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Background Despite antibiotic stewardship programs existing in most acute care hospitals, there continues to be variation in appropriate antibiotic use. While existing research examines individual prescriber behavior, contextual reasons for variation are poorly understood. Methods We conducted an explanatory, sequential mixed-methods study of a purposeful sample of 7 hospitals with varying discharge antibiotic overuse. For each hospital, we conducted surveys, document analysis, and semi-structured interviews with antibiotic stewardship and clinical stakeholders. Data were analyzed separately and mixed during the interpretation phase, where each hospital was examined as a case, with findings organized across cases using a strengths, weaknesses, opportunities, and threats framework to identify factors accounting for differences in antibiotic overuse across hospitals. Results Surveys included 85 respondents. Interviews included 90 respondents (31 hospitalists, 33 clinical pharmacists, 14 stewardship leaders, 12 hospital leaders). On surveys, clinical pharmacists at hospitals with lower antibiotic overuse were more likely to report feeling: respected by hospitalist colleagues (P =.001), considered valuable team members (P =.001), and comfortable recommending antibiotic changes (P =.02). Based on mixed-methods analysis, hospitals with low antibiotic overuse had 4 distinguishing characteristics: (1) robust knowledge of and access to antibiotic stewardship guidance; (2) high-quality clinical pharmacist–physician relationships; (3) tools and infrastructure to support stewardship; and (4) highly engaged infectious diseases physicians who advocated stewardship principles. Conclusions This mixed-methods study demonstrates the importance of organizational context for high performance in stewardship and suggests that improving antimicrobial stewardship requires attention to knowledge, interactions, and relationships between clinical teams and infrastructure that supports stewardship and team interactions. [ABSTRACT FROM AUTHOR]

Simple Summary: This study focuses on the spontaneous lesions observed in a captive colony of geriatric Julia Creek dunnarts, an endangered carnivorous marsupial. Despite their conservation status, no prior research has focused on the conditions affecting captive individuals attaining senescence. We examined one wild and thirty-five captive-born, mostly elderly dunnarts that failed to reproduce over several breeding periods. From these, ten dunnarts had normal findings. Among females, the most common issue was cystic glandular hyperplasia (eight cases); cutaneous lesions were infrequent (two cases). Males showed testicular degeneration, aspermatogenesis, or atrophy (three cases). Cutaneous lesions compatible with epitheliotropic T cell lymphomas were observed in both sexes (five cases) and thus, an underlying oncogenic viral etiology is suspected. This is the first study that documents spontaneous diseases in aging Julia Creek dunnarts, shedding light on geriatric conditions within a conservation context. Julia Creek dunnarts are an endangered species of carnivorous marsupials and the focus of multiple conservation strategies involving significant resources such as captive breeding programs. Despite the relevance for conservation, no study to date has focused on evaluating geriatric diseases in dunnarts. This study describes the pathology findings in a group of one wild and thirty-five captive-born, mostly geriatric Julia Creek dunnarts that failed to produce offspring over multiple breeding periods. A total of 20 females and 16 males were submitted for a postmortem examination, with ages ranging from 9 to 42 and 12 to 42 months for females and males, respectively. Of these, 10 had unremarkable findings. The most common condition in females was cystic glandular hyperplasia (n = 8), typical of hormonal dysregulation profiles in senescence, particularly hyperestrogenism. Rarely, cutaneous disease represented by unidentified dermal round cell infiltrates was observed in females (n = 2). Primary reproductive hormonal dysregulation was also suspected in males diagnosed with testicular degeneration, aspermatogenesis and/or atrophy (n = 3). Cutaneous round cell infiltrates, possibly compatible with epitheliotropic lymphomas, were seen in males (n = 3), and 2/3 affected males also had concurrent testicular degeneration or atrophy, indicating male sex could be a predictor for lymphoid neoplasia in aged dunnarts, especially in individuals with concurrent testosterone-luteinizing hormone dysregulation as it occurs in gonadectomized animals. The role of an underlying viral etiology is also explored. This study is the first to describe major spontaneous diseases in endangered aged Julia Creek dunnarts, providing an important understanding of senescence and geriatric diseases within a conservation context. [ABSTRACT FROM AUTHOR]

Joseph Conrad. The Rover. Edited by Alexandre Fachard and J. H. Stape. The Cambridge Edition of the Works of Joseph Conrad. Cambridge: Cambridge University Press, 2018. ISBN: 9781107149021. The Cambridge [...]

