BACKGROUND:Protracted bacterial bronchitis (PBB), chronic suppurative lung disease (CSLD) and bronchiectasis are parts of a disease spectrum characterised by chronic wet cough (CWC). Untreated PBB can develop into CSLD/bronchiectasis. Community-based data are limited, and longitudinal studies of children with CWC/PBB may provide insights into risks of developing CSLD/bronchiectasis and associations with lung function, particularly in priority populations. Our aim was to characterise the six-year respiratory outcomes of young Indigenous children with CWC/PBB, and risk factors associated with chronic respiratory disease. METHODS:In a whole-available population observational community-based cohort study in four-remote Western Australian communities, we undertook respiratory screening of Indigenous children aged < eight-years. The children were followed-up six-years later. RESULTS:Of the 203 children recruited in 2018-2019, 191 (94.1%) were re-screened in 2024, where 33/191 (17.3%) had a chronic respiratory condition; their median forced expiratory volume in-one-second and forced vital capacity z-scores were significantly lower than their healthy peers, mean-difference (MD) was -0.78 (95%CI -1.30, -0.30), and -1.30 (95%CI -1.90, -0.77) respectively. Of the 26 children with CWC in 2018-2019, nine (34.6%) had CSLD/bronchiectasis six-years later, with the risk of CSLD/bronchiectasis being 28.6 (95%CI 6.6, 124.9) times higher than those without CWC. Previous acute lower respiratory tract infection (ALRI) hospitalisation was associated with CSLD/bronchiectasis (prevalence odds ratio = 7.8, 95%CI 2.1, 41.6). CONCLUSIONS:In this first whole-available community longitudinal study of remote-based Indigenous children, there was high prevalence of chronic respiratory disease with corresponding low lung function. CWC in the first eight-years of life and previous ALRI-related hospitalisation were associated with significantly increased risk of CSLD/bronchiectasis.

AIM:To assess the prevalence, clinical features and treatment of otitis media (OM) among Aboriginal children in the Kimberley region of Western Australia, and to determine if a correlation exists between OM and protracted bacterial bronchitis (PBB). METHODS:Data was extracted from clinic records of Aboriginal children from four remote Kimberley communities participating in a whole-population lung health screening program during 2018-2019. Records were retrospectively reviewed 3 months before and after the screening date. OM prevalence and related complications were determined. Management was assessed against regional guidelines. The relationship between OM and the presence of PBB was assessed using chi-square testing. RESULTS:One-hundred ninety-one children (median age 3.5 years, 48.7% female) were included. Otorrhoea and/or otalgia was documented in 14.1% of children, and 53.9% had abnormal otoscopy findings. Earwax obscured visualisation of the tympanic membrane in 31.4% of examinations. Audiometry was performed in 27.2% of children, with hearing loss detected in 46.1% of those tested. OM, including acute OM with or without perforation, OM with effusion, or chronic suppurative OM, was diagnosed in 43.5% of children. Adherence to guideline-recommended antibiotic route and duration was seen in 15.8% of children with acute OM. No association was found between OM and PBB. CONCLUSION:Despite the absence of a relationship between OM and PBB, there is a high burden of OM among Aboriginal children in the Kimberley. Training clinicians in earwax removal and improving eardrum visualisation may enhance detection and timely treatment of OM, improving ear health disparities among Aboriginal populations.

