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Otitis media affects nearly all children worldwide. Despite an enormous amount of research, our understanding of this common condition continues to be challenged. New pathogens involved in otitis media are still being identified. The importance of interactions between viral and bacterial infection and the role of new vaccines need to be clarified. The proposal that bacteria can become more resistant to therapy through biofilm formation and intracellular infection could have important implications for treatment. The most important clinical research findings have been summarised in systematic reviews. In developed countries, research supporting "watchful waiting" of otitis media with effusion and acute otitis media have had most impact on evidence-based clinical practice guidelines. Indigenous Australian children remain at risk of more severe otitis media. Research programs targeting this population have been well supported. Unfortunately, interventions that can dramatically improve outcomes have remained elusive. For children at high risk of otitis media, health care services should concentrate on accurate diagnosis, antibiotic treatment of suppurative infections, and scheduled follow-up of affected children. Despite the lack of recent studies, strategies to minimise the impact the hearing loss associated with otitis media are important. Improvements in education, hygiene practices, and living conditions are likely to reduce the incidence and severity of otitis media. Studies of these types of interventions are needed. [ABSTRACT FROM AUTHOR]

Background: For children at high risk of chronic suppurative otitis media (CSOM), strategies to prevent acute otitis media with perforation (AOMwiP) may reduce progression to CSOM.Methods: In a double blind study in northern Australia, 103 Aboriginal infants with first detection of OME were randomised to receive either amoxicillin (50 mg/kg/d BD) or placebo for 24 weeks, or until bilateral aerated middle ears were diagnosed at two successive monthly examinations (success). Standardised clinical assessments and international standards for microbiology were used.Results: Five of 52 infants in the amoxicillin group and none of 51 infants in the placebo group achieved success at the end of therapy (Risk Difference = 9.6% [95% confidence interval 1.6,17.6]). Amoxicillin significantly reduced the proportion of children with i) perforation at the end of therapy (27% to 12% RD = -16% [-31,-1]), ii) recurrent perforation during therapy (18% to 4% RD = -14% [-25,-2]), and iii) reduced the proportion of examinations with a diagnosis of perforation during therapy (20% to 8% adjusted risk ratio 0.36 [0.15,0.83] p = 0.017). During therapy, the proportion of examinations with penicillin non-susceptible (MIC > 0.1 microg/ml) pneumococci was not significantly different between the amoxicillin group (34%) and the placebo group (40%). Beta-lactamase positive non-capsular H. influenzae (NCHi) were uncommon during therapy but more frequent in the amoxicillin group (10%) than placebo (5%).Conclusion: Aboriginal infants receiving continuous amoxicillin had more normal ears, fewer perforations, and less pneumococcal carriage. There was no statistically significant increase in resistant pneumococci or NCHi in amoxicillin children compared to placebo children who received regular paediatric care and antibiotic treatment for symptomatic illnesses. [ABSTRACT FROM AUTHOR]

