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.

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.

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.

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.

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.

Molecular Dynamics and Theratyping in Airway and Gut Organoids Reveal R352Q-CFTR Conductance Defect.

A significant challenge to making targeted cystic fibrosis transmembrane conductance regulator (CFTR) modulator therapies accessible to all individuals with cystic fibrosis (CF) are many mutations in the CFTR gene that can cause CF, most of which remain uncharacterized. Here, we characterized the structural and functional defects of the rare CFTR mutation R352Q, with a potential role contributing to intrapore chloride ion permeation, in patient-derived cell models of the airway and gut. CFTR function in differentiated nasal epithelial cultures and matched intestinal organoids was assessed using an ion transport assay and forskolin-induced swelling assay, respectively. CFTR potentiators (VX-770, GLPG1837, and VX-445) and correctors (VX-809, VX-445, with or without VX-661) were tested. Data from R352Q-CFTR were compared with data of 20 participants with mutations with known impact on CFTR function. R352Q-CFTR has residual CFTR function that was restored to functional CFTR activity by CFTR potentiators but not the corrector. Molecular dynamics simulations of R352Q-CFTR were carried out, which indicated the presence of a chloride conductance defect, with little evidence supporting a gating defect. The combination approach of in vitro patient-derived cell models and in silico molecular dynamics simulations to characterize rare CFTR mutations can improve the specificity and sensitivity of modulator response predictions and aid in their translational use for CF precision medicine.

Tuning Defects in a Halide Double Perovskite with Pressure.

Dopant defects in semiconductors can trap charge carriers or ionize to produce charge carriers─playing a critical role in electronic transport. Halide perovskites are a technologically important semiconductor family with a large pressure response. Yet, to our knowledge, the effect of high pressures on defects in halide perovskites has not been experimentally investigated. Here, we study the structural, optical, and electronic consequences of compressing the small-bandgap double perovskites Cs2AgTlX6 (X = Cl or Br) up to 56 GPa. Mild compression to 1.7 GPa increases the conductivity of Cs2AgTlBr6 by ca. 1 order of magnitude and decreases its bandgap from 0.94 to 0.7 eV. Subsequent compression yields complex optoelectronic behavior: the bandgap varies by 1.2 eV and conductivity ranges by a factor of 104. These conductivity changes cannot be explained by the evolving bandgap. Instead, they can be understood as tuning of the bromine vacancy defect with pressure─varying between a delocalized shallow defect state with a small ionization energy and a localized deep defect state with a large ionization energy. Activation energy measurements reveal that the shallow-to-deep defect transition occurs near 1.5 GPa, well before the cubic-to-tetragonal phase transition. An analysis of the orbital interactions in Cs2AgTlBr6 illustrates how the bromine vacancy weakens the adjacent Tl s-Br p antibonding interaction, driving the shallow-to-deep defect transition. Our orbital analysis leads us to propose that halogen vacancies are most likely to be shallow donors in halide double perovskites that have a conduction band derived from the octahedral metal's s orbitals.

Transplacental transfer of RSV antibody in Australian First Nations infants.

Respiratory syncytial virus (RSV) is the leading cause of acute lower respiratory infection hospitalisations in Aboriginal infants specifically those aged <6 months. Maternally derived RSV antibody (Ab) can protect against severe RSV disease in infancy. However, the efficiency of transplacental transfer of maternal anti-RSV Ab remains unknown in Aboriginal infants. We characterised RSV Ab in Australian First Nations mother-infant pairs (n = 78). We investigated impact of covariates including low birthweight, gestational age (GA), sex of the baby, maternal age and multiparity of the mother on cord to maternal anti-RSV Ab titre ratio (CMTR) using multivariable logistic regression model. All (n = 78) but one infant was born full term (median GA: 39 weeks, interquartile range: 38-40 weeks) and 56% were males. The mean log2 RSV Ab titre was 10.7 (SD± 1.3) in maternal serum and 11.0 (SD ± 1.3) in cord serum at birth; a ratio of 1.02 (SD ± 0.06). One-third of the pairs had a CMTR of <1 indicating impaired transfer. Almost 9% (7/78) of the term infants had cord RSV Ab levels below

Development and validation of a risk score to identify children at risk of life-threatening asthma.

