Identifying SETBP1 haploinsufficiency molecular pathways to improve patient diagnosis using induced pluripotent stem cells and neural disease modelling.

BACKGROUND: SETBP1 Haploinsufficiency Disorder (SETBP1-HD) is characterised by mild to moderate intellectual disability, speech and language impairment, mild motor developmental delay, behavioural issues, hypotonia, mild facial dysmorphisms, and vision impairment. Despite a clear link between SETBP1 mutations and neurodevelopmental disorders the precise role of SETBP1 in neural development remains elusive. We investigate the functional effects of three SETBP1 genetic variants including two pathogenic mutations p.Glu545Ter and SETBP1 p.Tyr1066Ter, resulting in removal of SKI and/or SET domains, and a point mutation p.Thr1387Met in the SET domain. METHODS: Genetic variants were introduced into induced pluripotent stem cells (iPSCs) and subsequently differentiated into neurons to model the disease. We measured changes in cellular differentiation, SETBP1 protein localisation, and gene expression changes. RESULTS: The data indicated a change in the WNT pathway, RNA polymerase II pathway and identified GATA2 as a central transcription factor in disease perturbation. In addition, the genetic variants altered the expression of gene sets related to neural forebrain development matching characteristics typical of the SETBP1-HD phenotype. LIMITATIONS: The study investigates changes in cellular function in differentiation of iPSC to neural progenitor cells as a human model of SETBP1 HD disorder. Future studies may provide additional information relevant to disease on further neural cell specification, to derive mature neurons, neural forebrain cells, or brain organoids. CONCLUSIONS: We developed a human SETBP1-HD model and identified perturbations to the WNT and POL2RA pathway, genes regulated by GATA2. Strikingly neural cells for both the SETBP1 truncation mutations and the single nucleotide variant displayed a SETBP1-HD-like phenotype.

From classroom to collaboration: how pre-graduation interprofessional learning shapes health professional graduates' interactions in practice.

Interprofessional education (IPE) aims to prepare health professional students with the knowledge, attitudes and skills required for collaborative healthcare practice. Although positive outcomes have been documented at the completion of university-based IPE experiences, or longitudinally across health care degrees, the literature is unclear on how university-based IPE influences graduate practice. This study therefore explores how health professional graduates experience interprofessional interactions in practice and how these may be connected to their university-based IPE experiences. Interviews with seven health professional graduates who had participated in an 11-week IPE course as part of their pre-licensure degrees were analyzed using interpretative phenomenological analysis. The participants were able to articulate instances of effective and less effective collaboration from their professional experiences, making sense of these experiences with explicit reference to the themes of role understanding, collaborative working relationships, interprofessional communication, patient-centered care and contextual influences; all ideas introduced in their university-based IPE. They connected their understanding of roles, collaborative working relationships and interprofessional communication explicitly to their prior university-based IPE, identifying these learnings as foundational knowledge. This connection was not as explicit for patient-centered care and contextual issues. These findings highlight the critical importance of IPE in preparing health professionals for high-quality contemporary practice.

CRISPR-Cas9-generated PTCHD1 2489T>G stem cells recapitulate patient phenotype when undergoing neural induction.

An estimated 3.5%-5.9% of the global population live with rare diseases, and approximately 80% of these diseases have a genetic cause. Rare genetic diseases are difficult to diagnose, with some affected individuals experiencing diagnostic delays of 5-30 years. Next-generation sequencing has improved clinical diagnostic rates to 33%-48%. In a majority of cases, novel variants potentially causing the disease are discovered. These variants require functional validation in specialist laboratories, resulting in a diagnostic delay. In the interim, the finding is classified as a genetic variant of uncertain significance (VUS) and the affected individual remains undiagnosed. A VUS (PTCHD1 c. 2489T>G) was identified in a child with autistic behavior, global developmental delay, and hypotonia. Loss of function mutations in PTCHD1 are associated with autism spectrum disorder and intellectual disability; however, the molecular function of PTCHD1 and its role in neurodevelopmental disease is unknown. Here, we apply CRISPR gene editing and induced pluripotent stem cell (iPSC) neural disease modeling to assess the variant. During differentiation from iPSCs to neural progenitors, we detect subtle but significant gene signatures in synaptic transmission and muscle contraction pathways. Our work supports the causal link between the genetic variant and the child's phenotype, providing evidence for the variant to be considered a pathogenic variant according to the American College of Medical Genetics and Genomics guidelines. In addition, our study provides molecular data on the role of PTCHD1 in the context of other neurodevelopmental disorders.