Background: In Australian remote communities, First Nations children with otitis media (OM)-related hearing loss are disproportionately at risk of developmental delay and poor school performance, compared to those with normal hearing. Our objective was to compare OM-related hearing loss in children randomised to one of 2 pneumococcal conjugate vaccine (PCV) formulations., Methods and Findings: In 2 sequential parallel, open-label, randomised controlled trials (the PREVIX trials), eligible infants were first allocated 1:1:1 at age 28 to 38 days to standard or mixed PCV schedules, then at age 12 months to PCV13 (13-valent pneumococcal conjugate vaccine, +P) or PHiD-CV10 (10-valent pneumococcal Haemophilus influenzae protein D conjugate vaccine, +S) (1:1). Here, we report prevalence and level of hearing loss outcomes in the +P and +S groups at 6-monthly scheduled assessments from age 12 to 36 months. From March 2013 to September 2018, 261 infants were enrolled and 461 hearing assessments were performed. Prevalence of hearing loss was 78% (25/32) in the +P group and 71% (20/28) in the +S group at baseline, declining to 52% (28/54) in the +P groups and 56% (33/59) in the +S group at age 36 months. At primary endpoint age 18 months, prevalence of moderate (disabling) hearing loss was 21% (9/42) in the +P group and 41% (20/49) in the +S group (difference -19%; (95% confidence interval (CI) [-38, -1], p = 0.07) and prevalence of no hearing loss was 36% (15/42) in the +P group and 16% (8/49) in the +S group (difference 19%; (95% CI [2, 37], p = 0.05). At subsequent time points, prevalence of moderate hearing loss remained lower in the +P group: differences -3%; (95% CI [-23, 18], p = 1.00 at age 24 months), -12%; (95% CI [-30, 6], p = 0.29 at age 30 months), and -9%; (95% CI [-23, 5], p = 0.25 at age 36 months). A major limitation was the small sample size, hence low power to reach statistical significance, thereby reducing confidence in the effect size., Conclusions: In this study, we observed a high prevalence and persistence of moderate (disabling) hearing loss throughout early childhood. We found a lower prevalence of moderate hearing loss and correspondingly higher prevalence of no hearing loss in the +P group, which may have substantial benefits for high-risk children, their families, and society, but warrant further investigation., Trial Registration: ClinicalTrials.gov NCT01735084 and NCT01174849., Competing Interests: AJL received funds from NHMRC paid to the institution, and GSK provided materials for immunogenicity assays. AJL received funds from Merck Sharp and Dohme for analysis of pneumococcal carriage, payment to institution. ABC served as advisor on a Data Safety Monitoring Board for an unlicensed vaccine (GlaxoSmithKline) and an unlicensed monoclonal antibody (AstraZeneca), was an adviser on an unlicensed molecule for chronic cough (Merck); and has multiple project grants and a Centre of Research Excellence relating to various aspects of bronchiectasis in children from the National Health and Medical Research Council. ABC received Royalties or licences as an author of cough and bronchiectasis topics, and Partial reimbursement for airfares as a speaker for European Respiratory Society. All payments were to the institution. PM served on a data safety and monitoring board for the Novavax COVID-19 vaccine. JB provided a report to Merck Sharp and Dohme Australia. All other authors (DL, CGB-J, HS-V, MJB, MDC, PVL, PSM, PJT) declare no competing interests., (Copyright: © 2024 Leach et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.)

Chronic suppurative otitis media (CSOM) is a leading global cause of potentially preventable hearing loss in children and adults, associated with socioeconomic deprivation. There is an absence of consensus on the definition of CSOM, which complicates efforts for prevention, treatment, and monitoring. CSOM occurs when perforation of the tympanic membrane is associated with severe or persistent inflammation in the middle ear, leading to hearing loss and recurrent or persistent ear discharge (otorrhoea). Cholesteatoma, caused by the inward growth of the squamous epithelium of the tympanic membrane into the middle ear, can also occur. The optimal treatment of discharge in CSOM is topical antibiotics. In resource-limited settings where topical antibiotics might not be available, topical antiseptics are an alternative. For persistent disease, surgery to repair the tympanic membrane or remove cholesteatoma might offer long-term resolution of otorrhoea and potential improvement to hearing. Recent developments in self-fitted air-conduction and bone-conduction hearing aids offer promise as new options for rehabilitation., Competing Interests: Declaration of interests MFB serves in honorary roles as consultant to the WHO Programme for the Prevention of Deafness and Hearing Loss, council member of the British Society of Otology, and board member of the Children's Surgical Centre, Cambodia; he has received research grants to his institution from the National Institute for Health and Care Research, ENT UK, and Karl-Storz UK. AJL and CGB-J are members of the Australian Otitis Media Guidelines Technical Advisory Group. AJL has received research grants to her institution from philanthropy, the Northern Territory and Australian Governments, and Merck Sharp & Dohme. CGB-J is supported by funding from the Government of Western Australia Department of Health and the National Health and Medical Research Council., (Copyright © 2024 Elsevier Ltd. All rights are reserved, including those for text and data mining, AI training, and similar technologies.)