OBJECTIVE: To develop and validate a prediction risk score for identification of children at risk of developing life-threatening asthma (LTA). METHODS: Our study utilized existing medical records and retrospective analysis to develop and validate a risk score. The study population included children aged 2-17 years, admitted with a primary diagnosis of asthma, to Sydney Children's Hospital between 2011-2016. Children admitted in the intensive care unit with asthma at risk of LTA (cases) and those admitted into general ward (comparison group), were randomly divided into a derivation and a validation cohort. Candidate predictors from derivation cohort were selected through multivariable regression, which were used to estimate each child's risk of developing LTA in the validation cohort. Predictive performance of the risk score was evaluated by the area under the receiver operating characteristic curve (AUROC) and Hosmer-Lemeshow goodness-of-fit test. RESULTS: The study population comprised of 1171 children; 586 in the derivation and 585 in the validation cohort. Four independent candidate variables from derivation cohort (age at admission, socioeconomic status, a family history of asthma/atopy and previous asthma hospitalizations) were retained in the predictive model (AUROC 0.759; 95% CI, 0.694-0.823), with a sensitivity of 78.5% and specificity of 46.6%. CONCLUSIONS: Our risk algorithm based on routinely collected clinical data may be used to develop a user-friendly risk score for early identification and monitoring of children at risk of developing LTA.

Assessing the impact of the 13 valent pneumococcal vaccine on childhood empyema in Australia.

BACKGROUND: Empyema is a serious complication of pneumonia frequently caused by Streptococcus pneumoniae (SP). We assessed the impact of the 13-valent pneumococcal conjugate vaccine (13vPCV) on childhood pneumonia and empyema after inclusion in the Australian National Immunisation Program. METHODS: For bacterial pneumonia and empyema hospitalisations, we ascertained incidence rates (IRs) using the National Hospital Morbidity Database International Statistical Classification of Disease discharge codes and relevant population denominators, and calculated incidence rate ratios (IRR) comparing the 13vPCV period (June 2012-May 2017) with the 7vPCV period (June 2007-May 2011). Blood and pleural fluid (PF) cultures and PF PCR of 401 children with empyema from 11 Australian hospitals during the 13vPCV period were compared with our previous study in the 7vPCV period. FINDINGS: Across 7vPCV and 13vPCV periods, IRs per million children (95% CIs) were 1605 (1588 to 1621) and 1272 (1259 to 1285) for bacterial pneumonia, and 14.23 (12.67 to 15.79) and 17.89 (16.37 to 19.42) for empyema hospitalisations. IRRs were 0.79 (0.78 to 0.80) for bacterial pneumonia and 1.25 (1.09 to 1.44) for empyema. Of 161 empyema cases with SP serotypes, 147 (91.3%) were vaccine types. ST3 accounted for 76.4% of identified serotypes in the 13vPCV period, more than double than the 7vPCV period (p<0.001); ST19A decreased from 36.4% to 12.4%. No cases of ST1 empyema were identified in the 13vPCV period versus 14.5% in the 7vPCV period. INTERPRETATION: 13vPCV resulted in a significant reduction in all-cause hospitalisations for bacterial pneumonia but empyema hospitalisations significantly increased, with emergence of pneumococcal ST3 as the dominant serotype in empyema. TRIAL REGISTRATION NUMBER: Australian and New Zealand Clinical Trial Registry ACTRN 12614000354684.

Prevention and management of respiratory disease in young people with cerebral palsy: consensus statement.

Respiratory illness is the leading cause of mortality in children with cerebral palsy (CP). Although risk factors for developing chronic respiratory illness have been identified, comprehensive clinical care recommendations for the prevention and management of respiratory illness do not currently exist. We invited over 200 clinicians and researchers from multiple disciplines with expertise in the management of respiratory illness in children with CP to develop care recommendations using a modified Delphi method on the basis of the RAND Corporation-University of California Los Angeles Appropriateness Method. These recommendations are intended for use by the wide range of practitioners who care for individuals living with CP. They provide a framework for recognizing multifactorial primary and secondary potentially modifiable risk factors and for providing coordinated multidisciplinary care. We describe the methods used to generate the consensus recommendations, and the overall perspective on assessment, prevention, and treatment of respiratory illness in children with CP. WHAT THIS PAPER ADDS: The first consensus statement for preventing and managing respiratory disease in cerebral palsy (CP). Risk factors for respiratory disease in CP should be identified early. Individuals with CP at risk of respiratory disease require regular assessment of risk factors. Effective partnerships between multidisciplinary teams, individuals with CP, and families are essential. Treatment of respiratory disease in individuals with CP must be proactive.

