Parental Perceptions and Knowledge towards Asthma Action Plans.

INTRODUCTION: Personalised Asthma Action Plans (AAPs) are a cornerstone of paediatric asthma management. We aimed to assess parental knowledge and perceptions of the use of AAPs in managing their child's asthma. METHODS: In 2023 we conducted a cross-sectional survey to assess knowledge and perceptions of AAPs in parents/caregivers of children aged 0-17 years with asthma who had an AAP and attended respiratory clinics at Sydney Children's Hospital, Randwick. The questionnaire included parental perceptions on the utility of AAPs, parental asthma management self-efficacy (PAMSE), and an adapted version of the Asthma Action Plan Knowledge Interview tool (AAPKI). Descriptive statistics and regression analyses were used to assess associations between AAPKI, PAMSE and other outcomes. RESULTS: Seventy-one parents completed the survey. Mean PAMSE score was 4.2/5 (SD 0.5). Median AAPKI score was 70.2% out of 100% (IQR 20.4%). Most parents (80.0%, n = 56) were satisfied/very satisfied with using AAPs to manage their child's asthma. Most agreed/strongly agreed that AAPs were helpful in knowing when to seek medical attention for their child's asthma (81.7%, n = 58), helped their understanding of asthma severity (81.7%, n = 58), and increased their confidence in asthma management (76.0%, n = 54). Over half of parents (55.7%, n = 39) would prefer AAPs digitally and majority (78.6%, n = 55) would like colour-coded AAPs. CONCLUSION: High levels of AAP knowledge and self-efficacy scores were demonstrated. Most parents expressed understanding of the benefits of AAPs. Our findings suggest parents of children with asthma prefer AAPs in colour and in digital version which may help guide standardisation of AAPs across Australia.

Mixed-Metal Alloying in Hybrid Bronzes.

We show that substitutional alloying during the aqueous self-assembly of layered organic-templated metal oxides produces single-phase mixed-metal hybrids. Single-crystal X-ray diffraction, bulk elemental analyses, and vibrational and electronic spectroscopies corroborate a solid solution of Mo and W atoms at lattice sites within the two-dimensional metal oxide layers. Mild postsynthetic reduction then introduces relatively delocalized electrons to afford mixed-metal hybrid bronzes. To our knowledge, this represents the first demonstration of mixed-metal alloying in a hybrid metal oxide and a rare example of solid-solution formation at low temperature. We show this approach yields mixed-metal congeners with optical band gaps over 130 meV smaller than those of single-metal analogs, while achieving activation energies (Ea) of conduction as low as 78.4(2) meV. Further, metal substitution appears to tune collective electronic phenomena by suppressing the non-Arrhenius behavior observed for Mo-based hybrids. This work considerably expands the nascent hybrid bronze platform to help address energy-related challenges and fundamental solid-state physical questions.

Social deprivation and spatial clustering of childhood asthma in Australia.

BACKGROUND: Asthma is the most common chronic respiratory illness among children in Australia. While childhood asthma prevalence varies by region, little is known about variations at the small geographic area level. Identifying small geographic area variations in asthma is critical for highlighting hotspots for targeted interventions. This study aimed to investigate small area-level variation, spatial clustering, and sociodemographic risk factors associated with childhood asthma prevalence in Australia. METHODS: Data on self-reported (by parent/carer) asthma prevalence in children aged 0-14 years at statistical area level 2 (SA2, small geographic area) and selected sociodemographic features were extracted from the national Australian Household and Population Census 2021. A spatial cluster analysis was used to detect hotspots (i.e., areas and their neighbours with higher asthma prevalence than the entire study area average) of asthma prevalence. We also used a spatial Bayesian Poisson model to examine the relationship between sociodemographic features and asthma prevalence. All analyses were performed at the SA2 level. RESULTS: Data were analysed from 4,621,716 children aged 0-14 years from 2,321 SA2s across the whole country. Overall, children's asthma prevalence was 6.27%, ranging from 0 to 16.5%, with significant hotspots of asthma prevalence in areas of greater socioeconomic disadvantage. Socioeconomically disadvantaged areas had significantly higher asthma prevalence than advantaged areas (prevalence ratio [PR] = 1.10, 95% credible interval [CrI] 1.06-1.14). Higher asthma prevalence was observed in areas with a higher proportion of Indigenous individuals (PR = 1.13, 95% CrI 1.10-1.17). CONCLUSIONS: We identified significant geographic variation in asthma prevalence and sociodemographic predictors associated with the variation, which may help in designing targeted asthma management strategies and considerations for service enhancement for children in socially deprived areas.