Diabetic wound healing is uniquely challenging to manage due to chronic inflammation and heightened microbial growth from elevated interstitial glucose. Carbon monoxide (CO), widely acknowledged as a toxic gas, is also known to provide unique therapeutic immune modulating effects. To facilitate delivery of CO, we have designed hyaluronic acid-based CO-gas-entrapping materials (CO-GEMs) for topical and prolonged gas delivery to the wound bed. We demonstrate that CO-GEMs promote the healing response in murine diabetic wound models (full-thickness wounds and pressure ulcers) compared to N 2 -GEMs and untreated controls.

Purpose: To evaluate effectiveness and safety of large-bore mechanical thrombectomy of intermediate- or high-risk pulmonary embolism (PE) and factors associated with effectiveness., Materials and Methods: A retrospective review of 257 patients with intermediate- or high-risk PE who underwent mechanical thrombectomy using the Flowtriever system (Inari Medical, Irvine, California) between July 2019 and November 2021 was conducted. Data were analyzed using the linear regression and Kaplan-Meier methods with a Type 1 error set at 0.05., Results: Patients' mean age was 62 years, and 51% were male. PE risk was classified as high, intermediate-high, and intermediate-low in 37 (14%), 201 (78%), and 18 (7%) of the patients, respectively. Procedural technical success was 100%. The mean pulmonary artery pressure (MPAP) decreased from a mean of 32 mmHg (SD ± 9) before to 24 mmHg (SD ± 9) after thrombectomy (mean decrease, 8 mmHg [SD ± 6]; P < .0001). Immediate complications occurred in 2% of the patients. Postprocedural 30-day and all-time PE-attributable mortality in a mean of 1.3-year follow-up was 2% and 6%, respectively. In multivariate analysis, the presence of lower extremity DVT at presentation (β ± SE, -7.60 ± 3.22; P = .019) and a higher prethrombectomy MPAP (β ± SE, -0.19 ± 0.04; P < .001) were associated with lower degrees of decrease in MPAP in the intermediate-high-risk PE group. Among 14 patients with postthrombectomy PE-attributable mortality, 13 had postthrombectomy MPAPs of >20 mmHg., Conclusions: Large-bore aspiration thrombectomy is a safe and effective treatment for reducing PAP in patients with intermediate- or high-risk PE. Postthrombectomy MPAPs of >20 mmHg might indicate postthrombectomy PE-attributable mortality in high-risk patients., (Copyright © 2023 SIR. Published by Elsevier Inc. All rights reserved.)

Objectives: To explore the views of parents and carers regarding the management of acute otitis media in urban Aboriginal and Torres Strait Islander children who are at low risk of complications living in urban communities., Study Design: Qualitative study; semi-structured interviews and short telephone survey., Setting, Participants: Interviews: purposive sample of parents and carers of urban Aboriginal and Torres Strait Islander children (18 months - 16 years old) screened in Aboriginal medical services in Queensland, New South Wales, and Canberra for the WATCH study, a randomised controlled trial that compared immediate antibiotic therapy with watchful waiting for Aboriginal and Torres Strait Islander children with acute otitis media., Survey: parents and carers recruited for the WATCH trial who had completed week two WATCH surveys., Results: We interviewed twenty-two parents and carers, including ten who had declined participation in or whose children were ineligible for the WATCH trial. Some interviewees preferred antibiotics for managing acute otitis media, others preferred watchful waiting, expressing concerns about side effects and reduced efficacy with overuse of antibiotics. Factors that influenced this preference included the severity, duration, and recurrence of infection, and knowledge about management gained during the trial and from personal and often multigenerational experience of ear disease. Participants highlighted the importance of shared decision making by parents and carers and their doctors. Parents and carers of 165 of 262 WATCH participants completed telephone surveys (63%); 81 were undecided about whether antibiotics should always be used for treating acute otitis media. Open-ended responses indicated that antibiotic use should be determined by clinical need, support for general practitioners' decisions, and the view that some general practitioners prescribed antibiotics too often., Conclusions: Parents and carers are key partners in managing acute otitis media in urban Aboriginal and Torres Strait Islander children. Our findings support shared decision making informed by the experience of parents and carers, which could also lead to reduced antibiotic use for managing acute otitis media., (© 2024 The Authors. Medical Journal of Australia published by John Wiley & Sons Australia, Ltd on behalf of AMPCo Pty Ltd.)