La enfermedad respiratoria es la principal causa de mortalidad en niños con parálisis cerebral (PC). Aunque se han identificado los factores de riesgo para desarrollar enfermedades respiratorias crónicas, actualmente no existen recomendaciones completas de atención clínica para la prevención y el tratamiento de las enfermedades respiratorias. Invitamos a más de 200 médicos e investigadores de múltiples disciplinas con experiencia en el manejo de enfermedades respiratorias en niños con PC para desarrollar recomendaciones de atención utilizando un método Delphi modificado sobre la base del Método de adecuación RAND Corporation - Universidad de California en Los Ángeles. Estas recomendaciones están destinadas a ser utilizadas por la amplia gama de profesionales que atienden a personas que viven con PC. Proporcionan un marco para reconocer factores de riesgo multifactoriales primarios y secundarios potencialmente modificables y para proporcionar atención coordinada multidisciplinaria. Describimos los métodos utilizados para generar las recomendaciones de consenso, y la perspectiva general sobre la evaluación, prevención y tratamiento de enfermedades respiratorias de niños con PC.

Doença respiratória é a principal causa de mortalidade em crianças com paralisia cerebral (PC). Embora fatores de risco para desenvolver doença respiratória crônica tenham sido identificados, recomendações abrangentes de cuidado clínico e gerenciamento de doença respiratória não existem atualmente. Convidamos cerca de 200 clínicos e pesquisadores de múltiplas disciplinas com experiência no manejo de doença respiratória em crianças com PC para desenvolver recomendações de cuidado usando um método Delphi com base no método de Apropriação da Corporação RAND - Universidade da Califórnia. Estas recomendações são para uso de profissionais que atendem indivíduos com PC. Elas oferecem uma estrutura para reconhecer fatores de risco multifatoriais potencialmente modificáveis e prover cuidado multidisciplinar. Descrevemos métodos usados para gerar as recomendações do consenso, e a perspectiva geral de avaliação, prevenção e tratamento de doença respiratória em crianças com PC.

Surfactant protein disorders in childhood interstitial lung disease.

Surfactant, which was first identified in the 1920s, is pivotal to lower the surface tension in alveoli of the lungs and helps to lower the work of breathing and prevents atelectasis. Surfactant proteins, such as surfactant protein B and surfactant protein C, contribute to function and stability of surfactant film. Additionally, adenosine triphosphate binding cassette 3 and thyroid transcription factor-1 are also integral for the normal structure and functioning of pulmonary surfactant. Through the study and improved understanding of surfactant over the decades, there is increasing interest into the study of childhood interstitial lung diseases (chILD) in the context of surfactant protein disorders. Surfactant protein deficiency syndrome (SPDS) is a group of rare diseases within the chILD group that is caused by genetic mutations of SFTPB, SFTPC, ABCA3 and TTF1 genes.Conclusion: This review article seeks to provide an overview of surfactant protein disorders in the context of chILD. What is Known: • Surfactant protein disorders are an extremely rare group of disorders caused by genetic mutations of SFTPB, SPTPC, ABCA3 and TTF1 genes. • Given its rarity, research is only beginning to unmask the pathophysiology, inheritance, spectrum of disease and its manifestations. What is New: • Diagnostic and treatment options continue to be explored and evolve in these conditions. • It is, therefore, imperative that we as paediatricians are abreast with current development in this field.

Rare diseases research and policy in Australia: On the journey to equitable care.

Almost exactly 10 years after the publication of 'Call for a national plan for rare diseases' in this journal, the Federal Government launched the National Strategic Action Plan for Rare Diseases (the Action Plan) on the 26th of February 2020, in the lead up to Rare Disease Day on the 29th of February - a rare day for rare diseases. The Action Plan is the culmination of effective advocacy by Rare Voices Australia (RVA) and other stakeholders in the rare disease (RD) sector. RVA is the peak body for Australians living with a RD. The organisation works collaboratively with RD organisations, researchers and clinicians. Since the initial call for a RD plan, a number of health-care initiatives and policy changes have gathered apace including expanded antenatal and newborn screening, the increasing application of next generation sequencing and advances in gene and cell therapeutics. The development of new models of care, diagnostic and treatment pathways, and communities of practice have started to ease the considerable burden and inequitable access to care experienced by RD patients and their families. However, much work remains to be done. The Action Plan outlines the actions to bring about the best possible health and well-being outcomes for Australians living with RD. It is centred around three pillars - awareness and education, care and support, research and data - and will be delivered against the principles of person centredness, equity, and sustainable systems and workforce.

