Individual interactions in a multi-country implementation-focused quality of care network for maternal, newborn and child health: A social network analysis

The Network for Improving Quality of Care for Maternal, Newborn and Child Health (QCN) was established to build a cross-country platform for joint-learning around quality improvement implementation approaches to reduce mortality. This paper describes and explores the structure of the QCN in four countries and at global level. Using Social Network Analysis (SNA), this cross-sectional study maps the QCN networks at global level and in four countries (Bangladesh, Ethiopia, Malawi and Uganda) and assesses the interactions among actors involved. A pre-tested closed-ended structured questionnaire was completed by 303 key actors in early 2022 following purposeful and snowballing sampling. Data were entered into an online survey tool, and exported into Microsoft Excel for data management and analysis. This study received ethical approval as part of a broader evaluation. The SNA identified 566 actors across the four countries and at global level. Bangladesh, Malawi and Uganda had multiple-hub networks signifying multiple clusters of actors reflecting facility or district networks, whereas the network in Ethiopia and at global level had more centralized networks. There were some common features across the country networks, such as low overall density of the network, engagement of actors at all levels of the system, membership of related committees identified as the primary role of actors, and interactions spanning all types (learning, action and information sharing). The most connected actors were facility level actors in all countries except Ethiopia, which had mostly national level actors. The results reveal the uniqueness and complexity of each network assessed in the evaluation. They also affirm the broader qualitative evaluation assessing the nature of these networks, including composition and leadership. Gaps in communication between members of the network and limited interactions of actors between countries and with global level actors signal opportunities to strengthen QCN

Heterogeneity of Multifunctional IL-17A Producing S. Typhi-Specific CD8+ T Cells in Volunteers following Ty21a Typhoid Immunization

Salmonella enterica serovar Typhi (S. Typhi), the causative agent of typhoid fever, continues to cause significant morbidity and mortality world-wide. CD8+ T cells are an important component of the cell mediated immune (CMI) response against S. Typhi. Recently, interleukin (IL)-17A has been shown to contribute to mucosal immunity and protection against intracellular pathogens. To investigate multifunctional IL-17A responses against S. Typhi antigens in T memory subsets, we developed multiparametric flow cytometry methods to detect up to 6 cytokines/chemokines (IL-10, IL-17A, IL-2, interferon-γ (IFN-γ), tumor necrosis factor-α (TNF-α) and macrophage inflammatory protein-1β (MIP-1β)) simultaneously. Five volunteers were immunized with a 4 dose regimen of live-attenuated S. Typhi vaccine (Ty21a), peripheral blood mononuclear cells (PBMC) were isolated before and at 11 time points after immunization, and CMI responses were evaluated. Of the 5 immunized volunteers studied, 3 produced detectable CD8+ T cell responses following stimulation with S. Typhi-infected autologous B lymphoblastoid cell lines (B-LCL). Additionally, 2 volunteers had detectable levels of intracellular cytokines in response to stimulation with S. Typhi-infected HLA-E restricted cells. Although the kinetics of the responses differed among volunteers, all of the responses were bi- or tri-phasic and included multifunctional CD8+ T cells. Virtually all of the IL-17A detected was derived from multifunctional CD8+ T cells. The presence of these multifunctional IL-17A+ CD8+ T cells was confirmed using an unsupervised analysis program, flow cytometry clustering without K (FLOCK). This is the first report of IL-17A production in response to S. Typhi in humans, indicating the presence of a Tc17 response which may be important in protection. The presence of IL-17A in multifunctional cells co-producing Tc1 cytokines (IL-2, IFN-γ and TNF-α) may also indicate that the distinction between Tc17 and Tc1 responses in humans is not as clearly delineated as suggested by in vitro experiments and animal models

End-to-End Memory Networks: A Survey

Constructing a dialog system which can speak naturally with a human is considered as a major challenge of artificial intelligence. End-to-end dialog system is taken to be a primary research topic in the area of conversational systems. Since an end-to-end dialog system is structured based on learning a dialog policy from transactional dialogs in a defined extent, therefore, useful datasets are required for evaluating the learning procedures. In this paper, different deep learning techniques are applied to the Dialog bAbI datasets. On this dataset, the performance of the proposed techniques is analyzed. The performance results demonstrate that all the proposed techniques attain decent precisions on the Dialog bAbI datasets. The best performance is obtained utilizing end-to-end memory network with a unified weight tying scheme (UN2N)