BACKGROUND:Pulmonary exacerbations pose a significant clinical burden on people with cystic fibrosis (pwCF). Whether management of exacerbations should change in the context of modulator therapy is unclear. We describe the characteristics, treatment and lung function outcomes of pulmonary exacerbations requiring intravenous antibiotic therapy (PERITs) in a contemporary Australian cohort of pwCF, in an era of rapidly broadening access to modulator therapy. METHODS:PwCF receiving care at 11 Australian specialist centres were prospectively enrolled between 14 October 2020 and 9 October 2024. Spirometry data and treatments received during a PERIT were collected systematically. RESULTS:A total of 982 pwCF were enrolled, with 593 PERITs recorded in 323 individuals. The median (interquartile range) age at PERIT start was 12 (7-17) years and the mean±sd baseline forced expiratory volume in 1 s (FEV1) % predicted across PERITs was 80±21%. Approximately 62% (n=366) of PERITs occurred in people receiving modulator therapy. Intravenous tobramycin (63%) and piperacillin-tazobactam (43%) were the most frequently used antibiotics. Among participants with spirometry at baseline and at Day 7 (n=296) or Day 60 (n=383), 41% (n=120) and 44% (n=169) were below their baseline at Day 7 and Day 60 after commencing treatment, respectively; 8% were >10% below their baseline FEV1 % predicted at both time-points. Recovery patterns were consistent regardless of baseline lung function, Pseudomonas aeruginosa colonisation or modulator use. CONCLUSION:The pattern and magnitude of lung function impairment during PERITs is similar among those receiving and not receiving modulator therapy. This underscores the continued need for evidence to help clinicians balance treatment burden against the risk of irreversible loss of lung function.

OBJECTIVE:To identify the barriers and facilitators for timely detection and optimal management of otitis media (OM) in Aboriginal children in a primary care setting from the perspective of Health Care Providers (HCPs). SETTING:A large regional town in the Kimberley region of Western Australia. PARTICIPANTS:Thirty HCPs to Aboriginal children. DESIGN:A qualitative, aboriginal co-designed, participatory action research study with semi-structured interviews and focus groups. RESULTS:Barriers were identified throughout the child's presentation and management and included challenges with paediatric ear examinations, earwax obstructing the view of the tympanic membrane, unfamiliarity with diagnostic tools, multiple guidelines with varying recommendations, and confusion with accessing ENT specialists. Multiple facilitators were identified and included training HCPs in paediatric examination techniques and wax removal, a single best practice guideline, and system changes to facilitate access to ENT specialist support if required. Importantly, an expanded clinical role of Aboriginal Health Practitioners (AHPs) was identified to augment efficient and effective clinical OM assessment and management in children presenting to clinic. CONCLUSIONS:All barriers could potentially be overcome through a programme that enhances theoretical knowledge and practical skills in paediatric ear examination, otoscopy, and safe, timely removal of earwax, improved communication with ENT specialists, and an expanded clinical role for AHPs. Our findings carry important implications for managing OM in primary care services across Australia.

BACKGROUND:Allergic bronchopulmonary aspergillosis (ABPA) contributes to progressive lung damage in people with cystic fibrosis (pwCF), particularly when diagnosis is delayed. Early diagnosis remains challenging due to insidious onset and non-specific symptoms. We aimed to assess the utility of routinely collected biomarkers in predicting ABPA in children with CF. METHODS:A retrospective analysis of pwCF aged 0-18 years in Western Australia from 2000 to 2020. Longitudinal levels of total IgE, eosinophils (Eo), and Aspergillus-specific IgE (Asp-sp IgE) preceding ABPA diagnosis were compared with age- and sex-matched controls. RESULTS:Among 346 children with CF, 19 (5.4%) were diagnosed with ABPA. Distinct elevations in Asp-sp IgE, total IgE, and Eo were observed up to five years before clinical diagnosis. Total IgE almost doubled and Asp-sp IgE nearly tripled in the three years preceding diagnosis. Persistent normal values across all three markers were strongly associated with low risk of ABPA. Children with total IgE levels <500 IU/mL, Asp-sp IgE <0.35 IU/mL, and Eo <0.5 × 109 cells/L, had a negligible risk (<1.0%) of ABPA over the next five years and very low risk (4.5%) over twelve years. DISCUSSION:Biomarker elevations in children who develop ABPA are not sudden but emerge early and persist over time. Conversely, children with low levels in at least two of total IgE, Eo, and Asp-sp IgE are at negligible risk of ABPA for at least five years and therefore may only require screening every five years. In contrast, children with elevated levels should be monitored more closely.