Gene editing and cardiac disease modelling for the interpretation of genetic variants of uncertain significance in congenital heart disease.

BACKGROUND: Genomic sequencing in congenital heart disease (CHD) patients often discovers novel genetic variants, which are classified as variants of uncertain significance (VUS). Functional analysis of each VUS is required in specialised laboratories, to determine whether the VUS is disease causative or not, leading to lengthy diagnostic delays. We investigated stem cell cardiac disease modelling and transcriptomics for the purpose of genetic variant classification using a GATA4 (p.Arg283Cys) VUS in a patient with CHD. METHODS: We performed high efficiency CRISPR gene editing with homology directed repair in induced pluripotent stem cells (iPSCs), followed by rapid clonal selection with amplicon sequencing. Genetic variant and healthy matched control cells were compared using cardiomyocyte disease modelling and transcriptomics. RESULTS: Genetic variant and healthy cardiomyocytes similarly expressed Troponin T (cTNNT), and GATA4. Transcriptomics analysis of cardiomyocyte differentiation identified changes consistent with the patient's clinical human phenotype ontology terms. Further, transcriptomics revealed changes in calcium signalling, and cardiomyocyte adrenergic signalling in the variant cells. Functional testing demonstrated, altered action potentials in GATA4 genetic variant cardiomyocytes were consistent with patient cardiac abnormalities. CONCLUSIONS: This work provides in vivo functional studies supportive of a damaging effect on the gene or gene product. Furthermore, we demonstrate the utility of iPSCs, CRISPR gene editing and cardiac disease modelling for genetic variant interpretation. The method can readily be applied to other genetic variants in GATA4 or other genes in cardiac disease, providing a centralised assessment pathway for patient genetic variant interpretation.

The AdvICE course: leveraging clinician experience in interprofessional education to promote collaborative practice.

As part of the global agenda to increase the interprofessional collaborative practice capability of the healthcare workforce, it is recognized that post-qualification health professionals require interprofessional education (IPE) to upskill them in the key competencies of collaborative practice. Previously published accounts of IPE initiatives directed as post-qualification health professionals have been based in a specific practice setting within a health service or related to a specific health condition. Differing from these initiatives, the Advancing Interdisciplinary Clinical Excellence (AdvICE) IPE course is offered to experienced clinicians across settings and professions in a large regional Australian health service. This study evaluated the impact of the AdvICE course on participants' interprofessional collaborative practice beliefs, attitudes and behaviours. Pre- and post-course completion of the Interprofessional Socialization and Valuing Scale (ISVS-21) demonstrated that participants experienced improvements in self-perceived interprofessional beliefs, attitudes, and behaviours, and willingness to work in interprofessional relationships. Participants also reported interprofessional learning related to role clarification, interprofessional communication, conflict resolution, clinical teaching and supervision. Interprofessional education initiatives, such as the AdvICE course, that target experienced clinicians across a health service may be valuable in contributing to the World Health Organization's recommendation to develop champions of interprofessional collaborative practice.

Preterm sepsis is associated with acute lung injury as measured by pulmonary severity score.

BACKGROUND: Sepsis related acute lung injury (ALI) is established in adults but has not been investigated in premature infants. Herein, we used pulmonary severity score (PSS) trajectories and C-reactive protein (CRP) to examine the relation between sepsis and ALI in premature infants. METHODS: This retrospective study identified 211 sepsis and 123 rule out (RO) events in 443 infants born <31 weeks and <1500 grams. The PSS was calculated prior to, at the time of, and up to 1 week after each event. Initial and peak CRP values were collected for each event. RESULTS: PSS significantly increased at 0 h from baseline (-72h) and remained increased at all subsequent time points (all p < 0.002) in sepsis events. Mean PSS in sepsis episodes were also higher compared to RO events at +24 h, +48 h, +72 h, and +168 h (all p < 0.004). A positive correlation was noted between peak CRP values in sepsis events and PSS at 0 h, +24 h, +48 h, and +72 h. CONCLUSIONS: The temporal PSS trends and correlation with CRP levels observed in sepsis but not in RO events supports the hypothesis that neonatal sepsis is associated with ALI and contributes to the accumulating evidence that neonatal ARDS occurs. IMPACT: To evaluate pulmonary severity scores and c-reactive protein values over time to establish an association between preterm neonatal sepsis and acute lung injury (ALI). Though sepsis is well established as the most common indirect cause of ALI leading to acute respiratory distress syndrome (ARDS) in adults and pediatrics, this phenomenon remains undefined in neonates. This study validates the proposal by the Neonatal ARDS Project that ARDS also occurs in neonates by demonstrating acute and sustained changes in markers of pulmonary injury temporally related to a diagnosis of neonatal sepsis in preterm infants.

