–2 wk through repeated injections or osmotic pumps enhanced humoral responses, with exponentially increasing (exp-inc) dosing profiles eliciting >10-fold increases in antibody production relative to bolus vaccination post prime. Computational modeling of the germinal center response suggested that antigen availability as higher-affinity antibodies evolve enhances antigen capture in lymph nodes. Consistent with these predictions, we found that exp-inc dosing led to prolonged antigen retention in lymph nodes and increased Tfh cell and germinal center B-cell numbers. Thus, regulating the antigen and adjuvant kinetics may enable increased vaccine potency.

Resting memory CD4+ T-cells harboring latent HIV proviruses represent a critical barrier to viral eradication. Histone deacetylase inhibitors (HDACis), such as suberanilohydroxamic acid (SAHA), romidepsin, and panobinostat have been shown to induce HIV expression in these resting cells. Recently, it has been demonstrated that the low levels of viral gene expression induced by a candidate HDACi may be insufficient to cause the death of infected cells by viral cytopathic effects, necessitating their elimination by immune effectors, such as cytotoxic T-lymphocytes (CTL). Here, we study the impact of three HDACis in clinical development on T-cell effector functions. We report two modes of HDACi-induced functional impairment: i) the rapid suppression of cytokine production from viable T-cells induced by all three HDACis ii) the selective death of activated T-cells occurring at later time-points following transient exposures to romidepsin or, to a lesser extent, panobinostat. As a net result of these factors, HDACis impaired CTL-mediated IFN-γ production, as well as the elimination of HIV-infected or peptide-pulsed target cells, both in liquid culture and in collagen matrices. Romidepsin exerted greater inhibition of antiviral function than SAHA or panobinostat over the dose ranges tested. These data suggest that treatment with HDACis to mobilize the latent reservoir could have unintended negative impacts on the effector functions of CTL. This could influence the effectiveness of HDACi-based eradication strategies, by impairing elimination of infected cells, and is a critical consideration for trials where therapeutic interruptions are being contemplated, given the importance of CTL in containing rebound viremia.

PurposeClimate data, including historical climate observations and climate model outputs, are often used in climate impact assessments, to explore potential climate futures. However, characteristics often associated with “islandness”, such as smallness, land boundedness and isolation, may mean that climate impact assessment methods applied at broader scales cannot simply be downscaled to island settings. This paper aims to discuss information needs and the limitations of climate models and datasets in the context of small islands and explores how such challenges might be addressed.Design/methodology/approachReviewing existing literature, this paper explores challenges of islandness in top-down, model-led climate impact assessment and bottom-up, vulnerability-led approaches. It examines how alternative forms of knowledge production can play a role in validating models and in guiding adaptation actions at the local level and highlights decision-making techniques that can support adaptation even when data is uncertain.FindingsSmall island topography is often too detailed for global or even regional climate models to resolve, but equally, local meteorological station data may be absent or uncertain, particularly in island peripheries. However, rather than viewing the issue as decision-making with big data at the regional/global scale versus with little or no data at the small island scale, a more productive discourse can emerge by conceptualising strategies of decision-making with unconventional types of data.Originality/valueThis paper provides a critical overview and synthesis of issues relating to climate models, data sets and impact assessment methods as they pertain to islands, which can benefit decision makers and other end-users of climate data in island communities.

The dissemination of HIV from an initial site of infection is facilitated by motile HIV-infected CD4(+) T-cells. However, the impact of infected target cell migration on antigen recognition by HIV-specific CD8(+) T-cells is unclear. Using a 3D in vitro model of tissue, we visualized dynamic interactions between HIV-infected or peptide-pulsed CD4(+) T-cells and HIV-specific CD8(+) T-cells. CTLs engaged motile HIV-infected targets, but ∼ 50% of targets broke contact and escaped. In contrast, immobilized target cells were readily killed, indicating target motility directly inhibits CD8(+) T-cell function. Strong calcium signals occurred in CTLs killing a motile target but calcium signaling was weak or absent in CTLs which permitted target escape. Neutralization of adhesion receptors LFA-1 and CD58 inhibited CD8(+) T-cell function within the 3D matrix, demonstrating that efficient motile target lysis as dependent on adhesive engagement of targets. Antigen sensitivity (a convolution of antigen density, TCR avidity and CD8 coreceptor binding) is also critical for target recognition. We modulated this parameter (known as functional avidity but referred to here as \"avidity\" for the sake of simplicity) by exploiting common HIV escape mutations and measured their impact on CTL function at the single-cell level. Targets pulsed with low avidity mutant antigens frequently escaped while CTLs killed targets bearing high avidity antigen with near-perfect efficiency. CTLs engaged, arrested, and killed an initial target bearing high avidity antigen within minutes, but serial killing was surprisingly rare. CD8 cells remained committed to their initial dead target for hours, accumulating TCR signals that sustained secretion of soluble antiviral factors. These data indicate that high-avidity CD8(+) T-cells execute an antiviral program in the precise location where antigen has been sensed: CTL effector functions are spatiotemporally coordinated with an early lytic phase followed by a sustained stationary secretory phase to control local viral infection.