Background : Cystic Fibrosis (CF) is a genetic condition caused by mutation of the Cystic Fibrosis Transmembrane Regulator (CFTR) gene. Recently licensed modulator therapies target the defective CFTR protein and have transformed the formerly life-limiting trajectory of people with CF (pwCF). elexacaftor/tezacaftor/ivacaftor (ETI) has shown outstanding clinical efficacy in pwCF homozygous for F508del, (approximately 50%), and those with a F508del mutation paired with any of the >2000 other mutations identified in the CFTR gene (heterozygous pairing). However, clinical response to the very expensive modulators are variable within this treatment-targeted population. Further, people with rare CF mutations (i.e., CFTR mutations other than F508del) are often excluded from modulator access worldwide. Methods : Based on the in vitro testing, participants will be eligible to enter the interventional phase of the trial. Participantswill be administered blinded study drug (i.e., ETI or placebo) for a 14-day treatment block followed by a 14-day washout period prior to beginning the alternate treatment, again for a 14-day period. A treatment cycle will be defined as one ETI treatment block, one placebo treatment block and the intervening wash-out period. Treatment blocks sequency will be randomly assigned. Participants will complete a minimum of two treatment cycles and up to four consecutive cycles depending on the results of planned interim analyses. Discussion : The ORIGIN-1 trial isdesigned to demonstrate a precision medicine approach that targets CFTR modulator therapy to ensure the optimal use of these very high-cost therapies. This pathway may expand the application of CFTR modulators to include pwCF with rare mutations of the CFTR gene for whom CFTR modulators efficacy have not been (and are unlikely to ever be) proven by conventional, parallel group clinical trials. We anticipate that a personalised organoid model that measures patient-specific CFTR responses to modulators in vitro will enable the reliable identification of pwCFwith these rare CFTR mutations who are likely to respond to existing modulator therapy. Trial registration : Australia New Zealand Clinical Trials Registry (ANZCTR)- ID: ACTRN12623001136695 Registered on November 03, 2023.

Cystic fibrosis (CF) is a genetic condition caused by mutation of the cystic fibrosis transmembrane regulator (CFTR) gene. Recently licensed modulator therapies target the defective CFTR protein and have transformed the formerly life-limiting trajectory of people with CF (pwCF). elexacaftor/tezacaftor/ivacaftor (ETI) has shown outstanding clinical efficacy in pwCF homozygous for F508del (approximately 50

BACKGROUND:Managing bronchiectasis exacerbations is a priority for patients, parents, and caregivers of children with bronchiectasis. However, evidence-based strategies among the pediatric population remain limited. RESEARCH QUESTION:Does the use of a personalized, written bronchiectasis action management plan (BAMP), compared with standard care, reduce nonscheduled physician visits among children and adolescents with chronic suppurative lung disease (CSLD)/bronchiectasis? STUDY DESIGN AND METHODS:This multicenter, double-anonymized, superiority, randomized controlled trial enrolled children from 3 Australian respiratory departments between June 2018 and December 2020. Children and adolescents aged < 19 years with CSLD/bronchiectasis were randomized to receive a personalized BAMP (intervention) or standard care (control participants). The primary outcome was the annual rate of acute nonscheduled physician visits for respiratory exacerbations, after randomization. Secondary outcomes were the annualized rate of acute exacerbations, scores on the 8-item Parent Cough-specific Quality of Life questionnaire, and proportion receiving timely annual influenza vaccination. RESULTS:Of the 207 children enrolled, 194 were included in the known-case intention-to-treat analysis (BAMP group, n = 99; control group, n = 95). There was no significant difference in the annualized rates of nonscheduled respiratory-related physician visits (median [interquartile range]: BAMP, 2 [0-4]; control, 2 [0-4)]; incident rate ratio, 0.98 [95% CI, 0.71-1.36]). However, in the sensitivity analysis limited to pre-COVID-19 data (BAMP group, n = 42; control group, n = 44), there was a reduction in nonscheduled respiratory-related physician-related visits in the BAMP group (incident rate ratio, 0.63; 95% CI, 0.38-1.04; P = .07). In the intention-to-treat analysis, patients in the BAMP group were significantly more likely than control partcipants to receive timely annual influenza vaccination (74 of 103 vs 58 of 102, respectively; OR, 2.03; 95% CI, 1.13-3.65; P = .017). INTERPRETATION:Among children and adolescents with CSLD/bronchiectasis, using a BAMP was shown to improve timely influenza vaccination uptake but did not significantly reduce nonscheduled physician visits. However, the results were likely influenced by the COVID-19 pandemic, and data prior to the COVID-19 pandemic show a clear trend toward efficacy of the BAMP, with a 37% reduction in unscheduled physician visits. In addition, consumer feedback was strongly positive regarding the BAMP's usefulness and practicality. CLINICAL TRIAL REGISTRATION:Australian and New Zealand Clinical Trials Register; No. ACTRN12618000604202; URL: www.anzctr.org.au.