Making a meaningful difference through collaboration: The experiences of healthcare staff redeployed to a contact tracing and monitoring team as part of the COVID-19 response.

During the coronavirus disease 2019 (COVID-19) pandemic, the health care system experienced unprecedented demands with many health care workers being redeployed. Although there are emerging studies investigating redeployment to acute care, the experience of redeployment to roles outside of these settings, such as to contact tracing and monitoring (CTM) teams, has not been reported. This research was designed to explore health care workers' experience of redeployment to a regional COVID-19 CTM team. Staff redeployed to this CTM team completed an anonymous online survey following the second wave of the COVID-19 pandemic in Victoria, Australia. The survey used open-ended questions to explore participants' perceptions of what did and did not work well during their redeployment. Inductive template thematic analysis of the data found that during their redeployment to CTM teams, participants experienced a sense of collaboration, the opportunity for professional growth, and the perception of making a meaningful contribution to the pandemic. Redeployed CTM team members also described a need to adapt to constant change and felt that the redeployment took a personal toll on them. The findings from this research may be useful to support preparedness of health care workers for redeployment in future complex or crisis situations.

Primary Nasal Epithelial Cells as a Surrogate Cell Culture Model for Type-II Alveolar Cells to Study ABCA-3 Deficiency.

ATP Binding Cassette Subfamily A Member 3 (ABCA-3) is a lipid transporter protein highly expressed in type-II alveolar (AT-II) cells. Mutations in ABCA3 can result in severe respiratory disease in infants and children. To study ABCA-3 deficiency in vitro, primary AT-II cells would be the cell culture of choice although sample accessibility is limited. Our aim was to investigate the suitability of primary nasal epithelial cells, as a surrogate culture model for AT-II cells, to study ABCA-3 deficiency. Expression of ABCA3, and surfactant protein genes, SFTPB and SFTPC, was detected in primary nasal epithelial cells but at a significantly lower level than in AT-II cells. ABCA-3, SP-B, and SP-C were detected by immunofluorescence microscopy in primary nasal epithelial cells. However, SP-B and SP-C were undetectable in primary nasal epithelial cells using western blotting. Structurally imperfect lamellar bodies were observed in primary nasal epithelial cells using transmission electron microscopy. Functional assessment of the ABCA-3 protein demonstrated that higher concentrations of doxorubicin reduced cell viability in ABCA-3 deficient nasal epithelial cells compared to controls in an assay-dependent manner. Our results indicate that there may be a role for primary nasal epithelial cell cultures to model ABCA-3 deficiency in vitro, although additional cell culture models that more effectively recapitulate the AT-II phenotype may be required.

Functional validation of variants of unknown significance using CRISPR gene editing and transcriptomics: A Kleefstra syndrome case study.

There are an estimated > 400 million people living with a rare disease globally, with genetic variants the cause of approximately 80% of cases. Next Generation Sequencing (NGS) rapidly identifies genetic variants however they are often of unknown significance. Low throughput functional validation in specialist laboratories is the current ad hoc approach for functional validation of genetic variants, which creating major bottlenecks in patient diagnosis. This study investigates the application of CRISPR gene editing followed by genome wide transcriptomic profiling to facilitate patient diagnosis. As proof-of-concept, we introduced a variant in the Euchromatin histone methyl transferase (EHMT1) gene into HEK293T cells. We identified changes in the regulation of the cell cycle, neural gene expression and suppression of gene expression changes on chromosome 19 and chromosome X, that are in keeping with Kleefstra syndrome clinical phenotype and/or provide insight into disease mechanism. This study demonstrates the utility of genome editing followed by functional readouts to rapidly and systematically validating the function of variants of unknown significance in patients suffering from rare diseases.

