Abrahamsenkaufman6371

The antivirulence activity of PAβN was found to be dependent on the ToxR periplasmic sensing domain (PPD), suggesting that a feedback mechanism was involved in its activity. Collectively, the data indicated that PAβN inhibited V. Eeyarestatin 1 cholerae virulence factor production by activating a ToxR-dependent metabolic feedback mechanism to repress the expression of the ToxR virulence regulon. This suggests that efflux pump inhibitors could be used as antivirulence therapeutics for the treatment of cholera and perhaps that of other Gram-negative pathogens.The gut microbiome orchestrates epithelial homeostasis and both local and remote immunological responses. Critical to these regulatory interactions are innate immune receptors termed toll-like receptors. Studies to date have implicated innate immunity and toll-like receptors in shaping key features of the gut microbiome. However, a variety of biological and environmental variables are also implicated in determining gut microbiota composition. In this report, we hypothesized that co-housing and environment dominated the regulation of gut microbiota in animal models independent of innate immunity. To determine the importance of these variables, innate immunity or environment in shaping gut microbiota, we used a randomized co-housing strategy and transgenic TLR-deficient mice. We have found that mice co-housed together by genotype exhibited limited changes over time in the composition of gut microbiota. However, in mice randomized to cage, we report extensive changes in gut microbiota, independent of TLR function whereby the fecal microbiota of TLR-deficient mice converge with wild type. TLR5-deficient mice in these experiments exhibit a greater susceptibility for comparative changes in microbiota to other TLR-deficient mice and wild type mice. Our work has broad implications for the study of innate immunity and host-microbiota interactions. Given the profound impact that gut dysbiosis may have on immunity, this report highlights the potential impact of co-housing on gut microbiota and indices of inflammation as outcomes in biological models of infectious or inflammatory disease.Trypanosoma cruzi is the intracellular parasite of Chagas disease, a chronic condition characterized by cardiac and gastrointestinal morbidity. Protective immunity requires CD4+ T cells, and Th1 cells and gamma interferon (IFN-γ) are important players in host defense. More recently, Th17 cells and interleukin 17A (IL-17A) have been shown to exert protective functions in systemic T. cruzi infection. However, it remains unclear whether Th17 cells and IL-17A protect in the mucosa, the initial site of parasite invasion in many human cases. We found that IL-17RA knockout (KO) mice are highly susceptible to orogastric infection, indicating an important function for this cytokine in mucosal immunity to T. cruzi. To investigate the specific role of Th17 cells for mucosal immunity, we reconstituted RAG1 KO mice with T. cruzi-specific T cell receptor transgenic Th17 cells prior to orogastric T. cruzi challenges. We found that Th17 cells provided protection against gastric mucosal T. cruzi infection, indicated by significantly lower stomach parasite burdens. In vitro macrophage infection assays revealed that protection by Th17 cells is reduced with IL-17A neutralization or reversed by loss of macrophage NADPH oxidase activity. Consistently with this, mice lacking functional NADPH oxidase were not protected by Th17 cell transfer. These data are the first report that Th17 cells protect against mucosal T. cruzi infection and identify a novel protective mechanism involving the induction of NADPH oxidase activity by IL-17A. These studies provide important insights for Chagas vaccine development and, more broadly, increase our understanding of the diverse roles of Th17 cells in host defense.

People who are homeless or vulnerably housed are subject to disproportionately high risks of physical and mental illness and are further disadvantaged by difficulties in access to services. Research has been conducted examining a wide range of issues in relation to end-of-life care for homeless and vulnerably housed people, however, a contemporary scoping review of this literature is lacking.

To understand the provision of palliative care for people who are homeless or vulnerably housed from the perspective of, and for the benefit of, all those who should be involved in its provision.

Scoping review with thematic synthesis of qualitative and quantitative literature.

MEDLINE, Embase, PsycINFO, Social Policy and Practice and CINAHL databases were searched, from inception to May 2020. Citation chasing and manual searching of grey literature were also employed.

Sixty-four studies, involving 2117 homeless and vulnerably housed people were included, with wide variation in methodology, population and perspective. The thematic synthesis identified three themes around experiences, beliefs and wishes; relationships; and end-of-life care.

Discussion highlighted gaps in the evidence base, especially around people experiencing different types of homelessness. Existing evidence advocates for service providers to offer needs-based and non-judgemental care, for organisations to use existing assets in co-producing services, and for researchers to address gaps in the evidence base, and to work with providers in transforming existing knowledge into evaluable action.

Discussion highlighted gaps in the evidence base, especially around people experiencing different types of homelessness. Existing evidence advocates for service providers to offer needs-based and non-judgemental care, for organisations to use existing assets in co-producing services, and for researchers to address gaps in the evidence base, and to work with providers in transforming existing knowledge into evaluable action.

Identification of patients with shortened life expectancy is a major obstacle to delivering palliative/end-of-life care. We previously developed the modified Hospitalised-patient One-year Mortality Risk (mHOMR) model for the automated identification of patients with an elevated 1-year mortality risk. Our goal was to investigate whether patients identified by mHOMR at high risk for mortality in the next year also have unmet palliative needs.

We conducted a prospective observational study at two quaternary healthcare facilities in Toronto, Canada, with patients admitted to general internal medicine service and identified by mHOMR to have an expected 1-year mortality risk of 10% or more. We measured patients' unmet palliative needs-a severe uncontrolled symptom on the Edmonton Symptom Assessment Scale or readiness to engage in advance care planning (ACP) based on Sudore's ACP Engagement Survey.

Of 518 patients identified by mHOMR, 403 (78%) patients consented to participate; 87% of those had either a severe uncontrolled symptom or readiness to engage in ACP, and 44% had both.