Asthma Care from Home: Study protocol for an effectiveness-implementation evaluation of a virtually enabled asthma care initiative in children in rural NSW.

BACKGROUND: Asthma is the leading source of unscheduled hospitalisation in Australian children, with a high burden placed upon children, their parents/families, and the healthcare system. In Australia, there are widening disparities in paediatric asthma care including inequitable access to comprehensive ongoing and planned asthma care for children. METHODS: The Asthma Care from Home Project is a comprehensive virtually enabled asthma model of care that aims to a. supports families, communities and healthcare providers, b. flexible and locally acceptable, and c. allow for adoption of innovations such as digital technologies so that asthma care can be provided "from home", reduce potentially preventable asthma hospitalisation, and ensure satisfaction at a patient, family, and healthcare provider level. The model of care includes standardisation of discharge care through provision of an asthma discharge resource pack containing individual asthma action plan, follow-up letters for the child's general practitioner (GP) and school/child care, and access to online asthma educational sessions and resource; post-discharge care coordination through text message reminders for families for regular GP review, email correspondence with their child's GP and school/childcare; and virtual home visits to discuss home environmental triggers, provide personalised asthma education and respond to parental concerns relating to their child's asthma. This study is comprised of three components: 1) a quasi-experimental pre/post impact evaluation assessing the impact of the model on healthcare utilisation and asthma control measures; 2) a mixed-methods implementation evaluation to understand how and why our intervention was effective or ineffective in producing systems change; 3) an economic evaluation to assess the cost-effectiveness of the proposed model of care from a family and health services perspective. DISCUSSION: This study aims to improve access to asthma care for children in rural and remote areas. Implementation evaluation and economic evaluation will provide insights into the sustainability and scalability of the asthma model of care.

Psychological wellbeing among parents of a child living with a serious chronic illness: A cross-sectional survey study.

Parents of a child with a chronic illness can experience greater distress than the average population, yet little is understood about differences between illness groups. This cross-sectional survey study aimed to compare parents' psychological distress and perceived wellbeing across five chronic illnesses. Parents from one Australian pediatric hospital completed the Kessler Psychological Distress Scale and seven purpose-designed items about their wellbeing. Data from 106 parents (cancer = 48, cystic fibrosis [CF] = 27, kidney disease = 12, gastrointestinal condition/disorder = 9, developmental and epileptic encephalopathy [DEE] = 10) was analysed using bivariate Pearson's Correlation and linear mixed-effects models. Parents' distress scores differed between groups (F(4,80) = 2.50, p = .049), with the DEE group reporting higher distress than the CF group (mean difference = 6.76, 95% CI [0.11, 13.42]). Distress scores were moderately correlated to parents' perceptions of their child's health and their own wellbeing. Parents' self-reported coping with their child's condition/treatments differed (F(4,81) = 3.24, p = .016), with the DEE group rating their coping as poorer than the CF group (mean difference = -25.32, 95% CI [-46.52, 4.11]). Across all groups, parents reported unmet needs, particularly for psychosocial support and practical/financial assistance. Support interventions may be most effective if tailored to the child's illness, with greater support potentially needed for parents who have a child with DEE and/or severe comorbidities.

Risk Factors and Clinical Prognosis Associated With RSV-ALRI Intensive Care Unit Admission in Children <2 Years of Age: A Multicenter Study.

BACKGROUND: Respiratory syncytial virus (RSV) is the leading cause of acute lower respiratory infections (ALRIs) in children <2 years of age. Currently, there are limited data on risk factors for very severe RSV-ALRI requiring intensive care unit (ICU) admission. METHODS: We conducted a case-control study of children <2 years old admitted with RSV-ALRI to the Sydney Children's Hospital Network, comprising 2 large tertiary pediatric hospitals. Cases were children with laboratory-confirmed RSV-ALRI admitted to ICU, and controls were (1:2, matched on date of admission) children hospitalized with RSV-ALRI but not requiring ICU transfer. Data on risk factors were retrieved from the electronic medical record system. Adjusted odds ratios (aORs) with 95% confidence intervals (95% CI) associated with risk factors for ICU admission and the association with clinical and treatment factors were determined from logistic regression models. RESULTS: A total of 44 (44%) of 100 cases and 90 (48.1%) of 187 controls were male. Age <6 months and preterm births were associated with a 2.10-fold (95% CI: 1.14-3.79) and 2.35-fold (95% CI: 1.26-4.41) increased risk in ICU admissions, respectively. The presence of any chronic health condition was a significant risk factor for ICU admission. The clinical presentations on admission more commonly seen in cases were apnea (aOR: 5.01, 95% CI: 1.50-17.13) and respiratory distress (aOR: 15.91, 95% CI: 4.52-55.97). Cases were more likely to be hospitalized for longer duration and require respiratory support. CONCLUSIONS: Our results can be translated into a clinical risk algorithm to identify children at risk of very severe RSV disease.