CRISPR single base editing, neuronal disease modelling and functional genomics for genetic variant analysis: pipeline validation using Kleefstra syndrome EHMT1 haploinsufficiency.

BACKGROUND: Over 400 million people worldwide are living with a rare disease. Next Generation Sequencing (NGS) identifies potential disease causative genetic variants. However, many are identified as variants of uncertain significance (VUS) and require functional laboratory validation to determine pathogenicity, and this creates major diagnostic delays. METHODS: In this study we test a rapid genetic variant assessment pipeline using CRISPR homology directed repair to introduce single nucleotide variants into inducible pluripotent stem cells (iPSCs), followed by neuronal disease modelling, and functional genomics on amplicon and RNA sequencing, to determine cellular changes to support patient diagnosis and identify disease mechanism. RESULTS: As proof-of-principle, we investigated an EHMT1 (Euchromatin histone methyltransferase 1; EHMT1 c.3430C > T; p.Gln1144*) genetic variant pathogenic for Kleefstra syndrome and determined changes in gene expression during neuronal progenitor cell differentiation. This pipeline rapidly identified Kleefstra syndrome in genetic variant cells compared to healthy cells, and revealed novel findings potentially implicating the key transcription factors REST and SP1 in disease pathogenesis. CONCLUSION: The study pipeline is a rapid, robust method for genetic variant assessment that will support rare diseases patient diagnosis. The results also provide valuable information on genome wide perturbations key to disease mechanism that can be targeted for drug treatments.

' breaks down silos': allied health clinicians' perceptions of informal interprofessional interactions in the healthcare workplace.

Informal interprofessional interactions have gained interest in recent interprofessional care, education, health services and social sciences research literature. Some of the established benefits associated with these interactions include enhanced communication, teamwork, research translation and the provision of safer care. Limited evidence about how informal interprofessional interactions are perceived by the allied health workforce, exists. The survey conducted at a large Australian health service explored allied health clinicians' perceptions of the benefits, challenges and enablers of informal interprofessional interactions and their recommendations to improve opportunities for these workplace interactions. Sixty-four responses were analysed descriptively (for close-ended questions) and using a framework analysis approach, informed by Bourdieu's social space theory (for open-ended questions). Perceived benefits were aligned with three themes: teams and organisations, individual clinicians and service-users. Challenges to, and enablers of, informal interprofessional interactions were identified according to five themes: socio-cultural practices, physical environment, timing-related factors, individual and organisational factors. Participant recommendations to increase opportunities for informal interprofessional workplace interactions for allied health reflected three of the aforementioned themes: socio-cultural practices, physical environment and organisational factors. This theoretically-informed analysis may aid in the development of strategies to support these types of workplace interactions and realise the benefits identified.

Dysregulated Notch Signaling in the Airway Epithelium of Children with Wheeze.

The airway epithelium of children with wheeze is characterized by defective repair that contributes to disease pathobiology. Dysregulation of developmental processes controlled by Notch has been identified in chronic asthma. However, its role in airway epithelial cells of young children with wheeze, particularly during repair, is yet to be determined. We hypothesized that Notch is dysregulated in primary airway epithelial cells (pAEC) of children with wheeze contributing to defective repair. This study investigated transcriptional and protein expression and function of Notch in pAEC isolated from children with and without wheeze. Primary AEC of children with and without wheeze were found to express all known Notch receptors and ligands, although pAEC from children with wheeze expressed significantly lower NOTCH2 (10-fold, p = 0.004) and higher JAG1 (3.5-fold, p = 0.002) mRNA levels. These dysregulations were maintained in vitro and cultures from children with wheeze displayed altered kinetics of both NOTCH2 and JAG1 expression during repair. Following Notch signaling inhibition, pAEC from children without wheeze failed to repair (wound closure rate of 76.9 ± 3.2%). Overexpression of NOTCH2 in pAEC from children with wheeze failed to rescue epithelial repair following wounding. This study illustrates the involvement of the Notch pathway in airway epithelial wound repair in health and disease, where its dysregulation may contribute to asthma development.

Retrospective study of aldosterone and progesterone secreting adrenal tumors in 10 cats.