Background While physical (in) activity surveillance has grown and continues to grow globally, surveillance of sedentary behaviour is in its infancy. As surveillance evolves to meet the changing nature of these behaviours, there is a need for the development of national health survey questions to provide accurate and consistent measures over time. The development of national health survey content is a complex, detailed and often undocumented process. The objective of this paper is to outline the process that the Public Health Agency of Canada (PHAC) and Statistics Canada took in partnership with academic experts to develop a short, flexible, sedentary behaviour module for the Canadian Health Measures Survey (CHMS) and to provide an approach for the development of future survey content. Methods Development of the module followed a multi-step process. The results of this paper describe this process and present a framework for content development. Results Initially, PHAC and Statistics Canada analysts worked together to identify key content required for a potential survey module. Next, this work was formalized through a contract with academic experts, the scope included a: review of existing Canadian sedentary behaviour modules; literature review linking different sedentary behaviours to health outcomes; and, international scan of modules currently in use in large national health surveys and research. The key output from both review processes was recommendations for a short sedentary behaviour questionnaire module (International Sedentary Assessment Tool). These recommendations provided an evidence-informed basis for discussions about how to revise and update the CHMS sedentary behaviour questionnaire content. Qualitative testing was undertaken and a final module was developed using survey design best practices. Conclusions Content volume in national surveys is limited due to demand to measure core content in addition to emerging health topics while keeping surveys as short as possible. Questions must therefore, be concise, valid/reliable, evidence-based, and developed using best practices. The paper describes the development process of a new survey module addressing the emerging area of sedentary behaviour for use in a national survey that may serve as a model for future population survey content development.

Resting memory CD4+ T-cells harboring latent HIV proviruses represent a critical barrier to viral eradication. Histone deacetylase inhibitors (HDACis), such as suberanilohydroxamic acid (SAHA), romidepsin, and panobinostat have been shown to induce HIV expression in these resting cells. Recently, it has been demonstrated that the low levels of viral gene expression induced by a candidate HDACi may be insufficient to cause the death of infected cells by viral cytopathic effects, necessitating their elimination by immune effectors, such as cytotoxic T-lymphocytes (CTL). Here, we study the impact of three HDACis in clinical development on T-cell effector functions. We report two modes of HDACi-induced functional impairment: i) the rapid suppression of cytokine production from viable T-cells induced by all three HDACis ii) the selective death of activated T-cells occurring at later time-points following transient exposures to romidepsin or, to a lesser extent, panobinostat. As a net result of these factors, HDACis impaired CTL-mediated IFN-γ production, as well as the elimination of HIV-infected or peptide-pulsed target cells, both in liquid culture and in collagen matrices. Romidepsin exerted greater inhibition of antiviral function than SAHA or panobinostat over the dose ranges tested. These data suggest that treatment with HDACis to mobilize the latent reservoir could have unintended negative impacts on the effector functions of CTL. This could influence the effectiveness of HDACi-based eradication strategies, by impairing elimination of infected cells, and is a critical consideration for trials where therapeutic interruptions are being contemplated, given the importance of CTL in containing rebound viremia.

The dissemination of HIV from an initial site of infection is facilitated by motile HIV-infected CD4.sup.+ T-cells. However, the impact of infected target cell migration on antigen recognition by HIV-specific CD8.sup.+ T-cells is unclear. Using a 3D in vitro model of tissue, we visualized dynamic interactions between HIV-infected or peptide-pulsed CD4.sup.+ T-cells and HIV-specific CD8.sup.+ T-cells. CTLs engaged motile HIV-infected targets, but ~50% of targets broke contact and escaped. In contrast, immobilized target cells were readily killed, indicating target motility directly inhibits CD8.sup.+ T-cell function. Strong calcium signals occurred in CTLs killing a motile target but calcium signaling was weak or absent in CTLs which permitted target escape. Neutralization of adhesion receptors LFA-1 and CD58 inhibited CD8.sup.+ T-cell function within the 3D matrix, demonstrating that efficient motile target lysis as dependent on adhesive engagement of targets. Antigen sensitivity (a convolution of antigen density, TCR avidity and CD8 coreceptor binding) is also critical for target recognition. We modulated this parameter (known as functional avidity but referred to here as \"avidity\" for the sake of simplicity) by exploiting common HIV escape mutations and measured their impact on CTL function at the single-cell level. Targets pulsed with low avidity mutant antigens frequently escaped while CTLs killed targets bearing high avidity antigen with near-perfect efficiency. CTLs engaged, arrested, and killed an initial target bearing high avidity antigen within minutes, but serial killing was surprisingly rare. CD8 cells remained committed to their initial dead target for hours, accumulating TCR signals that sustained secretion of soluble antiviral factors. These data indicate that high-avidity CD8.sup.+ T-cells execute an antiviral program in the precise location where antigen has been sensed: CTL effector functions are spatiotemporally coordinated with an early lytic phase followed by a sustained stationary secretory phase to control local viral infection.