Oligella urethralis are opportunistic pathogens typically associated with genitourinary infections. Here, we report the complete genome for an Oligella urethralis isolate recovered from ear discharge of a child with chronic suppurative otitis media (strain MSHR-50412PR). The genome comprises 2.58 Mb, with 2,448 coding sequences and 46.26% average GC content., Competing Interests: The authors declare no conflict of interest.

Objectives: To identify and synthesize key research advances from the literature published between 2019 and 2023 on the advances in preventative measures, and medical and surgical treatment of uncomplicated otitis media (OM) including the impact of the COVID-19 pandemic on OM management., Data Sources: Medline (PubMed), Embase, and the Cochrane Library., Review Methods: All relevant original articles published in English between June 2019 and February 2023 were identified. Studies related to guideline adherence, impact of treatment on immune response and/or microbiology, tympanoplasty, Eustachian tube balloon dilatation, mastoidectomy procedures, and those focusing on children with Down's syndrome or cleft palate were excluded., Main Findings: Of the 9280 unique records screened, 64 were eligible for inclusion; 23 studies related to medical treatment, 20 to vaccines, 13 to surgical treatment, 6 to prevention (excl. vaccines) and 2 to the impact of COVID-19 on OM management. The level of evidence was judged 2 in 11 studies (17.2 %) and 3 or 4 in the remaining 53 studies (82.8 %) mainly due to the observational design, study limitations or low sample sizes. Some important advances in OM management have been made in recent years. Video discharge instructions detailing the identification and management of pain and fever for parents of children with acute otitis media (AOM) was more effective than paper instructions in reducing symptomatology; compared to placebo, levofloxacin solution was more effective for treating chronic suppurative otitis media, whereas AOM recurrences during two years of follow-up did not differ between children with recurrent AOM who received tympanostomy tube (TT) insertion or medical management. Further, novel pneumococcal conjugate vaccines (PCV) schedules for preventing OM in Aboriginal children appeared ineffective, and a protein-based pneumococcal vaccine had no added value over PCV13 for preventing AOM in native American infants. During the COVID-19 pandemic, a decline in OM and TT case volumes and complications was observed., Implication for Practice and Future Research: Whether the observed impact of the COVID-19 pandemic on OM management extends to the post-pandemic era is uncertain. Furthermore, the impact of the pandemic on the conduct of urgently needed prospective methodologically rigorous interventional studies aimed at improving OM prevention and treatment remains to be elucidated since the current report consisted of studies predominantly conducted in the pre-pandemic era., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Crown Copyright © 2023. Published by Elsevier B.V. All rights reserved.)

Objectives: Indigenous children in Australia experience high burden of persistent otitis media (OM) from very early age. The aim was to identify distinct trajectories of OM in children up to age 10-12 years and examine the association with socio-economic determinants., Study Design: A multistage clustered national panel survey., Methods: The study analysed the birth cohort of the Longitudinal Study of Indigenous Children from 2008 to 2018, comprising 11 study waves. Group-based trajectory modelling was used to identify different trajectories of OM outcome. Multinomial logistic regression was applied to examine the relationship between trajectories and individual, household and community-level socio-economic determinants., Results: This analysis included 894 children with at least three responses on OM over the 11 waves, and the baseline mean age was 15.8 months. Three different trajectories of OM were identified: non-severe OM prone, early/persistent severe OM and late-onset severe OM. Overall, 11.4% of the children had early/persistent severe OM from birth to 7.5 to nine years, while late-onset severe OM consisted of 9.8% of the children who had first OM from age 3.5 to five years. Children in communities with middle and the highest socio-economic outcomes have lower relative risk of early/persistent severe OM (adjusted relative risk ratio = 0.39, 95% confidence interval = 0.22-0.70 and adjusted relative risk ratio = 0.22, 95% confidence interval = 0.09-0.52, respectively) compared to children in communities with lowest socio-economic outcomes., Conclusion: Efforts to close the gap in the quality of life of Indigenous children must prioritise strategies that prevent severe ear disease (runny ears and perforation), including improved healthcare access, reduced household crowding, and better education, and more employment opportunities., (Copyright © 2023 The Author(s). Published by Elsevier Ltd.. All rights reserved.)