BACKGROUND: Primary hyperaldosteronism caused by adrenal neoplasia has been well described in cats. Multiple corticosteroid abnormalities occur in a subset of affected cats, but characterizations of this syndrome are limited to several case reports. OBJECTIVES: To describe a series of cats with adrenal tumors secreting aldosterone and additional corticosteroids. ANIMALS: Ten cats with multiple corticosteroid secreting adrenocortical tumors. METHODS: Retrospective case series. Medical records of cats with adrenal tumors secreting both aldosterone and progesterone were identified. Data concerning historical findings, clinicopathologic features, treatments, and outcomes were retrieved from medical records. RESULTS: All 10 cats had diabetes mellitus in addition to biochemical features of hyperaldosteronism such as hypokalemia. High corticosterone concentrations were observed in all 3 cats in which this corticosteroid was measured. Ultrasound examinations revealed unilateral adrenal tumors in all 10 cases, and the contralateral adrenal gland was either atrophied or not identified in 5 cats. Three of 4 cats developed hypoadrenocorticism after surgical adrenalectomy. Three cats achieved diabetic remission after adrenalectomy. Two cats treated with adrenalectomy survived >1 year, 1 cat survived 6.5 months, and 1 cat was alive 5.5 months after diagnosis. Survival >1 year occurred in 2 of 4 cats treated with medical management alone. Two cats were not treated. CONCLUSIONS AND CLINICAL IMPORTANCE: The presence of multiple corticosteroid abnormalities should be considered in cats with aldosterone secreting adrenal tumors, especially those with concurrent diabetes mellitus. Both surgical and medical management can result in long-term survival, although diabetic remission was documented only in cats undergoing adrenalectomy.

Factors associated with adherence to follow-up calls in cancer patients receiving care at a community oncology practice.

BACKGROUND: Follow-up calls in the oncology setting are frequently used to augment care and encourage oral antineoplastic adherence. However, limited data are available on patient populations that would benefit from this intervention versus populations that may require alternative interventions. The purpose of this study was to identify characteristics among patients on oral antineoplastic agents that influence their likelihood to respond to follow-up calls. METHODS: Patients receiving care from one of the eight community oncology clinics within the same branch were analyzed. Patients were included if they were ≥18 years, received a new oral antineoplastic agent that was electronically prescribed between August 2018-October 2018, and picked up their first fill from their pharmacy of choice. Patients received up to six follow-up calls after picking up their first prescription. Calls were categorized as adherent (≥3 monthly interactions) or non-adherent (<3 monthly interactions). Logistic regression models were used to evaluate factors associated with follow-up call adherence. Factors included demographics, cancer stage, marital status, employment, pharmacy setting (internal pharmacy versus external pharmacy), and insurance used by the patient. Descriptive analysis was performed to analyze response rates, cancer diagnosis, and to determine the best time and day patients responded to follow-up calls. RESULTS: Data from 125 patients were analyzed, of which 65 patients (52%) were adherent to follow-up calls and the mean response rate over six months was 45% (range: 35% -- 54%). High success rates for follow-up calls were seen between 12-3 pm and on Tuesdays and Thursdays. After adjusting for covariates, patients with stage III-IV were 89% less likely to respond to follow-up calls compared to those with stage 0-II (95% CI: 0.02-0.64; p = 0.01), patients with commercial insurance were 79% less likely to adhere to follow-up calls compared to those on government insurance (95% CI: 0.06-0.71; p = 0.01), and patients using an external pharmacy had a 2.8 times increase odds of being adherent (95% CI 0.98-8.34; p = 0.05). All other factors were not significant. CONCLUSIONS: For patients taking oral antineoplastics, non-adherence to follow-up calls was observed in more than 45% of patients receiving care from a community oncology clinic. Findings demonstrated that those with advanced stages of cancer, on commercial insurance, and going to an internal pharmacy were at higher risk for not adhering to follow up calls. Therefore, alternative methods for managing adherence and side effects in these populations are warranted.

Ivacaftor or lumacaftor/ivacaftor treatment does not alter the core CF airway epithelial gene response to rhinovirus.