Asthma-community acquired pneumonia co-diagnosis in children: a scoping review.

OBJECTIVE: This scoping review investigated the existing literature and identified the evidence gaps related to diagnosis and management in children aged 2-18 years presenting to hospitals with a co-diagnosis of asthma and community-acquired pneumonia. DATA SOURCES: We designed a scoping review following Arksey and O'Malley's scoping review framework and PRISMA extension for a scoping review. We searched literature using five electronic databases: PubMed, CINAHL, Scopus, Web of Science, and Embase from 2003 to June 2023. RESULTS: A total of 1599 abstracts with titles were screened and 12 abstracts were selected for full review. Separate guidelines including Modified Global Initiative for Asthma (GINA) guidelines; modified Integrated Management of Childhood Illness (IMCI) guidelines; and a consensus guideline developed by the Pediatric Infectious Diseases Society (PIDS) and Infectious Diseases Society of America (IDSA) were used for diagnosing asthma and CAP individually. Chest X-rays were used in 83.3% (10/12) of studies to establish the co-diagnosis of asthma-CAP in children. Variations were observed in using different laboratory investigations across the studies. Infectious etiologies were detected in five (41.7%) studies. In 75% (9/12) of studies, children with asthma-CAP co-diagnosis were treated with antimicrobials, however, bacterial etiology was not reported in 44.4% (4/9) of the studies. CONCLUSIONS: Our scoping review suggests that chest X-rays are commonly used to establish the co-diagnosis of asthma-CAP and antibiotics are often used without laboratory confirmation of a bacterial etiology. Clinical practice guidelines for the management of asthma and pneumonia in children who present with co-diagnosis may standardize clinical care and reduce variation.

Controlling Electron Delocalization in Vanadium-Based Hybrid Bronzes through Molecular Templation.

We show that the conductivity of hybrid vanadium bronzes-mixed-valence organic-inorganic vanadium oxides-can be tuned over six orders of magnitude through judicious choice of molecular component. By systematically varying the steric profile, charge density, and propensity to hydrogen bond across a series of eight diammonium-based molecules, we engender multiple distinct motifs of V-O connectivity within the two-dimensional vanadium oxide layers of a family of bulk crystalline hybrid materials. A combination of single-crystal and powder X-ray diffraction analysis, variable-temperature electrical transport measurements, and a range of spectroscopic methods, including UV/Visible diffuse reflectance, X-ray photoelectron, and electron paramagnetic resonance are employed to probe how vanadium oxide layer topology correlates with electron localization. Specifically, alkylammonium molecules yield hybrids featuring more corrugated layers that contain V-O tetrahedra as well as a higher ratio of corner-sharing to edge-sharing polyhedra and that exhibit highly localized electronic behavior, while alkyl bipyridinium molecules yield more regular layers with polyhedral edge-sharing that show substantially delocalized electronic behavior. This work allows for the development of design principles based on structure-property relationships and brings the charge transport capabilities of hybrid vanadium bronzes to more technologically relevant levels.

Hybrid bronzes: mixed-valence organic-inorganic metal oxides as a tunable material platform.

