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Challenges in nursing, including an ageing population with increasingly complex health needs, an aging and decreasing global nursing workforce, and depressed government budgets, impact on the quality and availability of nursing students’ clinical placements as part of their education. Development and implementation of innovative activities are essential to ensure that students are both personally and professionally prepared for nursing practice. Simulation is an educational strategy adopted in nursing education to promote the safety and competence of nurses entering the clinical environment, and it offers a response to the problems around clinical placement. The current study investigated the simulated nursing practice activity of students in their first year of nursing education. The aims of this study were to explore and describe the experiences of students as nurses and patients in role play simulation and to develop a substantive theory through which to understand these experiences; to influence national simulation standards, policies, and guidelines; and to impact on the development of role play simulation activities for students in undergraduate nursing institutions. The research design adopted a grounded theory approach: incorporating the core elements of grounded theory, which frame all steps in the study. Data was gathered through semi-structured interviews through a purposive sample of 16 students in a New Zealand nursing institution. Findings emerging from the data revealed a substantive theory, connection in simulated nursing practice, consisting of the central category, connection, and its four principal categories: 1. discovering connections, 2. connecting with peers, 3.

ObjectiveInfantile spasms (IS) is a severe epilepsy in early childhood. Early treatment of IS provides the best chance of seizure remission and favorable developmental outcome. We aimed to develop a prediction rule to accurately predict which neonates with acute symptomatic seizures will develop IS.MethodsWe used data from the Neonatal Seizure Registry, a prospective, multicenter cohort of infants with acute symptomatic neonatal seizures born from July 2015 to March 2018. Neonates with acute symptomatic seizures who received clinical electroencephalography (EEG) and magnetic resonance imaging (MRI) and were younger than 2years of age at the time of enrollment were included. We evaluated the association of neonatal EEG, MRI, and clinical factors with subsequent IS using bivariate analysis and best subsets logistic regression. We selected a final model through a consensus process that balanced statistical significance with clinical relevance.ResultsIS developed in 12 of 204 infants (6%). Multiple potential predictors were associated with IS, including Apgar scores, EEG features, seizure characteristics, MRI abnormalities, and clinical status at hospital discharge. The final model included three risk factors: (a) severely abnormal EEG or ≥3days with seizures recorded on EEG, (b) deep gray or brainstem injury on MRI, and (c) abnormal tone on discharge exam. The stratified risk of IS was the following: no factors 0% (0/82, 95% confidence interval [CI] 0%-4%), one or two factors 4% (4/108, 95% CI 1%-9%), and all three factors 57% (8/14, 95% CI 29%-83%).SignificanceIS risk after acute symptomatic neonatal seizures can be stratified using commonly available clinical data. No child without risk factors, vs >50% of those with all three factors, developed IS. This risk prediction rule may be valuable for clinical counseling as well as for selecting participants for clinical trials to prevent post-neonatal epilepsy. This tailored approach may lead to earlier diagnosis and treatment and improve outcomes for a devastating early life epilepsy.

Autoimmune-mediated dry eye disease is a pathological feature of multiple disorders including Sjögren's syndrome, lupus and rheumatoid arthritis that has a life-long, detrimental impact on vision and overall quality of life. Although late stage disease outcomes such as epithelial barrier dysfunction, reduced corneal innervation and chronic inflammation have been well characterized in both human patients and mouse models, there is little to no understanding of early pathological processes. Moreover, the mechanisms underlying the loss of cornea homeostasis and disease progression are unknown. Here, we utilize the autoimmune regulatory (Aire)-deficient mouse model of autoimmune-mediated dry eye disease in combination with genome wide transcriptomics, high-resolution imaging and atomic force microscopy to reveal a potential extracellular matrix (ECM)-biomechanical-based mechanism driving cellular and morphological changes at early disease onset. Early disease in the Aire-deficient mouse model is associated with a mild reduction in tear production and moderate immune cell infiltration, allowing for interrogation of cellular, molecular and biomechanical changes largely independent of chronic inflammation. Using these tools, we demonstrate for the first time that the emergence of autoimmune-mediated dry eye disease is associated with an alteration in the biomechanical properties of the cornea. We reveal a dramatic disruption of the synthesis and organization of the extracellular matrix as well as degradation of the epithelial basement membrane during early disease. Notably, we provide evidence that the nerve supply to the cornea is severely reduced at early disease stages and that this is independent of basement membrane destruction or significant immune cell infiltration. Furthermore, diseased corneas display spatial heterogeneity in mechanical, structural and compositional changes, with the limbal compartment often exhibiting the opposite response compared to the central cornea. Despite these differences, however, epithelial hyperplasia is apparent in both compartments, possibly driven by increased activation of IL-1R1 and YAP signaling pathways. Thus, we reveal novel perturbations in corneal biomechanics, matrix organization and cell behavior during the early phase of dry eye that may underlie disease development and progression, presenting new potential targets for therapeutic intervention.

