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Abstract Background Paediatric palliative and hospice care aims to improve the quality of life of children with life-limiting and life-threatening conditions and their families. The number of these patients has risen significantly in recent years, resulting in an increased need for palliative care for this population. Although the need for paediatric palliative and hospice care is growing, meaningful outcome evaluation to demonstrate its effectiveness as a complex healthcare intervention is in its early stages. For complex interventions (programmes), theory-based evaluations have grown in prominence in recent years. They seek to understand how and why an intervention works by uncovering its underlying mechanisms by means of programme theory. To support both outcome evaluation in paediatric palliative care and a reflective practice of programme theorizing, we aimed to describe the construction of a programme theory for a specialist paediatric palliative and hospice care programme in Austria and to offer a reflective account of its development process. Methods We drew on a combination of theory-based evaluation frameworks to construct a programme theory consisting of an action and a change component. Through multiple iterations, incorporating different stakeholders’ perspectives and drawing on different sources of knowledge and theory, we theorized how and why the programme likely achieves its intended outcomes. Results The programme theory outlines the proposed chains of events, causal mechanisms and outcomes of a specialist paediatric palliative and hospice care programme for children and families in several areas corresponding to its main conceptual tenets. Through a range of activities and interventions, the programme triggers coping and adaptation mechanisms that ultimately contribute to family and child wellbeing in physical, psychological, social, and spiritual dimensions. Established trust and partnership between children/families and healthcare professionals as well as a person-centered and family-centered approach were identified as enabling factors. Conclusions Our findings provide insights into how a specialized paediatric palliative and hospice care programme works to achieve its intended outcomes for children and families. This helps demonstrate its impact, contributing to meaningful outcome evaluation and service improvement.

Objective To use cell‐based gene signatures to identify patients with systemic lupus erythematous (SLE) in the phase II/III APRIL–SLE and phase IIb ADDRESS II trials most likely to respond to atacicept. Methods A published immune cell deconvolution algorithm based on Affymetrix gene array data was applied to whole blood gene expression from patients entering APRIL‐SLE. Five distinct patient clusters were identified. Patient characteristics, biomarkers, and clinical response to atacicept were assessed per cluster. A modified immune cell deconvolution algorithm was developed based on RNA sequencing data and applied to ADDRESS II data to identify similar patient clusters and their responses. Results Patients in APRIL‐SLE (N = 105) were segregated into the following five clusters (P1‐5) characterized by dominant cell subset signatures: high neutrophils, T helper cells and natural killer (NK) cells (P1), high plasma cells and activated NK cells (P2), high B cells and neutrophils (P3), high B cells and low neutrophils (P4), or high activated dendritic cells, activated NK cells, and neutrophils (P5). Placebo‐ and atacicept‐treated patients in clusters P2,4,5 had markedly higher British Isles Lupus Assessment Group (BILAG) A/B flare rates than those in clusters P1,3, with a greater treatment effect of atacicept on lowering flares in clusters P2,4,5. In ADDRESS II, placebo‐treated patients from P2,4,5 were less likely to be SLE Responder Index (SRI)‐4, SRI‐6, and BILAG‐Based Combined Lupus Assessment responders than those in P1,3; the response proportions again suggested lower placebo effect and a greater treatment differential for atacicept in P2,4,5. Conclusion This exploratory analysis indicates larger differences between placebo‐ and atacicept‐treated patients with SLE in a molecularly defined patient subset.

