Micro-Ethical Decision Making Among Baccalaureate Nursing Students: A Qualitative Investigation

Nursing students frequently encounter micro-ethical nursing practice problems during their clinical experience. The purpose of this study was to understand the lived experiences of senior-level baccalaureate students faced with making micro-ethical clinical decisions in practice settings. A descriptive qualitative design was used, and five central themes emerged. A dominant finding was the experience of unapplied and forgotten ethics education revealing a mismatch between what faculty perceived was taught and students’ experiences of that education. When faced with micro-ethical decisions, participants trusted and deferred to staff nurse recommendations, even if the advice contradicted best-practice standards. Contextual naivete was brought out of concealment, contributing to the experience of moral disequilibrium (i.e., students felt conflicted about what they learned in school as best practice and what they observed being role modeled in the clinical environment). This study resulted in theory-guided implications for nursing education and recommendations for future study

The BMP antagonist Gremlin1 contributes to the development of cortical excitatory neurons, motor balance and fear responses

Bone morphogenetic protein (BMP) signaling is required for early forebrain development and cortical formation. How the endogenous modulators of BMP signaling regulate the structural and functional maturation of the developing brain remains unclear. Here we show that expression of the BMP antagonist, Grem1, marks committed layer Ⅴ and Ⅵ glutamatergic neurons in the embryonic mouse brain. Lineage tracing of Grem1-expressing cells in the embryonic brain was examined by administration of tamoxifen to pregnant Grem1creERT; Rosa26LSLTdtomato mice at 13.5 days post coitum (dpc), followed by collection of embryos later in gestation. In addition, at 14.5 dpc, bulk mRNA seq analysis of differentially expressed transcripts between FACS sorted Grem1 positive and negative cells was performed. We also generated Emx1-cre mediated Grem1 conditional knockout mice (Emx1-Cre;Grem1flox/flox) in which the Grem1 gene was deleted specifically in the dorsal telencephalon. Grem1Emx1cKO animals had reduced cortical thickness, especially layers Ⅴ and Ⅵ and impaired motor balance and fear sensitivity compared to littermate controls. This study has revealed new roles for Grem1 in the structural and functional maturation of the developing cortex.Mari Ichinose, Nobumi Suzuki, Tongtong Wang, Hiroki Kobayashi, Laura Vrbanac, Jia Q. Ng, Josephine A. Wright, Tamsin R. M. Lannagan, Krystyna A. Gieniec, Martin Lewis, Ryota Ando, Atsushi Enomoto, Simon Koblar, Paul Thomas, Daniel L. Worthley and Susan L. Wood

The management of diabetic ketoacidosis in children

The object of this review is to provide the definitions, frequency, risk factors, pathophysiology, diagnostic considerations, and management recommendations for diabetic ketoacidosis (DKA) in children and adolescents, and to convey current knowledge of the causes of permanent disability or mortality from complications of DKA or its management, particularly the most common complication, cerebral edema (CE). DKA frequency at the time of diagnosis of pediatric diabetes is 10%–70%, varying with the availability of healthcare and the incidence of type 1 diabetes (T1D) in the community. Recurrent DKA rates are also dependent on medical services and socioeconomic circumstances. Management should be in centers with experience and where vital signs, neurologic status, and biochemistry can be monitored with sufficient frequency to prevent complications or, in the case of CE, to intervene rapidly with mannitol or hypertonic saline infusion. Fluid infusion should precede insulin administration (0.1 U/kg/h) by 1–2 hours; an initial bolus of 10–20 mL/kg 0.9% saline is followed by 0.45% saline calculated to supply maintenance and replace 5%–10% dehydration. Potassium (K) must be replaced early and sufficiently. Bicarbonate administration is contraindicated. The prevention of DKA at onset of diabetes requires an informed community and high index of suspicion; prevention of recurrent DKA, which is almost always due to insulin omission, necessitates a committed team effort