Selective, High-Temperature O2 Adsorption in Chemically Reduced, Redox-Active Iron-Pyrazolate Metal-Organic Frameworks.

Developing O2-selective adsorbents that can produce high-purity oxygen from air remains a significant challenge. Here, we show that chemically reduced metal-organic framework materials of the type AxFe2(bdp)3 (A = Na+, K+; bdp2- = 1,4-benzenedipyrazolate; 0 < x ≤ 2), which feature coordinatively saturated iron centers, are capable of strong and selective adsorption of O2 over N2 at ambient (25 °C) or even elevated (200 °C) temperature. A combination of gas adsorption analysis, single-crystal X-ray diffraction, magnetic susceptibility measurements, and a range of spectroscopic methods, including 23Na solid-state NMR, Mössbauer, and X-ray photoelectron spectroscopies, are employed as probes of O2 uptake. Significantly, the results support a selective adsorption mechanism involving outer-sphere electron transfer from the framework to form superoxide species, which are subsequently stabilized by intercalated alkali metal cations that reside in the one-dimensional triangular pores of the structure. We further demonstrate O2 uptake behavior similar to that of AxFe2(bdp)3 in an expanded-pore framework analogue and thereby gain additional insight into the O2 adsorption mechanism. The chemical reduction of a robust metal-organic framework to render it capable of binding O2 through such an outer-sphere electron transfer mechanism represents a promising and underexplored strategy for the design of next-generation O2 adsorbents.

Role of technology in improving knowledge and confidence in asthma management in school staff.

Objective: To investigate the effectiveness of technology enabled learning in improving asthma first aid knowledge and self-confidence in providing asthma first aid to children in staff within a school setting. Study Design: A prospective randomized parallel study using a pre and post test design was conducted across Metropolitan schools of New South Wales (NSW), Australia. School staff in selected schools were randomly assigned to receive first aid asthma management training via a self-directed multimedia eBook learning resource or standard face-to-face training. Staff completed a 14 item validated Asthma First Aid Knowledge Questionnaire and a 4 item, 10-point Likert-scale asthma management self-confidence questionnaire immediately pre and post training. Results: 148 school staff from 46 schools were recruited with a total of 59 (78%) staff completing the eBook training and 62 (86%) completing face-to-face training. The mean asthma first aid knowledge score and self-confidence score in managing asthma increased significantly (p < 0.0001) in the eBook training group post training. There was no significant difference in the increase in the mean scores post training between the eBook and face-to-face training groups (p = 0.11). Conclusion: Asthma management knowledge and self-confidence increased in school staff following the eBook training. In school settings where human resources for health education are limited, technology enabled learning may be substituted to provide a self-directed approach to asthma first aid management training.

Targeted Activation of Cystic Fibrosis Transmembrane Conductance Regulator.

Cystic fibrosis (CF) is caused by mutations in the CF transmembrane conductance regulator (CFTR) gene. The majority of CFTR mutations result in impaired chloride channel function as only a fraction of the mutated CFTR reaches the plasma membrane. The development of a therapeutic approach that facilitates increased cell-surface expression of CFTR could prove clinically relevant. Here, we evaluate and contrast two molecular approaches to activate CFTR expression. We find that an RNA-guided nuclease null Cas9 (dCas9) fused with a tripartite activator, VP64-p65-Rta can activate endogenous CFTR in cultured human nasal epithelial cells from CF patients. We also find that targeting BGas, a long non-coding RNA involved in transcriptionally modulating CFTR expression with a gapmer, induced both strong knockdown of BGas and concordant activation of CFTR. Notably, the gapmer can be delivered to target cells when generated as electrostatic particles with recombinant HIV-Tat cell penetrating peptide (CPP), when packaged into exosomes, or when loaded into lipid nanoparticles (LNPs). Treatment of patient-derived human nasal epithelial cells containing F508del with gapmer-CPP, gapmer-exosomes, or LNPs resulted in increased expression and function of CFTR. Collectively, these observations suggest that CRISPR/dCas-VPR (CRISPR) and BGas-gapmer approaches can target and specifically activate CFTR.