BackgroundPharmacodynamic biomarkers are becoming increasingly valuable for assessing drug activity and target modulation in clinical trials. However, identifying quality biomarkers is challenging due to the increasing volume and heterogeneity of relevant data describing the biological networks that underlie disease mechanisms. A biological pathway network typically includes entities (e.g. genes, proteins and chemicals/drugs) as well as the relationships between these and is typically curated or mined from structured databases and textual co-occurrence data. We propose a hybrid Natural Language Processing and directed relationships-based network analysis approach using IBM Watson for Drug Discovery to rank all human genes and identify potential candidate biomarkers, requiring only an initial determination of a specific target-disease relationship.MethodsThrough natural language processing of scientific literature, Watson for Drug Discovery creates a network of semantic relationships between biological concepts such as genes, drugs, and diseases. Using Bruton's tyrosine kinase as a case study, Watson for Drug Discovery's automatically extracted relationship network was compared with a prominent manually curated physical interaction network. Additionally, potential biomarkers for Bruton's tyrosine kinase inhibition were predicted using a matrix factorization approach and subsequently compared with expert-generated biomarkers.ResultsWatson's natural language processing generated a relationship network matching 55 (86%) genes upstream of BTK and 98 (95%) genes downstream of Bruton's tyrosine kinase in a prominent manually curated physical interaction network. Matrix factorization analysis predicted 11 of 13 genes identified by Merck subject matter experts in the top 20% of Watson for Drug Discovery's 13,595 ranked genes, with 7 in the top 5%.ConclusionTaken together, these results suggest that Watson for Drug Discovery's automatic relationship network identifies the majority of upstream and downstream genes in biological pathway networks and can be used to help with the identification and prioritization of pharmacodynamic biomarker evaluation, accelerating the early phases of disease hypothesis generation.

In democracies with multi-party competition, government parties face a dual challenge in election campaigns: on the one hand, they have to compete against and criticize their coalition partners. On the other hand, they should avoid virulent attacks on their partners to preserve their chances of future collaboration in government. Going beyond a dichotomous operationalization of negative campaigning, this manuscript analyses the tonality and volume of negative campaigning. Studying 3030 party press releases in four national Austrian election campaigns, different patterns for the tonality and frequency of negative campaigning reflect the electoral dilemma of government parties. Coalition parties criticize each other abundantly but refrain from ‘burning bridges’ with their partners through virulent attacks. These findings have implications for studying negative campaigning and coalition politics.

The anti-phospholipid syndrome (APS) is characterized by recurrent thrombosis and occurrence of anti-phospholipid antibodies (aPL). aPL are necessary, but not sufficient for the clinical manifestations of APS. Growing evidence suggests a role of innate immune cells, in particular polymorphonuclear neutrophils (PMN) and Toll-like receptors (TLR) to be additionally involved. aPL activate endothelial cells and monocytes through a TLR4-dependent signalling pathway. Whether this is also relevant for PMN in a similar way is currently not known. To address this issue, we used purified PMN from healthy donors and stimulated them in the presence or absence of human monoclonal aPL and the TLR4 agonist LPS monitoring neutrophil effector functions, namely the oxidative burst, phagocytosis, L-Selectin shedding and IL-8 production. aPL alone were only able to induce minor activation of PMN effector functions at high concentrations. However, in the additional presence of LPS the activation threshold was markedly lower indicating a synergistic activation pathway of aPL and TLR in PMN. In summary, our results indicate that PMN effector functions are directly activated by aPL and boosted by the additional presence of microbial products. This highlights a role for PMN as important innate immune effector cells that contribute to the pathophysiology of APS.

Chronic obstructive pulmonary disease (COPD) is increasingly recognized as a systemic disease that is associated with increased serum levels of markers of systemic inflammation. The triggering receptor expressed on myeloid cells 1 (TREM-1) is a recently identified activating receptor on neutrophils, monocytes, and macrophage subsets. TREM-1 expression is upregulated by microbial products such as the toll-like receptor ligand lipoteichoic acid of Gram-positive or lipopolysaccharides of Gram-negative bacteria. In the present study, sera from 12 COPD patients (GOLD stages I–IV, FEV1 51 ± 6%) and 10 healthy individuals were retrospectively analyzed for soluble TREM-1 (sTREM-1) using a newly developed ELISA. In healthy subjects, sTREM-1 levels were low (median 0.25 ng/mL, range 0–5.9 ng/mL). In contrast, levels of sTREM-1 in sera of COPD patients were significantly increased (median 11.68 ng/mL, range 6.2–41.9 ng/mL, P

The article discusses a manuscript album owned by Iowa Wesleyan College's library. The album contains autographs, letters and documents and was created by activist Kate Newell Doggett to be sold at the Western Illinois Sanitary Fair to raise funds for soldiers wounded in the U.S. Civil War. Doggett's work as an activist and her participation in sanitary fairs are noted. The album includes antislavery documents by former Massachusetts governor John Albion Andrew, journalist Theodore Tilton and former U.S. president Andrew Johnson as well as autographs and letters by pastor Theodore Parker and author Josiah Phillips Quincy. Poems by Henry Wadsworth Longfellow and Ralph Waldo Emerson were also included in the album.