We demonstrate that mixed-valence layered organic-inorganic metal oxides of the form (L)zHxMO3 (L = neutral ligand; M = Mo, W; z = 0.5, 1; 0 < x < 2), which we call hybrid bronzes, can be readily synthesized through mild solution-state self-assembly reactions to integrate the stability and electronic utility of inorganic metal oxide bronzes with the chemical diversity and functionality of organic molecules. We use single-crystal and powder X-ray diffraction coupled with X-ray, electronic, and vibrational spectroscopies to show that the products of aqueous pre-, mid-, or post-synthetic reduction are mixed-valence versions of highly crystalline layered hybrid oxides. Pillaring, bilayered, or canted bilayered arrangements of molecular arrays relative to inorganic sheets are dictated by judicious choice of organic ligands that can also incorporate chemical, redox, or photoactive handles. Significantly, bond-valence sum analysis and diffuse reflectance spectroscopy indicate relatively delocalized electronic behavior and four-point variable-temperature electrical transport measurements show that hybrid bronzes have comparable conductivity to their all-inorganic parent compounds. This work establishes a solution-processable, inexpensive, air- and water-stable, and non-toxic material family whose electronic bands can be readily tuned and doped, thereby positioning hybrid bronzes to address myriad material challenges.

Screening for Cystic Fibrosis Related Complications in the Context of a Pandemic and Altered Models of Care.

Background: Standard of care recommend that patients with cystic fibrosis (CF) require screening investigations to assess for complications. Changing models of care due to the COVID19 pandemic may have impacted completion of recommended screening. Objective: To compare the frequency of screening investigations completed in people with CF before and after the onset of the COVID19 pandemic. Methods: Medical records were reviewed at 4 CF-specialist centers to identify screening investigations completed in the 12-months before and after pandemic onset. Results: Records of 625 patients were reviewed. Prior to pandemic onset, there was between center variability in completion of screening investigations. There was greatest baseline variation between centers in performing oral glucose tolerance test (OGTT); range 38%-69%, exercise tests; 3%-51% and sputum screening for non-tuberculous mycobacteria; 53%-81%. Following pandemic onset, blood tests, and sputum cultures were maintained at the highest rates. Exercise testing, CXR and OGTT exhibited the greatest declines, with reductions at individual centers ranging between 10%-24%, 22%-43%, and 20%-26%, respectively. Return to in-person visits following pandemic onset was variable, ranging from 16% to 74% between centers. Conclusion: Completion of screening investigations varies between CF centers and changes in models of care, such as increased virtual care in response to COVID19 pandemic was associated with reduction in completion of investigations. Centers would benefit from auditing their adherence to standards of care, particularly considering recent changes in care delivery.

Asthma and Susceptibility to COVID-19 in Australian Children During Alpha, Delta and Omicron Waves of the COVID-19 Pandemic.

Purpose: Earlier coronavirus-19 (COVID-19) pandemic reports did not implicate increased disease burden in asthmatics while subsequent findings have been inconsistent. To date, the impact of COVID-19 on childhood asthma remains undetermined and is further complicated with ongoing emergence of new variants. This study aimed to investigate association between asthma and COVID-19 for children in New South Wales (NSW), Australia and compare its differences across four major outbreaks from alpha, delta and omicron variants/subvariants. Methods: This is a retrospective cross-sectional study of all children aged ≤17 years old who sought care for COVID-19 at Sydney Children's Hospitals Network (SCHN) between 1 January 2020 and 31 May 2022. Results: Of the 18,932 children with polymerase chain reaction (PCR) confirmed COVID-19 who attended SCHN, 60% received their care during delta wave, and 5.41% (n = 913) had prior diagnosis of asthma. Among children with COVID-19, the odds of having asthma were lower during alpha (aOR = 0.43; 95% CI, 0.19-0.83) and delta wave (aOR = 0.84; 95% CI, 0.73-0.96), but were higher during omicron wave (aOR = 1.56; 95% CI, 1.23-1.95). Length of hospital stay (LOS) for asthmatic children were increased by 0.55 days and 1.17 days during delta and the second omicron wave, respectively. Intensive care and mechanical ventilation requirements were not significantly different between asthmatic and non-asthmatic children. Eleven deaths were reported but none had asthma. Conclusion: Although children with asthma were more susceptible to COVID-19 infections during omicron waves compared to that of alpha or delta waves, they were not at greater risk of COVID-19 severity at any stage of the outbreak regardless of the predominant SARS-CoV-2 variants/subvariants.

Automated detection of airflow obstructive diseases: A systematic review of the last decade (2013-2022).