Introduction: Presence of circulating tumor DNA (ctDNA) after treatment for early-stage breast cancer (EBC) is associated with poor outcomes, yet accurate detection of ctDNA clearance after treatment requires ultrasensitive methods. Here, we describe the clearance of ctDNA in EBC by multiple treatment modalities, including surgery and neoadjuvant chemotherapy (NAC), using an ultrasensitive ctDNA minimum residual disease (MRD) assay. Methods: The MSK-LINC study prospectively collected blood samples from EBC patients throughout their clinical care at MSK. MRD was monitored using Foresight CLARITY, an ultra-sensitive MRD research assay with LOD95 below 1 part-per-million (ppm). Whole genome sequencing (WGS) of primary tumor and WBC samples was used to identify tumor-derived phased variants. Personalized MRD assays were then designed to detect ctDNA. We assessed the relationship between ctDNA during distinct phases of treatment and clinical outcomes, including NAC, surgery, or adjuvant treatment. Results: We analyzed 390 samples from 50 EBC patients (Stages: I=22%, II=56%, III=22%) treated with curative-intent surgery for diverse subtypes (62% HR+/HER2-, 24% HER2+, 14% TNBC). Pretreatment ctDNA was present in 72% of patients, with a median variant allele frequency (VAF) of 100 ppm (range 8 - 226,000 ppm). Following neoadjuvant (44%) or adjuvant (48%) chemotherapy, 14% distant relapses were observed. Among 18 patients with detectable ctDNA before or during NAC, 56% cleared their ctDNA prior to surgery and remained disease free, with 60% of these achieving pathological complete response (pCR). In contrast, 44% of patients were ctDNA MRD positive (ctDNA+) at the last time-point prior to surgery (median 5 ppm, range: 3-12); 50% of these patients experienced disease recurrence and none achieved pCR. Clearance of ctDNA prior to surgery was associated with significantly improved DFS (p = 0.012). When considering the effect of surgery on patients with residual ctDNA after NAC, 63% had undetectable ctDNA at the first post-operative time-point while 38% did not, with ctDNA levels ranging from 0.9 to 322 ppm. All ctDNA+ patients experienced relapse. Among patients who cleared ctDNA at any postoperative timepoint, only one (13%) experienced relapse; ctDNA was detected in the next blood sample, 15 months prior to relapse. All patients experiencing relapse had ctDNA detected prior to recurrence by serial monitoring. Among evaluable patients not receiving NAC, 15 patients had ctDNA detected pre-surgery (median ctDNA level 40 ppm, range 8-913), with 87% achieving ctDNA clearance post-surgery. The two patients without ctDNA clearance post-surgery (VAF pre- vs post-surgery 124→3.8 ppm and 40→10 ppm) were HR+/HER2- and experienced no relapse. Interestingly, both patients received adjuvant chemotherapy and endocrine therapy, leading to ctDNA clearance at subsequent timepoints. Among 13 cases with ctDNA clearance post-surgery, 92% remain disease free. We observed a single late relapse at 54 mo in a patient with TNBC who cleared ctDNA at the post-operative landmark, with ctDNA detection re-emerging prior to relapse. Conclusion: In EBC, ctDNA clearance by NAC, surgery, or adjuvant therapy is strongly associated with favorable outcomes. Ultrasensitive MRD analysis demonstrates that surgery also leads to a high rate of ctDNA clearance, suggesting the ability to measure and differentiate responses to both local and systemic therapies. Ultrasensitive ctDNA in EBC is likely to become an important biomarker of response to therapeutic interventions and warrants further study. Citation Format: Luc Cabel, Julia Ah-Reum An, David Kurtz, Dara Ross, Esra Dikoglu, Enrico Moiso, Kevin Murphy, Kathleen Szuhany, Sierra Love Stowell, Dillon Maloney, Giselle Zamora-Chavez, Andre Schultz, Howard I. Scher, Jake Chabon, Mark E Robson, Monica Morrow, Bob T Li, Ash A Alizadeh, Sarat Chandarlapaty, George Plitas, Maximilian Diehn, Pedram Razavi. Circulating tumor DNA clearance by neoadjuvant chemotherapy or breast surgery detected using an ultrasensitive ctDNA MRD assay in early breast cancer [abstract]. In: Proceedings of the San Antonio Breast Cancer Symposium 2024; 2024 Dec 10-13; San Antonio, TX. Philadelphia (PA): AACR; Clin Cancer Res 2025;31(12 Suppl):Abstract nr P2-01-25.

