Neprilysin is a mediator of alternative renin-angiotensin-system activation in the murine and human kidney

Cardiovascular and renal pathologies are frequently associated with an activated renin-angiotensin-system (RAS) and increased levels of its main effector and vasoconstrictor hormone angiotensin II (Ang II). Angiotensin-converting-enzyme-2 (ACE2) has been described as a crucial enzymatic player in shifting the RAS towards its so-called alternative vasodilative and reno-protective axis by enzymatically converting Ang II to angiotensin-(1-7) (Ang-(1-7)). Yet, the relative contribution of ACE2 to Ang-(1-7) formation in vivo has not been elucidated. Mass spectrometry based quantification of angiotensin metabolites in the kidney and plasma of ACE2 KO mice surprisingly revealed an increase in Ang-(1-7), suggesting additional pathways to be responsible for alternative RAS activation in vivo. Following assessment of angiotensin metabolism in kidney homogenates, we identified neprilysin (NEP) to be a major source of renal Ang-(1-7) in mice and humans. These findings were supported by MALDI imaging, showing NEP mediated Ang-(1-7) formation in whole kidney cryo-sections in mice. Finally, pharmacologic inhibition of NEP resulted in strongly decreased Ang-(1-7) levels in murine kidneys. This unexpected new role of NEP may have implications for the combination therapy with NEP-inhibitors and angiotensin-receptor-blockade, which has been shown being a promising therapeutic approach for heart failure therapy

Role of the Programmed Death-1 Pathway in Regulation of Alloimmune Responses In Vivo

Abstract Programmed death-1 (PD-1), an inhibitory receptor up-regulated on activated T cells, has been shown to play a critical immunoregulatory role in peripheral tolerance, but its role in alloimmune responses is poorly understood. Using a novel alloreactive TCR-transgenic model system, we examined the functions of this pathway in the regulation of alloreactive CD4+ T cell responses in vivo. PD-L1, but not PD-1 or PD-L2, blockade accelerated MHC class II-mismatched skin graft (bm12 (I-Abm12) into B6 (I-Ab)) rejection in a similar manner to CTLA-4 blockade. In an adoptive transfer model system using the recently described anti-bm12 (ABM) TCR-transgenic mice directly reactive to I-Abm12, PD-1 and PD-L1 blockade enhanced T cell proliferation early in the immune response. In contrast, at a later time point preceding accelerated allograft rejection, only PD-L1 blockade enhanced T cell proliferation. In addition, PD-L1 blockade enhanced alloreactive Th1 cell differentiation. Apoptosis of alloantigen-specific T cells was inhibited significantly by PD-L1 but not PD-1 blockade, indicating that PD-1 may not be the receptor for the apoptotic effect of the PD-L1-signaling pathway. Interestingly, the effect of PD-L1 blockade was dependent on the presence of CD4+CD25+ regulatory T cells in vivo. These data demonstrate a critical role for the PD-1 pathway, particularly PD-1/PD-L1 interactions, in the regulation of alloimmune responses in vivo.</jats:p

How should health service organizations respond to diversity? A content analysis of six approaches

Background Health care organizations need to be responsive to the needs of increasingly diverse patient populations. We compared the contents of six publicly available approaches to organizational responsiveness to diversity. The central questions addressed in this paper are: what are the most consistently recommended issues for health care organizations to address in order to be responsive to the needs of diverse groups that differ from the majority population? How much consensus is there between various approaches? Methods We purposively sampled six approaches from the US, Australia and Europe and used qualitative textual analysis to categorize the content of each approach into domains (conceptually distinct topic areas) and, within each domain, into dimensions (operationalizations). The resulting classification framework was used for comparative analysis of the content of the six approaches. Results We identified seven domains that were represented in most or all approaches: organizational commitment, empirical evidence on inequalities and needs, a competent and diverse workforce, ensuring access for all users, ensuring responsiveness in care provision, fostering patient and community participation, and actively promoting responsiveness. Variations in the operationalization of these domains related to different scopes, contexts and types of diversity. For example, approaches that focus on ethnic diversity mostly provide recommendations to handle cultural and language differences; approaches that take an intersectional approach and broaden their target population to vulnerable groups in a more general sense also pay attention to factors such as socio-economic status and gender. Conclusions Despite differences in labeling, there is a broad consensus about what health care organizations need to do in order to be responsive to patient diversity. This opens the way to full scale implementation of organizational responsiveness in healthcare and structured evaluation of its effectiveness in improving patient outcomes