BACKGROUND AND OBJECTIVE: Obstructive airway diseases, including asthma and Chronic Obstructive Pulmonary Disease (COPD), are two of the most common chronic respiratory health problems. Both of these conditions require health professional expertise in making a diagnosis. Hence, this process is time intensive for healthcare providers and the diagnostic quality is subject to intra- and inter- operator variability. In this study we investigate the role of automated detection of obstructive airway diseases to reduce cost and improve diagnostic quality. METHODS: We investigated the existing body of evidence and applied Preferred Reporting Items for Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines to search records in IEEE, Google scholar, and PubMed databases. We identified 65 papers that were published from 2013 to 2022 and these papers cover 67 different studies. The review process was structured according to the medical data that was used for disease detection. We identified six main categories, namely air flow, genetic, imaging, signals, and miscellaneous. For each of these categories, we report both disease detection methods and their performance. RESULTS: We found that medical imaging was used in 14 of the reviewed studies as data for automated obstructive airway disease detection. Genetics and physiological signals were used in 13 studies. Medical records and air flow were used in 9 and 7 studies, respectively. Most papers were published in 2020 and we found three times more work on Machine Learning (ML) when compared to Deep Learning (DL). Statistical analysis shows that DL techniques achieve higher Accuracy (ACC) when compared to ML. Convolutional Neural Network (CNN) is the most common DL classifier and Support Vector Machine (SVM) is the most widely used ML classifier. During our review, we discovered only two publicly available asthma and COPD datasets. Most studies used private clinical datasets, so data size and data composition are inconsistent. CONCLUSIONS: Our review results indicate that Artificial Intelligence (AI) can improve both decision quality and efficiency of health professionals during COPD and asthma diagnosis. However, we found several limitations in this review, such as a lack of dataset consistency, a limited dataset and remote monitoring was not sufficiently explored. We appeal to society to accept and trust computer aided airflow obstructive diseases diagnosis and we encourage health professionals to work closely with AI scientists to promote automated detection in clinical practice and hospital settings.

Q1291H-CFTR molecular dynamics simulations and ex vivo theratyping in nasal epithelial models and clinical response to elexacaftor/tezacaftor/ivacaftor in a Q1291H/F508del patient.

Background: Cystic fibrosis (CF) is caused by a wide spectrum of mutations in the CF transmembrane conductance regulator (CFTR) gene, with some leading to non-classical clinical presentations. We present an integrated in vivo, in silico and in vitro investigation of an individual with CF carrying the rare Q1291H-CFTR allele and the common F508del allele. At age 56 years, the participant had obstructive lung disease and bronchiectasis, qualifying for Elexacaftor/Tezacaftor/Ivacaftor (ETI) CFTR modulator treatment due to their F508del allele. Q1291H CFTR incurs a splicing defect, producing both a normally spliced but mutant mRNA isoform and a misspliced isoform with a premature termination codon, causing nonsense mediated decay. The effectiveness of ETI in restoring Q1291H-CFTR is largely unknown. Methods: We collected clinical endpoint measurements, including forced expiratory volume in 1 s percent predicted (FEV1pp) and body mass index (BMI), and examined medical history. In silico simulations of the Q1291H-CFTR were compared to Q1291R, G551D, and wild-type (WT)-CFTR. We quantified relative Q1291H CFTR mRNA isoform abundance in patient-derived nasal epithelial cells. Differentiated pseudostratified airway epithelial cell models at air liquid interface were created and ETI treatment impact on CFTR was assessed by electrophysiology assays and Western blot. Results: The participant ceased ETI treatment after 3 months due to adverse events and no improvement in FEV1pp or BMI. In silico simulations of Q1291H-CFTR identified impairment of ATP binding similar to known gating mutants Q1291R and G551D-CFTR. Q1291H and F508del mRNA transcripts composed 32.91% and 67.09% of total mRNA respectively, indicating 50.94% of Q1291H mRNA was misspliced and degraded. Mature Q1291H-CFTR protein expression was reduced (3.18% ± 0.60% of WT/WT) and remained unchanged with ETI. Baseline CFTR activity was minimal (3.45 ± 0.25 µA/cm2) and not enhanced with ETI (5.73 ± 0.48 µA/cm2), aligning with the individual's clinical evaluation as a non-responder to ETI. Conclusion: The combination of in silico simulations and in vitro theratyping in patient-derived cell models can effectively assess CFTR modulator efficacy for individuals with non-classical CF manifestations or rare CFTR mutations, guiding personalized treatment strategies and optimizing clinical outcomes.

Saline at lower tonicity in cystic fibrosis (SALTI-CF) trial comparing 0.9% versus 3% versus 6% nebulised saline.