Advancing translational research for colorectal immuno-oncology

OnlinePublColorectal cancer (CRC) is a common and deadly disease. Unfortunately, immune checkpoint inhibitors (ICIs) fail to elicit effective anti-tumour responses in the vast majority of CRC patients. Patients that are most likely to respond are those with DNA mismatch repair deficient (dMMR) and microsatellite instability (MSI) disease. However, reliable predictors of ICI response are lacking, even within the dMMR/MSI subtype. This, together with identification of novel mechanisms to increase response rates and prevent resistance, are ongoing and vitally important unmet needs. To address the current challenges with translation of early research findings into effective therapeutic strategies, this review summarises the present state of preclinical testing used to inform the development of immuno-regulatory treatment strategies for CRC. The shortfalls and advantages of commonly utilised mouse models of CRC, including chemically induced, transplant and transgenic approaches are highlighted. Appropriate use of existing models, incorporation of patient-derived data and development of cutting-edge models that recapitulate important features of human disease will be key to accelerating clinically relevant research in this area.Elaine M. Thomas, Josephine A. Wright, Stephen J. Blake, Amanda J. Page, Daniel L. Worthley, and Susan L. Wood

Tandem lesions associate with angiographic progression of coronary artery stenoses

Available online 3 May 2024Background: Although the clinical factors associated with progression of coronary artery disease have been well studied, the angiographic predictors are less defined. Objectives: Our objective was to study the clinical and angiographic factors that associate with progression of coronary artery stenoses. Methods: We conducted a retrospective analysis of consecutive patients undergoing multiple, clinically indicated invasive coronary angiograms with an interval greater than 6 months, between January 2013 and December 2016. Lesion segments were analysed using Quantitative Coronary Angiography (QCA) if a stenosis ≥ 20 % was identified on either angiogram. Stenosis progression was defined as an increase ≥ 10 % in stenosis severity, with progressor groups analysed on both patient and lesion levels. Mixed-effects regression analyses were performed to evaluate factors associated with progression of individual stenoses. Results: 199 patients were included with 881 lesions analysed. 108 (54.3 %) patients and 186 (21.1 %) stenoses were classified as progressors. The median age was 65 years (IQR 56–73) and the median interval between angiograms was 2.1 years (IQR 1.2–3.0). On a patient level, age, number of lesions and presence of multivessel disease at baseline were each associated with progressor status. On a lesion level, presence of a stenosis downstream (OR 3.07, 95 % CI 2.04–4.63, p < 0.001) and circumflex artery stenosis location (OR 1.81, 95 % CI 1.21–2.7, p = 0.004) were associated with progressor status. Other lesion characteristics did not significantly impact progressor status or change in stenosis severity. Conclusion: Coronary lesions which have a downstream stenosis may be at increased risk of stenosis progression. Further research into the mechanistic basis of this finding is required, along with its implications for plaque vulnerability and clinical outcomes.Kyle B. Franke, Nicholas J. Montarello, Adam J. Nelson, Jessica A. Marathe, Dennis T.L. Wong, Rosanna Tavella, Margaret Arstall, Christopher Zeitz, Matthew I. Worthley, John F. Beltrame, Peter J. Psalti

Delineating proinflammatory microenvironmental signals by ex vivo modeling of the immature intestinal stroma

The intestinal stroma provides an important microenvironment for immune cell activation. The perturbation of this tightly regulated process can lead to excessive inflammation. We know that upregulated Toll-like receptor 4 (TLR4) in the intestinal epithelium plays a key role in the inflammatory condition of preterm infants, such as necrotizing enterocolitis (NEC). However, the surrounding stromal contribution to excessive inflammation in the pre-term setting awaits careful dissection. Ex vivo co-culture of embryonic day 14.5 (E14.5) or adult murine intestinal stromal cells with exogenous monocytes was undertaken. We also performed mRNAseq analysis of embryonic and adult stromal cells treated with vehicle control or lipopolysaccharide (LPS), followed by pathway and network analyses of differentially regulated transcripts. Cell characteristics were compared using flow cytometry and pHrodo red phagocytic stain, candidate gene analysis was performed via siRNA knockdown and gene expression measured by qPCR and ELISA. Embryonic stromal cells promote the differentiation of co-cultured monocytes to CD11b(high)CD11c(high) mononuclear phagocytes, that in turn express decreased levels of CD103. Global mRNAseq analysis of stromal cells following LPS stimulation identified TLR signaling components as the most differentially expressed transcripts in the immature compared to adult setting. We show that CD14 expressed by CD11b⁺CD45⁺ embryonic stromal cells is a key inducer of TLR mediated inflammatory cytokine production and phagocytic activity of monocyte derived cells. We utilise transcriptomic analyses and functional ex vivo modelling to improve our understanding of unique molecular cues provided by the immature intestinal stroma.Mari Ichinose, Nobumi Suzuki, Tongtong Wang, Josephine A. Wright, Tamsin R.M. Lannagan, Laura Vrbanac, Hiroki Kobayashi, Krystyna Gieniec, Jia Q. Ng, Souzaburo Ihara, Chris Mavrangelos, Yoku Hayakawa, Patrick Hughes, Daniel L. Worthley, Susan L. Wood