Objectives: In remote communities of northern Australia, First Nations children with hearing loss are disproportionately at risk of poor school readiness and performance compared to their peers with no hearing loss. The aim of this trial is to prevent early childhood persisting otitis media (OM), associated hearing loss and developmental delay. To achieve this, we designed a mixed pneumococcal conjugate vaccine (PCV) schedule that could maximise immunogenicity and thereby prevent bacterial otitis media (OM) and a trajectory of educational and social disadvantage., Methods: In two sequential parallel, open-label, randomised controlled trials, eligible infants were first allocated 1:1:1 to standard or mixed PCV primary schedules at age 28-38 days, then at age 12 months to a booster dose (1:1) of 13-valent PCV, PCV13 (Prevenar13®, +P), or 10-valent pneumococcal non-typeable Haemophilus influenzae protein D conjugated vaccine, PHiD-CV10 (Synflorix®, +S). Here we report findings of standardised ear assessments conducted six-monthly from age 12-36 months, by booster dose., Results: From March 2013 to September 2018, 261 children were allocated to booster + P (n = 131) or + S (n = 130). There were no significant differences in prevalence of any OM diagnosis by booster dose or when stratified by primary schedule. We found high, almost identical prevalence of OM in both boost groups at each age (for example 88% of 129 and 91% of 128 children seen, respectively, at primary endpoint age 18 months, difference -3% [95% Confidence Interval -11, 5]). At each age prevalence of bilateral OM was 52%-78%, and tympanic membrane perforation was 10%-18%., Conclusion: Despite optimal pneumococcal immunisation, the high prevalence of OM persists throughout early childhood. Novel approaches to OM prevention are needed, along with improved early identification strategies and evaluation of expanded valency PCVs., Competing Interests: Declaration of competing interest AJL received funds from NHMRC paid to the institution, and GSK provided materials for immunogenicity assays. AJL received funds from Merck Sharp and Dohme for analysis of pneumococcal carriage, payment to institution. ABC served as advisor on a Data Safety Monitoring Board for an unlicensed vaccine (GlaxoSmithKline) and an unlicensed monoclonal antibody (AstraZeneca), was an adviser on an unlicensed molecule for chronic cough (Merck); and has multiple project grants and a Centre of Research Excellence relating to various aspects of bronchiectasis in children from the National Health and Medical Research Council. ABC received Royalties or licences as an author of cough and bronchiectasis topics, and Partial reimbursement for airfares as a speaker for European Respiratory Society. All payments were to the institution. PM served on a data safety and monitoring board for the Novavax COVID-19 vaccine. JB provided a report to MSD Australia. All other authors (DL, HS-V, MB, MC, PL, PSM, PT) declare no competing interests., (Copyright © 2023 The Authors. Published by Elsevier B.V. All rights reserved.)

Background: In the Northern Territory (NT) the prevalence of otitis media (OM) in young Aboriginal children living in remote communities has persisted at around 90% over the last few decades. OM-associated hearing loss can cause developmental delay and adversely impact life course trajectories. This study examined the 5-year trends in OM prevalence and quality of ear health services in remote NT communities., Methods: A retrospective analysis was performed on de-identified clinical data for 50 remote clinics managed by the NT Government. We report a 6-monthly cascade analysis of the proportions of children 0-16 years of age receiving local guideline recommendations for surveillance, OM treatment and follow-up at selected milestones between 2014 and 2018., Results: Between 6,326 and 6,557 individual children were included in the 6-monthly analyses. On average, 57% (95%CI: 56-59%) of eligible children had received one or more ear examination in each 6-monthly period. Of those examined, 36% (95%CI: 33-40%) were diagnosed with some type of OM, of whom 90% had OM requiring either immediate treatment or scheduled follow-up according to local guidelines. Outcomes of treatment and follow-up were recorded in 24% and 23% of cases, respectively. Significant decreasing temporal trends were found in the proportion diagnosed with any OM across each age group. Overall, this proportion decreased by 40% over the five years (from 43 to 26%)., Conclusions: This cascade of care analysis found that ear health surveillance and compliance with otitis media guidelines for treatment and follow-up were both low. Further research is required to identify effective strategies that improve ear health services in remote settings., (© 2023. The Author(s).)