BACKGROUND: In people with cystic fibrosis (CF), regular nebulisation of 6% or 7% saline improves lung function; however, these concentrations are not always tolerable. Clinically, some CF patients report using lower concentrations of saline to improve tolerability, yet the effects of lower concentrations are unknown. This study therefore aimed to evaluate the relative effectiveness and tolerability of 0.9% versus 3% versus 6% saline nebulised twice daily with an eFlow rapid nebuliser. METHODS: This was a randomised, blinded, placebo-controlled, parallel-group, multicentre study where subjects inhaled 4 mL of 0.9%, 3% or 6% saline twice daily for 16 weeks. The primary outcome was forced expiratory volume in 1 s. The secondary outcomes were: forced vital capacity (FVC) and forced expiratory flow at 25-75% of FVC; quality of life; exercise capacity; acquisition or loss of bacterial organisms in expectorated sputum; tolerability of nebulised saline; pulmonary exacerbations; and adverse events. RESULTS: 140 participants were randomised to 0.9% (n=47), 3% (n=48) or 6% (n=45) saline. 134 participants (96%) contributed to the intention-to-treat analysis. 3% saline significantly improved lung function and increased the time to first pulmonary exacerbation compared with 0.9% saline but did not improve quality of life. 6% saline had similar benefits to 3% saline but also significantly improved quality of life compared with 3% saline. Only 6% saline delayed the time to intravenous antibiotics for pulmonary exacerbation. Tolerability and adherence were similar. CONCLUSIONS: Dilution of 6% saline to 3% maintains the benefits for lung function and exacerbation prevention; however, the positive impacts of 6% saline on quality of life and time to i.v. antibiotics for pulmonary exacerbations are lost.

Comparing Cytology Brushes for Optimal Human Nasal Epithelial Cell Collection: Implications for Airway Disease Diagnosis and Research.

Primary nasal epithelial cells and culture models are used as important diagnostic, research and drug development tools for several airway diseases. Various instruments have been used for the collection of human nasal epithelial (HNE) cells but no global consensus yet exists regarding the optimal tool. This study compares the efficiency of two cytology brushes (Olympus (2 mm diameter) and Endoscan (8 mm diameter)) in collecting HNE cells. The study involved two phases, with phase one comparing the yield, morphology and cilia beat frequency (CBF) of cells collected from paediatric participants using each of the two brushes. Phase two compared nasal brushing under general anaesthetic and in the awake state, across a wide age range, via the retrospective audit of the use of the Endoscan brush in 145 participants. Results indicated no significant difference in CBF measurements between the two brushes, suggesting that the choice of brush does not compromise diagnostic accuracy. However, the Endoscan brush collected significantly more total and live cells than the Olympus brush, making it a more efficient option. Importantly, the Endoscan brush is more cost-effective, with a notable price difference between the two brushes.

Single-arm, open-labelled, safety and tolerability of intrabronchial and nebulised bacteriophage treatment in children with cystic fibrosis and Pseudomonas aeruginosa.

INTRODUCTION: Cystic fibrosis (CF) is a multisystem condition that is complicated by recurrent pulmonary infections requiring aggressive antibiotic treatment. This predisposes the patient to complications such as sensorineural hearing loss, renal impairment, hypersensitivity and the development of antibiotic resistance. Pseudomonas aeruginosa is one of the more common organisms which cause recurrent infections and result in greater morbidity and mortality in people living with CF. Bacteriophages have been identified as a potential alternative or adjunct to antibiotics. We hypothesise that bacteriophage therapy is a safe and well-tolerated treatment in children with CF infected with P. aeruginosa infection in their airways. METHODS: This single-arm, open-labelled, non-randomised trial will run for a maximum period of 36 months with up to 10 participants. Adolescents (≥12 years and <18 years of age) who continue to shed P.aeruginosa (within 3 months of enrolment) despite undergoing eradication therapy previously, will be considered for this trial. Non-genetically modified bacteriophages that have demonstrated obligate lytic activity against each of the study participants' P. aeruginosa strains will be selected and prepared according to a combination of established protocols (isolation, purification, sterility testing and packaging) to achieve close to good manufacturing practice recommendations. The selected bacteriophage will be administered endo-bronchially first under direct vision, followed by two times a day nebulisation for 7 days in addition to standard CF treatment (intravenous antibiotics, physiotherapy to be completed as inpatient for 10-14 days). Safety and tolerability will be defined as the absence of (1) fever above 38.5°C occurring within 1 hour of the administration of the nebulised bacteriophage, (2) a 10% decline in spirometry (forced expiratory volume in 1 s %) measured preadministration and postadministration of the first dose of nebulised bacteriophage. Clinical reviews including repeat sputum cultures and spirometry will be performed at 3, 6, 9 and 12 months following bacteriophage treatment. ETHICS AND DISSEMINATION: Our clinical trial is conducted in accordance with (1) good clinical practice, (2) Australian legislation, (3) National Health and Medical Research Council guidelines for the ethical conduct of research. TRIAL REGISTRATION NUMBER: Australia and New Zealand Clinical Trial Registry (ACTRN12622000767707).