Portal Vein Injection of Colorectal Cancer Organoids to Study the Liver Metastasis Stroma

Hepatic metastasis of colorectal cancer (CRC) is a leading cause of cancer-related death. Cancer-associated fibroblasts (CAFs), a major component of the tumor microenvironment, play a crucial role in metastatic CRC progression and predict poor patient prognosis. However, there is a lack of satisfactory mouse models to study the crosstalk between metastatic cancer cells and CAFs. Here, we present a method to investigate how liver metastasis progression is regulated by the metastatic niche and possibly could be restrained by stroma-directed therapy. Portal vein injection of CRC organoids generated a desmoplastic reaction, which faithfully recapitulated the fibroblast-rich histology of human CRC liver metastases. This model was tissue-specific with a higher tumor burden in the liver when compared to an intra-splenic injection model, simplifying mouse survival analyses. By injecting luciferase-expressing tumor organoids, tumor growth kinetics could be monitored by in vivo imaging. Moreover, this preclinical model provides a useful platform to assess the efficacy of therapeutics targeting the tumor mesenchyme. We describe methods to examine whether adeno-associated virus-mediated delivery of a tumor-inhibiting stromal gene to hepatocytes could remodel the tumor microenvironment and improve mouse survival. This approach enables the development and assessment of novel therapeutic strategies to inhibit hepatic metastasis of CRC.Hiroki Kobayashi, Krystyna A. Gieniec, Jia Q. Ng, Jarrad Goyne, Tamsin R. M. Lannagan, Elaine M. Thomas, Georgette Radford, Tongtong Wang, Nobumi Suzuki, Mari Ichinose, Josephine A. Wright, Laura Vrbanac, Alastair D. Burt, Masahide Takahashi, Atsushi Enomoto, Daniel L. Worthley, Susan L. Wood

In-vivo dosimetry for field sizes down to 6~\texttimes~6~mm2 in shaped beam radiosurgery with microMOSFET

International audienc

Stromal DLK1 promotes proliferation and inhibits differentiation of the intestinal epithelium during development

First published January 20, 2021BACKGROUND & AIMS: The stem/progenitor cells of the developing intestine arebiologically distinct from their adult counterparts. Here we examine the microenvironmental cues that regulate the embryonic stem/progenitor population, focusing on the role of Notch pathway factor, Delta-Like Protein 1 (DLK1). METHODS: mRNAseq analyses of intestinal mesenchymal cells (IMC) collected from embryonic day 14.5 (E14.5) or adult IMCs and a novel co-culture system with E14.5 intestinal epithelial organoids were used. Following addition of recombinant DLK1 (rDLK) or Dlk1 siRNA (siDlk1), epithelial characteristics were compared using imaging, replating efficiency assays, qPCR and immunocytochemistry. The intestinal phenotype of littermate Dlk1 +/+ and Dlk1 -/- mice was compared using immunohistochemistry. RESULTS: Using transcriptomic analyses we identified morphogens derived from the embryonic mesenchyme that potentially regulate the developing epithelial cells, to focus on Notch family candidate, DLK1. Immunohistochemistry indicated that DLK1 was expressed exclusively in the intestinal stroma at E14.5 at the top of emerging villi, decreased after birth and shifted to the intestinal epithelium in adulthood. In co-culture experiments, addition of rDLK1 to adult IMCs inhibited organoid differentiation, whereas Dlk1 knock-down in embryonic IMCs increased epithelial differentiation to secretory lineage cells. Dlk1 -/- mice had restricted Ki67+ cells in the villi base and increased secretory lineage cells compared with Dlk1 +/+ embryos. CONCLUSIONS: Mesenchyme-derived DLK1 plays an important role in the promotion of epithelial stem/precursor expansion and prevention of differentiation to secretory lineages in the developing intestine.Mari Ichinose, Nobumi Suzuki, Tongtong Wang, Josephine A. Wright, Tamsin R. M. Lannagan, Laura Vrbanac ... et al