The article discusses the history of the Iowa Wesleyan College at Mt. Pleasant, Iowa. The author talks about the history of the German Building (also known as the Music Building or Physics Building) on the college's campus. The author explains that this building used to be the German College from 1873 to 1909. The German population in Iowa is examined. The Southwest German Conference of 1870 is mentioned, where the college was first planned. Subjects of the article also include German Methodist ministers, the German library, and the growth of the student body.

Objective: To use cell-based gene signatures to identify patients with systemic lupus erythematous (SLE) in the phase II/III APRIL-SLE and phase IIb ADDRESS II trials most likely to respond to atacicept., Methods: A published immune cell deconvolution algorithm based on Affymetrix gene array data was applied to whole blood gene expression from patients entering APRIL-SLE. Five distinct patient clusters were identified. Patient characteristics, biomarkers, and clinical response to atacicept were assessed per cluster. A modified immune cell deconvolution algorithm was developed based on RNA sequencing data and applied to ADDRESS II data to identify similar patient clusters and their responses., Results: Patients in APRIL-SLE (N = 105) were segregated into the following five clusters (P1-5) characterized by dominant cell subset signatures: high neutrophils, T helper cells and natural killer (NK) cells (P1), high plasma cells and activated NK cells (P2), high B cells and neutrophils (P3), high B cells and low neutrophils (P4), or high activated dendritic cells, activated NK cells, and neutrophils (P5). Placebo- and atacicept-treated patients in clusters P2,4,5 had markedly higher British Isles Lupus Assessment Group (BILAG) A/B flare rates than those in clusters P1,3, with a greater treatment effect of atacicept on lowering flares in clusters P2,4,5. In ADDRESS II, placebo-treated patients from P2,4,5 were less likely to be SLE Responder Index (SRI)-4, SRI-6, and BILAG-Based Combined Lupus Assessment responders than those in P1,3; the response proportions again suggested lower placebo effect and a greater treatment differential for atacicept in P2,4,5., Conclusion: This exploratory analysis indicates larger differences between placebo- and atacicept-treated patients with SLE in a molecularly defined patient subset., (© 2023 EMD Serono, Inc and The Authors. ACR Open Rheumatology published by Wiley Periodicals LLC on behalf of American College of Rheumatology.)

Because of its role in mediating both B cell and Fc receptor signaling, Bruton's tyrosine kinase (BTK) is a promising target for the treatment of autoimmune diseases such as rheumatoid arthritis (RA) and systemic lupus erythematosus (SLE). Evobrutinib is a novel, highly selective, irreversible BTK inhibitor that potently inhibits BCR- and Fc receptor - mediated signaling and, thus, subsequent activation and function of human B cells and innate immune cells such as monocytes and basophils. We evaluated evobrutinib in preclinical models of RA and SLE and characterized the relationship between BTK occupancy and inhibition of disease activity. In mouse models of RA and SLE, orally administered evobrutinib displayed robust efficacy, as demonstrated by reduction of disease severity and histological damage. In the SLE model, evobrutinib inhibited B cell activation, reduced autoantibody production and plasma cell numbers, and normalized B and T cell subsets. In the RA model, efficacy was achieved despite failure to reduce autoantibodies. Pharmacokinetic/pharmacodynamic modeling showed that mean BTK occupancy in blood cells of 80% was linked to near-complete disease inhibition in both RA and SLE mouse models. In addition, evobrutinib inhibited mast cell activation in a passive cutaneous anaphylaxis model. Thus, evobrutinib achieves efficacy by acting both on B cells and innate immune cells. Taken together, our data show that evobrutinib is a promising molecule for the chronic treatment of B cell - driven autoimmune disorders., (Copyright © 2019 by The American Association of Immunologists, Inc.)