Introduction: Globally, acute respiratory infections (ARIs) are a leading cause of childhood morbidity and mortality. While ARI-related mortality is low in Australia, First Nations infants are hospitalised with ARIs up to nine times more often than their non-First Nations counterparts. The gap is widest in the Northern Territory (NT) where rates of both acute and chronic respiratory infection are among the highest reported in the world. Vitamin D deficiency is common among NT First Nations neonates and associated with an increased risk of ARI hospitalisation. We hypothesise that perinatal vitamin D supplementation will reduce the risk of ARI in the first year of life., Methods and Analysis: 'D-Kids' is a parallel (1:1), double-blind (allocation concealed), randomised placebo-controlled trial conducted among NT First Nations mother-infant pairs. Pregnant women and their babies (n=314) receive either vitamin D or placebo. Women receive 14 000 IU/week or placebo from 28 to 34 weeks gestation until birth and babies receive 4200 IU/week or placebo from birth until age 4 months. The primary outcome is the incidence of ARI episodes receiving medical attention in the first year of life. Secondary outcomes include circulating vitamin D level and nasal pathogen prevalence. Tertiary outcomes include infant immune cell phenotypes and challenge responses. Blood, nasal swabs, breast milk and saliva are collected longitudinally across four study visits: enrolment, birth, infant age 4 and 12 months. The sample size provides 90% power to detect a 27.5% relative reduction in new ARI episodes between groups., Ethics and Dissemination: This trial is approved by the NT Human Research Ethics Committee (2018-3160). Study outcomes will be disseminated to participant families, communities, local policy-makers, the broader research and clinical community via written and oral reports, education workshops, peer-reviewed journals, national and international conferences., Trial Registration Number: ACTRN12618001174279., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2023. Re-use permitted under CC BY. Published by BMJ.)

Background: Aboriginal and Torres Strait Islander children experience a high burden of otitis media. We collected data on symptoms associated with acute otitis media (AOM) in a clinical trial involving children receiving primary care at urban Aboriginal Medical Services. Two scales were employed to monitor symptoms over time: the AOM-Severity of Symptoms scale (AOM-SOS) and the AOM-Faces Scale (AOM-FS). This study took place at a mid-point of the un-blinded trial., Methods: We examined symptoms at enrolment and day 7, and compared the scales for trends, and bivariate correlation (Spearman's rho) over 14 days. Responsiveness of the scales to clinical change was determined by Friedman's test of trend in two subgroups stratified by day 7 AOM status. We interviewed parents/carers and research officers regarding their experience of the scales and analysed data thematically., Results: Data derived from 224 children (18 months to 16 years; median 3.6 years). Common symptoms associated with AOM at baseline were runny nose (40%), cough (38%) and irritability (36%). More than one third had no or minimal symptoms at baseline according to AOM-SOS (1-2/10) and AOM-FS scores (1-2/7). The scales performed similarly, and were moderately correlated, at all study points. Although scores decreased from day 0 to 14, trends and mean scores were the same whether AOM was persistent or resolved at day 7. Users preferred the simplicity of the AOM-FS but encountered challenges when interpreting it., Conclusion: We found minimally symptomatic AOM was common among Aboriginal and Torres Strait Islander children in urban settings. The AOM-SOS and AOM-FS functioned similarly. However, it is likely the scales measured concurrent symptoms related to upper respiratory tract infections, given they did not differentiate children with persistent or resolved AOM based on stringent diagnostic criteria. This appears to limit the research and clinical value of the scales in monitoring AOM treatment among Aboriginal and Torres Strait Islander children., Competing Interests: The authors have declared that no competing interests exist., (Copyright: © 2023 Abbott et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.)