According to Anxiety/Uncertainty Management Theory, the automatic response to an unfamiliar environment is to reduce the uncertainty and anxiety that comes from encountering the unknown, thus contributing to the satisfaction and comfort of the individual. Extending AUM Theory has led theorists to speculate that it is possible to experience “anticipatory adjustment” to an unfamiliar culture before arrival, and that this pre-departure preparation can facilitate subsequent adjustment. This multiple case study explored the perceptions of the value of pre-departure cross-cultural training held by four accompanying spouses; two of whom had received such training, and two of whom had not. While the spouses were divided in their opinions of the value of cross-cultural training, their discussions brought forth other factors that may contribute to cross-cultural adjustment: degree of cultural novelty; in-country company support; previous expatriate experience; and personality factors, including orientation to action, extraversion, adventurousness/curiosity, flexibility, open mindedness, cultural empathy, and positivism/negativism. Key Words: cross-cultural training, spouse, anxiety/uncertainty reduction, satisfaction with life, cross-cultural adjustment.

This PhD presents a new term for contemporary ekphrastic poetry: curatorial ekphrasis. The thesis is composed of two elements, a critical essay followed by a collection of poetry that informs and is informed by the former, Entitled 'Curatorial Ekphrasis in Contemporary British Poetic Practice', the critical essay challenges established critical approaches to ekphrastic poetics by revealing a curatorial practice currently being undertaken by a number of contemporary poets writing about artworks. Chapter One identifies and evaluates key critical texts about ekphrasis and its role in the relationship between word and image and highlights how theorists have failed to account for the work of ekphrastic poets with a heightened interest or background in art- Chapter Two presents and defines the term curatorial ekphrasis. The chapter discusses the emergence of the contemporary curator in the art world and discusses how the term 'curator' can be appropriated for use in a literary context The following chapters analyse the work of contemporary poets who I argue are writing curatorial ekphrasis, Chapter Three analyses Roger Hilton's Sugar (2005), a poetic sequence by Kelvin Corcoran (b.1956). Chapter Four analyses Paul Klee's Diary (1995), a long poem by Peter Hughes (b.1956). Chapter Five analyses De Chirico's Threads (2011), a verse-drama with soundscape by Carol Rumens (b.1944). The conclusion summarizes my research and also anticipates the creative work, which follows, by highlighting elements in the analysed texts that resonate with my own poetry. The conclusion also suggests areas for future research by both critical and creative practitioners. The critical essay is followed by the creative component of the PhD, a collection of curatorial ekphrasis entitled 'Lucian Freud Portraits'. The poetry collection is sectioned into five rooms, reflecting the layout of an exhibition at an art gallery, The collection includes twenty-nine poems and a poem-libretto. The collection is precede-d by a Preface, which introduces the work, and is followed by a section of notes, The appendix of the thesis includes reproductions of the artworks referred to in the poetry collection, a chronology of Lucian Freud's life, a catalogue raisonne of his entire works and an extensive bibliography of material written about the artist and his works. This information is provided in a similar manner to the wall notes, exhibition guides and catalogues which are offered to visitors of a traditional art gallery. They are not prescribed reading material, but they may prove of interest to the reader seeking further information.

No breasts, no hair, no eyelashes, only a hint of eyebrows, nausea, heartburn, muscle aches and tremors, weakness, foods and drinks tasting like metal, and going through menopause due to the chemo -- that was my new reality. A crew of church and school moms cleaned this cute little 1920s house for us, top to bottom, stocked the kitchen shelves with food, pots, pans, dishes, silverware and glasses; put up shower curtains and bath rugs; and took pictures, mirrors and paintings off their own walls and hung them in this house so it would feel like home for us.