Recognition of the Major Histocompatibility Complex (MHC) class Ib molecule H2-Q10 by the natural killer cell receptor Ly49C

Murine natural killer (NK) cells are regulated by the interaction of Ly49 receptors with major histocompatibility complex class I molecules (MHC-I). Although the ligands for inhibitory Ly49 were considered to be restricted to classical MHC (MHC-Ia), we have shown that the non-classical MHC molecule (MHC-Ib) H2-M3 was a ligand for the inhibitory Ly49A. Here we establish that another MHC-Ib, H2-Q10, is a bona fide ligand for the inhibitory Ly49C receptor. H2-Q10 bound to Ly49C with a marginally lower affinity (∼5 μm) than that observed between Ly49C and MHC-Ia (H-2Kb/H-2Dd, both ∼1 μm), and this recognition could be prevented by cis interactions with H-2K in situ. To understand the molecular details underpinning Ly49·MHC-Ib recognition, we determined the crystal structures of H2-Q10 and Ly49C bound H2-Q10. Unliganded H2-Q10 adopted a classical MHC-I fold and possessed a peptide-binding groove that exhibited features similar to those found in MHC-Ia, explaining the diverse peptide binding repertoire of H2-Q10. Ly49C bound to H2-Q10 underneath the peptide binding platform to a region that encompassed residues from the α1, α2, and α3 domains, as well as the associated β2-microglobulin subunit. This docking mode was conserved with that previously observed for Ly49C·H-2Kb. Indeed, structure-guided mutation of Ly49C indicated that Ly49C·H2-Q10 and Ly49C·H-2Kb possess similar energetic footprints focused around residues located within the Ly49C β4-stand and L5 loop, which contact the underside of the peptide-binding platform floor. Our data provide a structural basis for Ly49·MHC-Ib recognition and demonstrate that MHC-Ib represent an extended family of ligands for Ly49 molecules

In Vivo Expression Pattern of MICA and MICB and Its Relevance to Auto-Immunity and Cancer

Non-conventional MHC class I MIC molecules interact not with the TCR, but with NKG2D, a C-type lectin activatory receptor present on most NK, γδ and CD8+ αβ T cells. While this interaction is critical in triggering/calibrating the cytotoxic activity of these cells, the actual extent of its in vivo involvement, in man, in infection, cancer or autoimmunity, needs further assessment. The latter has gained momentum along with the reported expansion of peripheral CD4+CD28−NKG2D+ T cells in rheumatoid arthritis (RA). We first initiated to extend this report to a larger cohort of not only RA patients, but also those affected by systemic lupus erythematosus (SLE) and Sjögren's syndrome (SS). In RA and SS, this initial observation was further tested in target tissues: the joint and the salivary glands, respectively. In conclusion and despite occasional and indiscriminate expansion of the previously incriminated T cell subpopulation, no correlation could be observed between the CD4+CD28−NKG2D+ and auto-immunity. Moreover, in situ, the presence of NKG2D matched that of CD8+, but not that of CD4+ T cells. In parallel, a total body tissue scan of both MICA and MICB transcription clearly shows that despite original presumptions, and with the exception of the central nervous system, both genes are widely transcribed and therefore possibly translated and membrane-bound. Extending this analysis to a number of human tumors did not reveal a coherent pattern of expression vs. normal tissues. Collectively these data question previous assumptions, correlating a tissue-specific expression/induction of MIC in relevance to auto-immune or tumor processes

Mycobacteria Attenuate Nociceptive Responses by Formyl Peptide Receptor Triggered Opioid Peptide Release from Neutrophils