Importance: In remote communities of the Northern Territory, Australia, children experience high rates of otitis media (OM), commonly caused by non-typeable Haemophilus influenzae (NTHi). Few data exist on antibiotic susceptibility of NTHi from OM., Objective: To determine whether population-level nasopharyngeal NTHi antibiotic susceptibility data could inform antibiotic treatment for OM., Methods: NTHi isolates ( n  = 92) collected from ear discharge between 2003 and 2013 were selected to time- and age-match NTHi isolates from the nasopharyngeal carriage ( n  = 95). Antimicrobial susceptibility were tested. Phylogenomic trees and a genome-wide association study (GWAS) were performed to determine the similarity of nasopharyngeal and ear isolates at a population level., Results: Among 174 NTHi isolates available for antimicrobial susceptibility testing, 10.3% (18/174) were resistant to ampicillin and 9.2% (16/174) were resistant to trimethoprim-sulfamethoxazole. Small numbers of isolates (≤3) were resistant to tetracycline, chloramphenicol, or amoxicillin-clavulanic acid. There was no statistical difference in the proportion of ampicillin-resistant ( P  = 0.11) or trimethoprim-sulfamethoxazole-resistant isolates ( P  = 0.70) between ear discharge and nasopharynx-derived NTHi isolates. Three multi-drug resistant NTHi isolates were identified. Phylogenomic trees showed no clustering of 187 Haemophilus influenzae isolates based on anatomical niche (nasopharynx or ear discharge), and no genetic variations that distinguished NTHi derived from ear discharge and nasopharyngeal carriage were evident in the GWAS., Interpretation: In this population-level study, nasopharyngeal and ear discharge isolates did not represent distinct microbial populations. These results support tracking of population-level nasopharyngeal NTHi antibiotic resistance patterns to inform clinical management of OM in this population., Competing Interests: The authors declare that they have no conflict of interest., (© 2023 Chinese Medical Association. Pediatric Investigation published by John Wiley & Sons Australia, Ltd on behalf of Futang Research Center of Pediatric Development.)

Background: Rotarix (GlaxoSmithKline) oral rotavirus vaccine is licensed as 2 doses in the first 6 months of life. In settings with high child mortality rates, clinical protection conferred by 2 doses of Rotarix is reduced. We assessed vaccine immune response when an additional dose of Rotarix was given to Australian Aboriginal children 6 to <12 months old., Methods: ORVAC is a 2-stage, double-blind, randomized, placebo-controlled trial. Australian Aboriginal children 6 to <12 months old who had received 1 or 2 prior doses of Rotarix rotavirus vaccine were randomized 1:1 to receive an additional dose of Rotarix or matched placebo. The primary immunological end point was seroresponse defined as an anti-rotavirus immunoglobulin A level ≥20 AU/mL, 28-56 days after the additional dose of Rotarix or placebo., Results: Between March 2018 and August 2020, a total of 253 infants were enrolled. Of these, 178 infants (70%) had analyzable serological results after follow-up; 89 were randomized to receive Rotarix, and 89 to receive placebo. The proportion with seroresponse was 85% after Rotarix compared with 72% after placebo. There were no occurrences of intussusception or any serious adverse events., Conclusions: An additional dose of Rotarix administered to Australian Aboriginal infants 6 to <12 months old increased the proportion with a vaccine seroresponse., Clinical Trials Registration: NCT02941107., Competing Interests: Potential conflict of interests. N. C. declares that his employer, the University of Liverpool, has received grant funding for rotavirus research from GlaxoSmithKline, the manufacturer of Rotarix. All other authors report no potential conflicts. All authors have submitted the ICMJE Form for Disclosure of Potential Conflicts of Interest. Conflicts that the editors consider relevant to the content of the manuscript have been disclosed., (© The Author(s) 2022. Published by Oxford University Press for the Infectious Diseases Society of America.)