Assessing appropriateness of paediatric asthma management: A population-based sample survey.

BACKGROUND AND OBJECTIVE: We conducted a comprehensive assessment of guideline adherence in paediatric asthma care, including inpatient and ambulatory services, in Australia. METHODS: National and international clinical practice guidelines (CPG) relating to asthma in children were searched and 39 medical record audit indicator questions were developed. Retrospective medical record review was conducted across hospital inpatient admissions, emergency department (ED) presentations, general practice (GP) and paediatrician consultations in three Australian states for children aged ≤15 years receiving care in 2012 and 2013. Eligibility of, and adherence to, indicators was assessed from medical records by nine experienced and purpose-trained paediatric nurses (surveyors). RESULTS: Surveyors conducted 18 453 asthma indicator assessments across 1600 visits for 881 children in 129 locations. Overall, the adherence for asthma care across the 39 indicators was 58.1%, with 54.4% adherence at GP (95% CI: 46.0-62.5), 77.7% by paediatricians (95% CI: 40.5-97.0), 79.9% in ED (95% CI: 70.6-87.3) and 85.1% for inpatient care (95% CI: 76.7-91.5). For 14 acute asthma indicators, overall adherence was 56.3% (95% CI: 47.6-64.7). Lowest adherences were for recording all four types of vital signs in children aged >2 years presenting with asthma attack (15.1%, 95% CI: 8.7-23.7), and reviewing patients' compliance, inhaler technique and triggers prior to commencing a new drug therapy (20.5%, 95% CI: 10.1-34.8). CONCLUSION: The study demonstrated differences between existing care and CPG recommendations for paediatric asthma care in Australia. Evidence-based interventions to improve adherence to CPG may help to standardize quality of paediatric asthma care and reduce variation of care.

Probiotics for people with cystic fibrosis.

BACKGROUND: Cystic fibrosis (CF) is a multisystem disease and the importance of growth and nutrition has been well established, given its implications for lung function and overall survival. It has been established that intestinal dysbiosis (i.e. microbial imbalance) and inflammation is present in people with CF. Probiotics are commercially available (over-the-counter) and may improve both intestinal and overall health. OBJECTIVES: To assess the efficacy and safety of probiotics for improving health outcomes in children and adults with CF. SEARCH METHODS: We searched the Cochrane Cystic Fibrosis Trials Register, compiled from electronic database searches and handsearching of journals and conference abstract books. Date of last register search: 20 January 2020. We also searched ongoing trials registries and the reference lists of relevant articles and reviews. Date of last search: 29 January 2019. SELECTION CRITERIA: Randomised or quasi-randomised controlled trials (RCTs) assessing efficacies and safety of probiotics in children and adults with CF. Cross-over RCTs with a washout phase were included and for those without a washout period, only the first phase of each trial was analysed. DATA COLLECTION AND ANALYSIS: We independently extracted data and assessed the risk of bias of the included trials; we used GRADE to assess the certainty of the evidence. We contacted trial authors for additional data. Meta-analyses were undertaken on outcomes at several time points. MAIN RESULTS: We identified 17 trials and included 12 RCTs (11 completed and one trial protocol - this trial was terminated early) (464 participants). Eight trials included only children, whilst four trials included both children and adults. Trial duration ranged from one to 12 months. Nine trials compared a probiotic (seven single strain and three multistrain preparations) with a placebo preparation, two trials compared a synbiotic (multistrain) with a placebo preparation and one trial compared two probiotic preparations. Overall we judged the risk of bias in the 12 trials to be low. Three trials had a high risk of performance bias, two trials a high risk of attrition bias and six trials a high risk of reporting bias. Only two trials were judged to have low or unclear risk of bias for all domains. Four trials were sponsored by grants only, two trials by industry only, two trials by both grants and industry and three trials had an unknown funding source. Combined data from four trials (225 participants) suggested probiotics may reduce the number of pulmonary exacerbations during a four to 12 month time-frame, mean difference (MD) -0.32 episodes per participant (95% confidence interval (CI) -0.68 to 0.03; P = 0.07) (low-certainty evidence); however, the 95% CI includes the possibility of both an increased and a reduced number of exacerbations. Additionally, two trials (127 participants) found no evidence of an effect on the duration of antibiotic therapy during the same time period. Combined data from four trials (177 participants) demonstrated probiotics may reduce faecal calprotectin, MD -47.4 µg/g (95% CI -93.28 to -1.54; P = 0.04) (low-certainty evidence), but the results for other biomarkers mainly did not show any difference between probiotics and placebo. Two trials (91 participants) found no evidence of effect on height, weight or body mass index (low-certainty evidence). Combined data from five trials (284 participants) suggested there was no difference in lung function (forced expiratory volume at one second (FEV1) % predicted) during a three- to 12-month time frame, MD 1.36% (95% CI -1.20 to 3.91; P = 0.30) (low-certainty evidence). Combined data from two trials (115 participants) suggested there was no difference in hospitalisation rates during a three- to 12-month time frame, MD -0.44 admissions per participant (95% CI -1.41 to 0.54; P = 0.38) (low-certainty evidence). One trial (37 participants) reported health-related quality of life and while the parent report favoured probiotics, SMD 0.87 (95% CI 0.19 to 1.55) the child self-report did not identify any effect, SMD 0.59 (95% CI -0.07 to 1.26) (low-certainty evidence). There were limited results for gastrointestinal symptoms and intestinal microbial profile which were not analysable. Only four trials and one trial protocol (298 participants) reported adverse events as a priori hypotheses. No trials reported any deaths. One terminated trial (12 participants and available as a protocol only) reported a severe allergic reaction (severe urticaria) for one participant in the probiotic group. Two trials reported a single adverse event each (vomiting in one child and diarrhoea in one child). The estimated number needed to harm for any adverse reaction (serious or not) is 52 people (low-certainty evidence). AUTHORS' CONCLUSIONS: Probiotics significantly reduce faecal calprotectin (a marker of intestinal inflammation) in children and adults with CF, however the clinical implications of this require further investigation. Probiotics may make little or no difference to pulmonary exacerbation rates, however, further evidence is required before firm conclusions can be made. Probiotics are associated with a small number of adverse events including vomiting, diarrhoea and allergic reactions. In children and adults with CF, probiotics may be considered by patients and their healthcare providers. Given the variability of probiotic composition and dosage, further adequately-powered multicentre RCTs of at least 12 months duration are required to best assess the efficacy and safety of probiotics for children and adults with CF.