Background: Pharmacodynamic biomarkers are becoming increasingly valuable for assessing drug activity and target modulation in clinical trials. However, identifying quality biomarkers is challenging due to the increasing volume and heterogeneity of relevant data describing the biological networks that underlie disease mechanisms. A biological pathway network typically includes entities (e.g. genes, proteins and chemicals/drugs) as well as the relationships between these and is typically curated or mined from structured databases and textual co-occurrence data. We propose a hybrid Natural Language Processing and directed relationships-based network analysis approach using IBM Watson for Drug Discovery to rank all human genes and identify potential candidate biomarkers, requiring only an initial determination of a specific target-disease relationship., Methods: Through natural language processing of scientific literature, Watson for Drug Discovery creates a network of semantic relationships between biological concepts such as genes, drugs, and diseases. Using Bruton's tyrosine kinase as a case study, Watson for Drug Discovery's automatically extracted relationship network was compared with a prominent manually curated physical interaction network. Additionally, potential biomarkers for Bruton's tyrosine kinase inhibition were predicted using a matrix factorization approach and subsequently compared with expert-generated biomarkers., Results: Watson's natural language processing generated a relationship network matching 55 (86%) genes upstream of BTK and 98 (95%) genes downstream of Bruton's tyrosine kinase in a prominent manually curated physical interaction network. Matrix factorization analysis predicted 11 of 13 genes identified by Merck subject matter experts in the top 20% of Watson for Drug Discovery's 13,595 ranked genes, with 7 in the top 5%., Conclusion: Taken together, these results suggest that Watson for Drug Discovery's automatic relationship network identifies the majority of upstream and downstream genes in biological pathway networks and can be used to help with the identification and prioritization of pharmacodynamic biomarker evaluation, accelerating the early phases of disease hypothesis generation., Competing Interests: Funding for this study was provided by Merck KGaA, Darmstadt Germany (https://www.emdgroup.com). Sonja Hatz, Philipp Haselmayer, Harsha Gurulingappa, and Ulrich Betz are employed by Merck KGaA. Andrew Bender and Matthew Studham are employed by EMD Serono. Scott Spangler, Alix Lacoste, Van C Willis, and Richard L Martin were all employed by IBM Watson Health during the time this research was conducted. None of these interests affected the choice of what and where to publish but the topic (pharmacodynamic biomarkers for BTK therapy) was of interest to Merck and learning what IBM's techniques showed in this case was also of interest to them. Watson for Drug Discovery is a product of IBM Watson Health. There are no patents, products in development or other marketed products to declare. This does not alter our adherence to all the PLOS ONE policies on data and materials.

The TNF family cytokines B-cell activating factor (BAFF) and a proliferation-inducing ligand (APRIL) support plasma cell survival. It is known that inhibitors of BAFF only (BAFFR-Fc) or BAFF and APRIL (TACI-Fc) administered early enough in an NZB/NZW F1 mouse model of systemic lupus erythematosus (SLE) ameliorate clinical outcomes, pointing to a pathogenic role of BAFF. In the present study, TACI-Fc administrated at a later stage of disease, after onset of autoimmunity, decreased the number of bone marrow plasma cells and slowed down further formation of autoantibodies. TACI-Fc prevented renal damage during a 12-week treatment period regardless of autoantibody levels, while BAFFR-Fc did not despite a similar BAFF-blocking activity in vivo. TACI-Fc also decreased established plasma cells in a T-dependent hapten/carrier immunization system better than single inhibitors of BAFF or APRIL, and sometimes better than combined single inhibitors with at least equivalent BAFF and APRIL inhibitory activities. These results indicate that TACI-Fc can prevent symptoms of renal damage in a mouse model of SLE when BAFFR-Fc cannot, and point to a plasticity of plasma cells for survival factors. Targeting plasma cells with TACI-Fc might be beneficial to prevent autoantibody-mediated damages in SLE., (© 2017 The Authors. European Journal of Immunology published by WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.)