Molecular and Functional Characteristics of Airway Epithelium under Chronic Hypoxia.

Localized and chronic hypoxia of airway mucosa is a common feature of progressive respiratory diseases, including cystic fibrosis (CF). However, the impact of prolonged hypoxia on airway stem cell function and differentiated epithelium is not well elucidated. Acute hypoxia alters the transcription and translation of many genes, including the CF transmembrane conductance regulator (CFTR). CFTR-targeted therapies (modulators) have not been investigated in vitro under chronic hypoxic conditions found in CF airways in vivo. Nasal epithelial cells (hNECs) derived from eight CF and three non-CF participants were expanded and differentiated at the air-liquid interface (26-30 days) at ambient and 2% oxygen tension (hypoxia). Morphology, global proteomics (LC-MS/MS) and function (barrier integrity, cilia motility and ion transport) of basal stem cells and differentiated cultures were assessed. hNECs expanded at chronic hypoxia, demonstrating epithelial cobblestone morphology and a similar proliferation rate to hNECs expanded at normoxia. Hypoxia-inducible proteins and pathways in stem cells and differentiated cultures were identified. Despite the stem cells' plasticity and adaptation to chronic hypoxia, the differentiated epithelium was significantly thinner with reduced barrier integrity. Stem cell lineage commitment shifted to a more secretory epithelial phenotype. Motile cilia abundance, length, beat frequency and coordination were significantly negatively modulated. Chronic hypoxia reduces the activity of epithelial sodium and CFTR ion channels. CFTR modulator drug response was diminished. Our findings shed light on the molecular pathophysiology of hypoxia and its implications in CF. Targeting hypoxia can be a strategy to augment mucosal function and may provide a means to enhance the efficacy of CFTR modulators.

Australian Genomics: Outcomes of a 5-year national program to accelerate the integration of genomics in healthcare.

Australian Genomics is a national collaborative partnership of more than 100 organizations piloting a whole-of-system approach to integrating genomics into healthcare, based on federation principles. In the first five years of operation, Australian Genomics has evaluated the outcomes of genomic testing in more than 5,200 individuals across 19 rare disease and cancer flagship studies. Comprehensive analyses of the health economic, policy, ethical, legal, implementation and workforce implications of incorporating genomics in the Australian context have informed evidence-based change in policy and practice, resulting in national government funding and equity of access for a range of genomic tests. Simultaneously, Australian Genomics has built national skills, infrastructure, policy, and data resources to enable effective data sharing to drive discovery research and support improvements in clinical genomic delivery.

Learning to make a difference for chILD: Value creation through network collaboration and team science.

Addressing the recognized challenges and inequalities in providing high quality healthcare for rare diseases such as children's interstitial lung disease (chILD) requires collaboration across institutional, geographical, discipline, and system boundaries. The Children's Interstitial Lung Disease Respiratory Network of Australia and New Zealand (chILDRANZ) is an example of a clinical network that brings together multidisciplinary health professionals for collaboration, peer learning, and advocacy with the goal of improving the diagnosis and management of this group of rare and ultra-rare conditions. This narrative review explores the multifaceted benefits arising from social learning spaces within rare disease clinical networks by applying the value creation framework. The operation of the chILDRANZ network is used as an example across the framework to highlight how value is generated, realized, and transferred within such collaborative clinical and research networks. The community of practice formed in the chILDRANZ multidisciplinary meetings provides a strong example of social learning that engages with the uncertainty inherent in rare disease diagnosis and management and pays attention to generate new knowledge and best practice to make a difference for children and families living with chILD. This review underscores international calls for further investment in, and support of, collaborative clinical networks and virtual centers of excellence for rare disease.