Assessing the appropriateness of paediatric antibiotic overuse in Australian children: a population-based sample survey.

BACKGROUND: Infections caused by antibiotic resistant pathogens are increasing, with antibiotic overuse a key contributing factor. OBJECTIVE: The CareTrack Kids (CTK) team assessed the care of children in Australia aged 0-15 years in 2012 and 2013 to determine the proportion of care in line with clinical practice guidelines (CPGs) for 17 common conditions. This study analyses indicators relating to paediatric antibiotic overuse to identify those which should be prioritised by antimicrobial stewardship and clinical improvement programs. METHOD: A systematic search was undertaken for national and international CPGs relevant to 17 target conditions for Australian paediatric care in 2012-2013. Recommendations were screened and ratified by reviewers. The sampling frame comprised three states containing 60% of the Australian paediatric population (South Australia, New South Wales and Queensland). Multi-stage cluster sampling was used to select general practices, specialist paediatric practices, emergency departments and hospital inpatient services, and medical records within these. Medical records were reviewed by experienced paediatric nurses, trained to assess eligibility for indicator assessment and compliance with indicators. Adherence rates were estimated. RESULTS: Ten antibiotic overuse indicators were identified; three for tonsillitis and one each for seven other conditions. A total of 2621 children were assessed. Estimated adherence for indicators ranged from 13.8 to 99.5% while the overall estimate of compliance was 61.9% (95% CI: 47.8-74.7). Conditions with high levels of appropriate avoidance of antibiotics were gastroenteritis and atopic eczema without signs of infection, bronchiolitis and croup. Indicators with less than 50% adherence were asthma exacerbation in children aged > 2 years (47.1%; 95% CI: 33.4-61.1), sore throat with no other signs of tonsillitis (40.9%; 95% CI: 16.9, 68.6), acute otitis media in children aged > 12 months who were mildly unwell (13.8%; 95% CI: 5.1, 28.0), and sore throat and associated cough in children aged < 4 years (14.3%; 95% CI: 9.9, 19.7). CONCLUSION: The results of this study identify four candidate indicators (two for tonsillitis, one for otitis media and one for asthma) for monitoring by antibiotic stewardship and clinical improvement programs in ambulatory and hospital paediatric care, and intervention if needed.