Communication barriers in maternity care of allophone migrants : experiences of women, healthcare professionals and intercultural interpreters

This is the peer reviewed version which has been published in final form at [https://doi.org/10.1111/jan.14093]. This article may be used for non-commercial purposes in accordance with Wiley Terms and Conditions for Use of Self-Archived Versions.Aim: To describe communication barriers faced by allophone migrant women in maternity care provision from the perspectives of migrant women, healthcare professionals and intercultural interpreters. Background: Perinatal health inequality of migrant women hinges on barriers to services, with a major barrier being language. Their care is often also perceived as demanding due to conflicting values or complex situations. Potentially divergent perceptions of users and providers may hinder efficient communication. Design: Qualitative explorative study. Methods: A convenience sample of 36 participants was recruited in the German speaking region of Switzerland. The sample consisted of four Albanian and six Tigrinya speaking women, 22 healthcare professionals and four intercultural interpreters (March‐June 2016) who participated in 3 focus group discussions and seven semi‐structured interviews. Audio recordings of the discussions and interviews were transcribed and thematically analysed. Results: The analysis revealed three main themes: the challenge of understanding each other's world, communication breakdowns and imposed health services. Without interpretation communication was reduced to a bare minimum and thus insufficient to adequately inform women about treatment and address their expectations and needs. Conclusion: A primary step in dismantling barriers is guaranteed intercultural interpreting services. Additionally, healthcare professionals need to continuously develop and reflect on their transcultural communication. Institutions must enable professionals to respond flexibly to allophone women's needs and to offer care options that are safe and in accordance to their cultural values. Impact: Our results provide the foundation of tenable care of allophonic women and emphasize the importance of linguistic understanding in care quality

Evaluating equity in healthcare: pilot implementation of a self-assessment tool

Abstract Background Several sets of standards aiming at improving access and quality of care for service users have been published in recent years. Certain standards focused on improving healthcare providers’ responsiveness to specific target groups. The general goal of this research was to improve organisations’ awareness of equity standards that are not focused on specific groups, but on all contributing factors that put vulnerable groups at risk of exclusion. The specific objective was to evaluate the degree of compliance with a set of equity standards in 52 health care organisations from 16 countries. Methods A self-assessment tool (SAT) was developed to allow healthcare organisations to measure their capacity to provide equitable care for service users. The SAT indicates the main areas that should be addressed: equity in policy; equitable access and utilisation; equitable quality of care; equity in participation; promoting equity. A cross-sectional survey addressing participants from pilot-organisations was used for data collection, concerning both the self-reported compliance score with the standards, as well as the additional information provided to support the score assigned. Data were analysed quantitatively as well as qualitatively. Results The findings confirm that healthcare providers do invest in improving equity in the access and delivery of services to vulnerable groups. However, many health organisations have inadequate strategies to address inequities and are insufficiently engaged in improving equity in participation and promoting equity outside the organisation. Conclusions The participating organisations reported a significant impact from use of the self-assessment tool: some received the support from regional/national authorities to continue working on improving equity in healthcare; others linked the equity standards to existing performance-measurement strategies; others invested in new frameworks to improve service users engagement. Key messages The implementation of the SAT contributes to a self-reflective process, involving health professionals and managers, in which gaps and potential improvements are identified. Pilot organisations utilised the SAT as part of a process of increasing their awareness of equity issues and changing their organisational culture. </jats:sec