SLE is a complex autoimmune inflammatory disease characterized by pathogenic autoantibody production as a consequence of uncontrolled T-B cell activity and immune-complex deposition in various organs, including kidney, leading to tissue damage and function loss. There is a high unmet need for better treatment options other than corticosteroids and immunosuppressants. Phosphoinositol-3 kinase δ (PI3Kδ) is a promising target in this respect as it is essential in mediating B- and T-cell function in mouse and human. We report the identification of selective PI3Kδ inhibitors that blocked B-, T-, and plasmacytoid dendritic cell activities in human peripheral blood and in primary cell co-cultures (BioMAP(®)) without detecting signs of undesired toxicity. In an IFNα-accelerated mouse SLE model, our PI3Kδ inhibitors blocked nephritis development, whether administered at the onset of autoantibody appearance or the onset of proteinuria. Disease amelioration correlated with normalized immune cell numbers in the spleen, reduced immune-complex deposition as well as reduced inflammation, fibrosis, and tissue damage in the kidney. Improvements were similar to those achieved with a frequently prescribed drug for lupus nephritis, the potent immunosuppressant mycophenolate mofetil. Finally, we established a pharmacodynamics/pharmacokinetic/efficacy model that revealed that a sustained PI3Kδ inhibition of 50% is sufficient to achieve full efficacy in our disease model. These data demonstrate the therapeutic potential of PI3Kδ inhibitors in SLE and lupus nephritis.

The anti-phospholipid syndrome (APS) is characterized by recurrent thrombosis and occurrence of anti-phospholipid antibodies (aPL). aPL are necessary, but not sufficient for the clinical manifestations of APS. Growing evidence suggests a role of innate immune cells, in particular polymorphonuclear neutrophils (PMN) and Toll-like receptors (TLR) to be additionally involved. aPL activate endothelial cells and monocytes through a TLR4-dependent signalling pathway. Whether this is also relevant for PMN in a similar way is currently not known. To address this issue, we used purified PMN from healthy donors and stimulated them in the presence or absence of human monoclonal aPL and the TLR4 agonist LPS monitoring neutrophil effector functions, namely the oxidative burst, phagocytosis, L-Selectin shedding and IL-8 production. aPL alone were only able to induce minor activation of PMN effector functions at high concentrations. However, in the additional presence of LPS the activation threshold was markedly lower indicating a synergistic activation pathway of aPL and TLR in PMN. In summary, our results indicate that PMN effector functions are directly activated by aPL and boosted by the additional presence of microbial products. This highlights a role for PMN as important innate immune effector cells that contribute to the pathophysiology of APS.

Chronic obstructive pulmonary disease (COPD) is increasingly recognized as a systemic disease that is associated with increased serum levels of markers of systemic inflammation. The triggering receptor expressed on myeloid cells 1 (TREM-1) is a recently identified activating receptor on neutrophils, monocytes, and macrophage subsets. TREM-1 expression is upregulated by microbial products such as the toll-like receptor ligand lipoteichoic acid of Gram-positive or lipopolysaccharides of Gram-negative bacteria. In the present study, sera from 12 COPD patients (GOLD stages I-IV, FEV1 51 +/- 6%) and 10 healthy individuals were retrospectively analyzed for soluble TREM-1 (sTREM-1) using a newly developed ELISA. In healthy subjects, sTREM-1 levels were low (median 0.25 ng/mL, range 0-5.9 ng/mL). In contrast, levels of sTREM-1 in sera of COPD patients were significantly increased (median 11.68 ng/mL, range 6.2-41.9 ng/mL, P<.05). Furthermore, serum levels of sTREM-1 showed a significant negative correlation with lung function impairment. In summary, serum concentrations of sTREM-1 are increased in patients with COPD. Prospective studies are warranted to evaluate the relevance of sTREM-1 as a potential marker of the disease in patients with COPD.