Loss of lung function in cystic fibrosis (CF) occurs progressively, punctuated by acute pulmonary exacerbations (PEx) in which abrupt declines in lung function are not fully recovered. A key component of CF management over the past half century has been the treatment of PEx to slow lung function decline. This has been credited with improvements in survival for people with CF (PwCF), but there is no consensus on the optimal approach to PEx management. BEAT-CF (Bayesian evidence-adaptive treatment of CF) was established to build an evidence-informed knowledge base for CF management. The BEAT-CF causal model is a directed acyclic graph (DAG) and Bayesian network (BN) for PEx that aims to inform the design and analysis of clinical trials comparing the effectiveness of alternative approaches to PEx management. The causal model describes relationships between background risk factors, treatments, and pathogen colonisation of the airways that affect the outcome of an individual PEx episode. The key factors, outcomes, and causal relationships were elicited from CF clinical experts and together represent current expert understanding of the pathophysiology of a PEx episode, guiding the design of data collection and studies and enabling causal inference. Here, we present the DAG that documents this understanding, along with the processes used in its development, providing transparency around our trial design and study processes, as well as a reusable framework for others.

OBJECTIVE:To assess the relationship between adherence to anti-staphylococcal prophylaxis with amoxycillin-clavulanic acid in the first 2 years of life in children with cystic fibrosis (CF) and microbiological outcomes in the first 6 years of life. METHODS:We conducted a retrospective cohort study of adherence to antistaphylococcal prophylaxis in children diagnosed with cystic fibrosis between 2000 and 2014 in Western Australia. Adherence (high defined as ≥ 90%, low defined as ≤ 70% days covered) was compared to microbial culture results from bronchoalveolar lavage collected during annual disease surveillance. Fisher's exact tests were used to examine the association between adherence and the presence of three major lung pathogens (S. aureus, P. aeruginosa, and Aspergillus species) across three age ranges (0-2 y.o., 3-4 y.o., and 5-6 y.o.). RESULTS:124 patients were included in the analysis. Adherence rates were high at 93% (median, interquartile range 67.8%-99.0%). Over 6 years prevalence of S. aureus ranged from 4% to 12%, P. aeruginosa ranged from 2% to 10% and Aspergillus ranged from 4% to 20%. There were no statistically significant differences in culture positivity between high and low adherence groups during the study period. Specifically, increased adherence was not associated with significant differences in the culture rates of lung pathogens. CONCLUSIONS:In children with CF, adherence to anti-staphylococcal prophylaxis in the first 2 years of life is not associated with a decrease in S. aureus in the lower airways, questioning the value of such prophylaxis.

Bronchiectasis is a chronic lung disease that often commences during childhood. The disease is often under-recognised but can have a significant lifelong impact and shorten survival. This review discussed bronchiectasis in the context of Aboriginal and Torres Strait Islander children and young people. The review includes section on disease prevalence, risk- and protective factors, prevention diagnosis and treatment, the role of the health system, government initiatives and future directions.