In inflammation, pain is regulated by a balance of pro- and analgesic mediators. Analgesic mediators include opioid peptides which are secreted by neutrophils at the site of inflammation, leading to activation of opioid receptors on peripheral sensory neurons. In humans, local opioids and opioid peptides significantly downregulate postoperative as well as arthritic pain. In rats, inflammatory pain is induced by intraplantar injection of heat inactivated Mycobacterium butyricum, a component of complete Freund's adjuvant. We hypothesized that mycobacterially derived formyl peptide receptor (FPR) and/or toll like receptor (TLR) agonists could activate neutrophils, leading to opioid peptide release and inhibition of inflammatory pain. In complete Freund's adjuvant-induced inflammation, thermal and mechanical nociceptive thresholds of the paw were quantified (Hargreaves and Randall-Selitto methods, respectively). Withdrawal time to heat was decreased following systemic neutrophil depletion as well as local injection of opioid receptor antagonists or anti-opioid peptide (i.e. Met-enkephalin, β-endorphin) antibodies indicating an increase in pain. In vitro, opioid peptide release from human and rat neutrophils was measured by radioimmunoassay. Met-enkephalin release was triggered by Mycobacterium butyricum and formyl peptides but not by TLR-2 or TLR-4 agonists. Mycobacterium butyricum induced a rise in intracellular calcium as determined by FURA loading and calcium imaging. Opioid peptide release was blocked by intracellular calcium chelation as well as phosphoinositol-3-kinase inhibition. The FPR antagonists Boc-FLFLF and cyclosporine H reduced opioid peptide release in vitro and increased inflammatory pain in vivo while TLR 2/4 did not appear to be involved. In summary, mycobacteria activate FPR on neutrophils, resulting in tonic secretion of opioid peptides from neutrophils and in a decrease in inflammatory pain. Future therapeutic strategies may aim at selective FPR agonists to boost endogenous analgesia

Towards sustainable electrochemistry: green synthesis and sintering aid modulations in the development of BaZr0.87Y0.1M0.03O3−δ (M = Mn, Co, and Fe) IT-SOFC electrolytes

In this study, BaZr0.87Y0.1M0.03O3−δ perovskite electrolytes with sintering aids (M = Mn, Co, and Fe) were synthesized by a sustainable approach using spinach powder as a chelating agent and then compared with chemically synthesized BaZr0.87Y0.1M0.03O3−δ (M = Mn, Co, and Fe) electrolytes for intermediate temperature SOFCs. This is the first example of such a sustainable synthesis of perovskite materials with sintering aids. Structural analysis revealed the presence of a cubic perovskite structure in BaZr0.87Y0.1M0.03O3−δ (M = Mn, Co, and Fe) samples synthesized by both green and conventional chemical methods. No significant secondary phases were observed in the samples synthesized by a sustainable approach. The observed phenomena of plane shift were because of the disparities between ionic radii of the dopants, impurities, and host materials. The surface morphology analysis revealed a denser microstructure for the electrolytes synthesized via green routes due to metallic impurities in the organic chelating agent. The absence of significant impurities was also observed by compositional analysis, while functional groups were identified through Fourier-transform infrared spectroscopy. Conductivity measurements showed that BaZr0.87Y0.1M0.03O3−δ (M = Mn, Co, and Fe) electrolytes synthesized by oxalic acid have higher conductivities compared to BaZr0.87Y0.1M0.03O3−δ (M = Mn, Co, and Fe) electrolytes synthesized by the green approach. The button cells employing BaZr0.87Y0.1Co0.03O3−δ electrolytes synthesized by the chemical and green routes achieved peak power densities 344 and 271 mW·cm−2 respectively, suggesting that the novel green route can be applied to synthesize SOFC perovskite materials with minimal environmental impact and without significantly compromising cell performance. Copyright © 2023 Ain, Irshad, Butt, Tabish, Hanif, Khalid, Ghaffar, Rafique, Shawar Kazmi, Siraj, Hafez, Abd-Rabboh, Zmrhalova, Filonova, Medvedev and Motola.Deanship of Scientific Research, King Khalid University: RGP.2/335/44The authors declare financial support was received for the research, authorship, and/or publication of this article. The authors extend their appreciation to the Deanship of Scientific Research at King Khalid University for funding this work through the Large Groups Project under grant number (RGP.2/335/44)