PurposeTo determine the intra-observer and inter-observer reliability of a novel ocular staining score among trained ophthalmologists.DesignReliability analysis within a prospective, observational, multicenter cohort study.MethodsThose enrolled in the National Institutes of Health-funded Sjögren's International Collaborative Clinical Alliance (SICCA) who presented for follow-up at the University of California San Francisco, Aravind Eye Hospital, Johns Hopkins University, and the University of Pennsylvania were included. Study participants were graded using the ocular staining score by at least 2 masked SICCA-trained ophthalmologists. The primary outcome for this study was the intraclass correlation coefficient (ICC) for the total ocular staining score. ICCs were also calculated for tear break-up time (TBUT) and conjunctival and corneal staining.ResultsTotal ocular staining score had an ICC of 0.91 for the right eye (95% confidence interval [CI] 0.85-0.96) and 0.90 for the left eye (95% CI 0.83-0.97). Corneal staining (right eye 0.86, 95% CI 0.76-0.93, left eye 0.90, 95% CI 0.81-0.95) and conjunctival staining (right eye 0.87, 95% CI 0.80-0.93, left eye 0.85, 95% CI 0.75-0.93) demonstrated excellent agreement. The ICC for TBUT was slightly lower (right eye 0.77, 95% CI 0.64-0.89; left eye 0.81, 95% CI 0.68-0.90).ConclusionsPrevious studies have shown that the ocular staining score is correlated with other diagnostic components of Sjögren syndrome. In this study, we demonstrate high reliability in grading among trained ophthalmologists, completing the validation of this test.

© 2015, BMJ Publishing Group. All rights reserved. Background/aims: To determine the ophthalmic manifestations of HIV in a cohort of long-term survivors of perinatally acquired HIV. Methods: Twenty-two patients with perinatally acquired HIV who were aged ≥ 12 years were prospectively studied at a university clinic. They underwent complete ophthalmic examinations and fundus photography. Their medical histories, medications and CD4 counts were abstracted from the medical records. To evaluate for keratoconjunctivitis sicca, both HIV patients and 44 healthy controls (matched by age, gender and contact lens wear) underwent Schirmer testing and ocular surface staining. Results: Nine male and 13 female HIV patients with mean age of 16.6 years (SD, 3.4) were examined. Of the 22 HIV patients, 21 had been treated with highly active antiretroviral therapy (HAART). Only one patient had a CD4 count nadir of

Cigarette smoke increases the risk of lung cancer by 20-fold and accounts for 87% of lung cancer deaths. In the normal airway, heavily O-glycosylated mucin-1 (MUC1) and adherens junctions (AJs) establish a structural barrier that protects the airway from infectious, inflammatory and noxious stimuli. Smoke disrupts cell-cell adhesion via its damaging effects on the AJ protein epithelial cadherin (E-cad). Loss of E-cad is a major hallmark of epithelial-mesenchymal transition (EMT) and has been reported in lung cancer, where it is associated with invasion, metastasis and poor prognosis. Using organotypic cultures of primary human bronchial epithelial (HBE) cells treated with smoke-concentrated medium (Smk), we have demonstrated that E-cad loss is regulated through the aberrant interaction of its AJ binding partner, p120-catenin (p120ctn), and the C-terminus of MUC1 (MUC1-C). Here, we reported that even before MUC1-C became bound to p120ctn, smoke promoted the generation of a novel 400 kDa glycoform of MUC1's N-terminus (MUC1-N) differing from the 230 kDa and 150 kDa glycoforms in untreated control cells. The subsequent smoke-induced, time-dependent shedding of glycosylated MUC1-N exposed MUC1-C as a putative receptor for interactions with EGFR, Src and p120ctn. Smoke-induced MUC1-C glycosylation modulated MUC1-C tyrosine phosphorylation (TyrP) that was essential for MUC1-C/p120ctn interaction through dose-dependent bridging of Src/MUC1-C/galectin-3/EGFR signalosomes. Chemical deglycosylation of MUC1 using a mixture of N-glycosylation inhibitor tunicamycin and O-glycosylation inhibitor benzyl-α-GalNAc disrupted the Src/MUC1-C/galectin-3/EGFR complexes and thereby abolished smoke-induced MUC1-C-TyrP and MUC1-C/p120ctn interaction. Similarly, inhibition of smoke-induced MUC1-N glycosylation using adenoviral shRNA directed against N-acetyl-galactosaminyl transferase-6 (GALNT6, an enzyme that controls the initiating step of O-glycosylation) successfully suppressed MUC1-C/p120ctn interaction, prevented E-cad degradation and maintained cellular polarity in response to smoke. Thus, GALNT6 shRNA represents a potential therapeutic modality to prevent the initiation of events associated with EMT in the smoker's airway.

The adherens junction protein p120-catenin (p120ctn) shuttles between E-cadherin-bound and cytoplasmic pools to regulate E-cadherin/catenin complex stability and cell migration, respectively. When released from the adherens junction, p120ctn promotes cell migration through modulation of the Rho GTPases Rac1, Cdc42, and RhoA. Accordingly, the down-regulation and cytoplasmic mislocalization of p120ctn has been reported in all subtypes of lung cancers and is associated with grave prognosis. Previously, we reported that cigarette smoke induced cytoplasmic translocation of p120ctn and cell migration, but the underlying mechanism was unclear. Using primary human bronchial epithelial cells exposed to smoke-concentrated medium (Smk), we observed the translocation of Rac1 and Cdc42, but not RhoA, to the leading edge of polarized and migrating human bronchial epithelial cells. Rac1 and Cdc42 were robustly activated by smoke, whereas RhoA was inhibited. Accordingly, siRNA knockdown of Rac1 or Cdc42 completely abolished Smk-induced cell migration, whereas knockdown of RhoA had no effect. p120ctn/Rac1 double knockdown completely abolished Smk-induced cell migration, whereas p120ctn/Cdc42 double knockdown did not. These data suggested that Rac1 and Cdc42 coactivation was essential to smoke-promoted cell migration in the presence of p120ctn, whereas migration proceeded via Rac1 alone in the absence of p120ctn. Thus, Rac1 may provide an omnipotent therapeutic target in reversing cell migration during the early (intact p120ctn) and late (loss of p120ctn) stages of lung carcinogenesis.