Thymus medulla epithelium establishes immune self-tolerance and comprises diverse cellular subsets. Functionally relevant medullary thymic epithelial cells (mTECs) include a self-antigen-displaying subset that exhibits genome-wide promiscuous gene expression promoted by the nuclear protein Aire and that resembles a mosaic of extrathymic cells including mucosal tuft cells. An additional mTEC subset produces the chemokine CCL21, thereby attracting positively selected thymocytes from the cortex to the medulla. Both self-antigen-displaying and thymocyte-attracting mTEC subsets are essential for self-tolerance. Here, we identify a developmental pathway by which mTECs gain their diversity in functionally distinct subsets. We show that CCL21-expressing mTECs arise early during thymus ontogeny in mice. Fate-mapping analysis reveals that self-antigen-displaying mTECs, including Aire-expressing mTECs and thymic tuft cells, are derived from CCL21-expressing cells. The differentiation capability of CCL21-expressing embryonic mTECs is verified in reaggregate thymus experiments. These results indicate that CCL21-expressing embryonic mTECs carry a developmental potential to give rise to self-antigen-displaying mTECs, revealing that the sequential conversion of thymocyte-attracting subset into self-antigen-displaying subset serves to assemble functional diversity in the thymus medulla epithelium. [ABSTRACT FROM AUTHOR]

The thymus is a unique primary lymphoid organ that supports the production of self‐tolerant T‐cells essential for adaptive immunity. Intrathymic microenvironments are microanatomically compartmentalised, forming defined cortical, and medullary regions each differentially supporting critical aspects of thymus‐dependent T‐cell maturation. Importantly, the specific functional properties of thymic cortical and medullary compartments are defined by highly specialised thymic epithelial cells (TEC). For example, in the medulla heterogenous medullary TEC (mTEC) contribute to the enforcement of central tolerance by supporting deletion of autoreactive T‐cell clones, thereby counterbalancing the potential for random T‐cell receptor generation to contribute to autoimmune disease. Recent advances have further shed light on the pathways and mechanisms that control heterogeneous mTEC development and how differential mTEC functionality contributes to control self‐tolerant T‐cell development. Here we discuss recent findings in relation to mTEC development and highlight examples of how mTEC diversity contribute to thymus medulla function. [ABSTRACT FROM AUTHOR]

Exploratory analysis to conceptualize and evaluate the potential cost-effectiveness and economic drivers of using a novel tissue valve compared with mechanical heart valves for surgical aortic valve replacement (SAVR) in people aged 55–64 and 65+ with aortic stenosis (AS) from a National Health Service (NHS) UK perspective. A decision-analytic model was developed using a partitioned survival model. Parameter inputs were obtained from published literature. Deterministic and probabilistic sensitivity analyses (DSA and PSA) were conducted to explore the uncertainty around the parameters. The novel tissue valve was potentially associated with higher quality-adjusted life years (QALYs) of 0.01 per person. Potential cost savings were greatest for those aged 55–64 (£408) versus those aged 65+(£53). DSA indicated the results to be most dependent on relative differences in general mortality, procedure costs, and reoperation rates. PSA estimated around 75% of the iterations to be cost-effective at £20,000 per QALY for those aged 55–64, and 57% for those aged 65+. The exploratory analysis suggests that the novel tissue valve could be a cost-effective intervention for people over the age of 55 with AS who are suitable for SAVR in the UK. [ABSTRACT FROM AUTHOR]