BACKGROUND: Aberrant responses by the cystic fibrosis airway epithelium during viral infection may underly the clinical observations. Whether CFTR modulators affect antiviral responses by CF epithelia is presently unknown. We tested the hypothesis that treatment of CF epithelial cells with ivacaftor (Iva) or ivacaftor/lumacaftor (Iva/Lum) would improve control of rhinovirus infection. METHODS: Nineteen CF epithelial cultures (10 homozygous for p.Phe508del as CFTR Class 2, 9 p.Phe508del/p.Gly551Asp as Class 3) were infected with rhinovirus 1B at multiplicity of infection 12 for 24 h. Culture RNA and supernatants were harvested to assess gene and protein expression respectively. RESULTS: RNA-seq analysis comparing rhinovirus infected cultures to control identified 796 and 629 differentially expressed genes for Class 2 and Class 3, respectively. This gene response was highly conserved when cells were treated with CFTR modulators and were predicted to be driven by the same interferon-pathway transcriptional regulators (IFNA, IFNL1, IFNG, IRF7, STAT1). Direct comparisons between treated and untreated infected cultures did not yield any differentially expressed genes for Class 3 and only 68 genes for Class 2. Changes were predominantly related to regulators of lipid metabolism and inflammation, aspects of epithelial biology known to be dysregulated in CF. In addition, CFTR modulators did not affect viral copy number, or levels of pro-inflammatory cytokines produced post-infection. CONCLUSIONS: Though long-term clinical data is not yet available, results presented here suggest that first generation CFTR modulators do not interfere with core airway epithelial responses to rhinovirus infection. Future work should investigate the latest triple modulation therapies.

Serum thyroxine and thyrotropin concentrations decrease with severity of nonthyroidal illness in cats and predict 30-day survival outcome.

BACKGROUND: In cats, nonthyroidal illness affects serum thyroid hormone concentrations. Serum thyroxine (T4 ) and triiodothyronine (T3 ) concentrations commonly decrease, whereas free T4 (fT4 ) concentrations vary unpredictably. Limited information exists regarding effects on serum thyrotropin (thyroid-stimulating hormone [TSH]) concentrations in cats with nonthyroidal illness syndrome (NTIS). OBJECTIVES: To characterize alterations in thyroid function that develop in cats with NTIS and to correlate these alterations with severity and outcome of the nonthyroidal illness. ANIMALS: Two hundred and twenty-two cats with NTIS and 380 clinically normal cats of similar age and sex. METHODS: Prospective, cross-sectional study. All cats had serum T4 , T3 , free T4 , and TSH concentrations measured. Cats were grouped based on illness severity and 30-day survival. RESULTS: Cats with NTIS had lower serum T4 and T3 concentrations than did normal cats (P < .001). Serum fT4 and TSH concentrations did not differ between groups. Serum T4 , T3 , and fT4 concentrations progressively decreased with increasing disease severity (P < .001). The 56 cats that died had lower T4 , T3 , and TSH concentrations than did the 166 survivors, with no difference in fT4 concentration. Multivariable logistic regression modeling indicated that serum T4 and TSH concentrations both predicted survival (P < .02). CONCLUSIONS AND CLINICAL IMPORTANCE: Cats with NTIS commonly develop low serum T4 , T3 , and TSH concentrations, the prevalence and extent of which increases with disease severity. Clinicians should consider evaluating thyroid function in cats with severe NTIS, because doing so could help determine probability of successful treatment responses before investing considerable time, effort, and finances in addressing the underlying disease.

Aberrant cell migration contributes to defective airway epithelial repair in childhood wheeze.

Abnormal wound repair has been observed in the airway epithelium of patients with chronic respiratory diseases, including asthma. Therapies focusing on repairing vulnerable airways, particularly in early life, present a potentially novel treatment strategy. We report defective lower airway epithelial cell repair to strongly associate with common pre-school-aged and school-aged wheezing phenotypes, characterized by aberrant migration patterns and reduced integrin α5ß1 expression. Next generation sequencing identified the PI3K/Akt pathway as the top upstream transcriptional regulator of integrin α5ß1, where Akt activation enhanced repair and integrin α5ß1 expression in primary cultures from children with wheeze. Conversely, inhibition of PI3K/Akt signaling in primary cultures from children without wheeze reduced α5ß1 expression and attenuated repair. Importantly, the FDA-approved drug celecoxib - and its non-COX2-inhibiting analogue, dimethyl-celecoxib - stimulated the PI3K/Akt-integrin α5ß1 axis and restored airway epithelial repair in cells from children with wheeze. When compared with published clinical data sets, the identified transcriptomic signature was also associated with viral-induced wheeze exacerbations highlighting the clinical potential of such therapy. Collectively, these results identify airway epithelial restitution via targeting the PI3K-integrin α5ß1 axis as a potentially novel therapeutic avenue for childhood wheeze and asthma. We propose that the next step in the therapeutic development process should be a proof-of-concept clinical trial, since relevant animal models to test the crucial underlying premise are unavailable.

Azithromycin Partially Mitigates Dysregulated Repair of Lung Allograft Small Airway Epithelium.

BACKGROUND: Dysregulated airway epithelial repair following injury is a proposed mechanism driving posttransplant bronchiolitis obliterans (BO), and its clinical correlate bronchiolitis obliterans syndrome (BOS). This study compared gene and cellular characteristics of injury and repair in large (LAEC) and small (SAEC) airway epithelial cells of transplant patients. METHODS: Subjects were recruited at the time of routine bronchoscopy posttransplantation and included patients with and without BOS. Airway epithelial cells were obtained from bronchial and bronchiolar brushing performed under radiological guidance from these patients. In addition, bronchial brushings were also obtained from healthy control subjects comprising of adolescents admitted for elective surgery for nonrespiratory-related conditions. Primary cultures were established, monolayers wounded, and repair assessed (±) azithromycin (1 µg/mL). In addition, proliferative capacity as well as markers of injury and dysregulated repair were also assessed. RESULTS: SAEC had a significantly dysregulated repair process postinjury, despite having a higher proliferative capacity than large airway epithelial cells. Addition of azithromycin significantly induced repair in these cells; however, full restitution was not achieved. Expression of several genes associated with epithelial barrier repair (matrix metalloproteinase 7, matrix metalloproteinase 3, the integrins ß6 and ß8, and ß-catenin) were significantly different in epithelial cells obtained from patients with BOS compared to transplant patients without BOS and controls, suggesting an intrinsic defect. CONCLUSIONS: Chronic airway injury and dysregulated repair programs are evident in airway epithelium obtained from patients with BOS, particularly with SAEC. We also show that azithromycin partially mitigates this pathology.

Interprofessional education and practice guide No. 10: Developing, supporting and sustaining a team of facilitators in online interprofessional education.

Whilst we have seen a growth in the use of information and communication technologies to deliver interprofessional education (IPE) in the last decade, little has been written about facilitating IPE in the online environment. For the last 10 years, the Faculty of Health at Deakin University has offered a fully online IPE course that has consistently employed facilitators to guide interprofessional teams in both asynchronous and synchronous (real-time) online interprofessional learning experiences. This Interprofessional Education and Practice Guide draws on the Deakin University leadership experience in supporting teams of online IPE facilitators over the last decade, underpinned by prior research and key literature. The key lessons provided in this guide aim to assist others in developing, supporting and sustaining a team of online IPE facilitators to guide asynchronous and synchronous online interprofessional learning experiences.

Evaluating a wayfinding video.

BACKGROUND: Many occupational therapy students experience anxiety and distraction when entering a new setting at the beginning of a clinical placement. Orientation processes may provide students with the information they need to feel more comfortable in an unfamiliar clinical setting. The aim of this project was to evaluate a revised wayfinding video for first- and second-year occupational therapy students, with a particular focus on reducing anxiety. METHODS: A revised version of a wayfinding video (with a duration of 3 minutes and 40 seconds) was created by final-year occupational therapy students and then evaluated using a paper-based descriptive survey. All data were analysed using a content analysis approach. RESULTS: A total of 71 responses were received, demonstrating a response rate of 47%. The students indicated that the video addressed the main sources of pre-placement anxiety and supported their pre-existing anxiety management strategies. Anxiety-reducing features of the video included an overview and visual introduction to the facility, hearing the positive experiences of other students, the provision of placement expectations and an introduction to the student coordinators. All but two of the students indicated that they would watch the video if it were attached to their welcome pack. Many occupational therapy students experience anxiety and distraction when entering a new setting CONCLUSIONS: The revised wayfinding video addressed many of the students' anxieties about commencing placement and now forms part of a broader suite of student orientation materials. There are several limitations to the development of wayfinding videos, but they are surmountable via collaboration and investment in careful planning.