Background: Australian First Nations children are at very high risk of early, recurrent, and persistent bacterial otitis media and respiratory tract infection. With the PREVIX randomised controlled trials, we aimed to evaluate the immunogenicity of novel pneumococcal conjugate vaccine (PCV) schedules., Methods: PREVIX&#95;BOOST was a parallel, open-label, outcome-assessor-blinded, randomised controlled trial. Aboriginal children living in remote communities of the Northern Territory of Australia were eligible if they had previously completed the three-arm PREVIX&#95;COMBO randomised controlled trial of the following vaccine schedules: three doses of a 13-valent PCV (PCV13; PPP) or a ten-valent pneumococcal Haemophilus influenzae protein D conjugate vaccine (PHiD-CV10; SSS) given at 2, 4, and 6 months, or SSS given at 1, 2, and 4 months followed by PCV13 at 6 months (SSSP). At age 12 months, eligible children were randomly assigned by a computer-generated random sequence (1:1, stratified by primary group allocation) to receive either a PCV13 booster or a PHiD-CV10 booster. Analyses used intention-to-treat principles. Co-primary outcomes were immunogenicity against protein D and serotypes 3, 6A, and 19A. Immunogenicity measures were geometric mean concentrations (GMC) and proportion of children with IgG concentrations of 0·35 μg/mL or higher (threshold for invasive pneumococcal disease), and GMCs and proportion of children with antibody levels of 100 EU/mL or higher against protein D. Standardised assessments of otitis media, hearing impairment, nasopharyngeal carriage, and developmental outcomes are reported. These trials are registered with ClinicalTrials.gov (NCT01735084 and NCT01174849)., Findings: Between April 10, 2013, and Sept 4, 2018, 261 children were randomly allocated to receive a PCV13 booster (n=131) or PHiD-CV10 booster (n=130). Adequate serum samples for pneumococcal serology were obtained from 127 (95%) children in the PCV13 booster group and 126 (97%) in the PHiD-CV10 booster group; for protein D, adequate samples were obtained from 126 (96%) children in the PCV13 booster group and 123 (95%) in the PHiD-CV10 booster group. The proportions of children with IgG concentrations above standard thresholds in PCV13 booster versus PHiD-CV10 booster groups were the following: 71 (56%) of 126 versus 81 (66%) of 123 against protein D (difference 10%, 95% CI -2 to 22), 85 (67%) of 127 versus 59 (47%) of 126 against serotype 3 (-20%, -32 to -8), 119 (94%) of 127 versus 91 (72%) of 126 against serotype 6A (-22%, -31 to -13), and 116 (91%) of 127 versus 108 (86%) of 126 against serotype 19A (-5%, -13 to 3). Infant PCV13 priming mitigated differences between PCV13 and PHiD-CV10 boosters. In both groups, we observed a high prevalence of otitis media (about 90%), hearing impairment (about 75%), nasopharyngeal carriage of pneumococcus (about 66%), and non-typeable H influenzae (about 57%). Of 66 serious adverse events, none were vaccine related., Interpretation: Low antibody concentrations 6 months post-booster might indicate increased risk of pneumococcal infection. The preferred booster was PCV13 if priming did not have PCV13, otherwise either PCV13 or PHiD-CV10 boosters provided similar immunogenicity. Mixed schedules offer flexibility to regional priorities. Non-PCV13 serotypes and non-typeable H influenzae continue to cause substantial disease and disability in Australian First Nation's children., Funding: National Health and Medical Research Council (NHMRC)., Competing Interests: Declaration of interests ABC served as advisor on an unlicensed vaccine (GlaxoSmithKline) and an unlicensed monoclonal antibody (AstraZeneca), was an adviser on an unlicensed molecule for chronic cough (Merck); and has various project grants and a Centre of Research Excellence relating to various aspects of bronchiectasis in children from the National Health and Medical Research Council. PM served on a data safety and monitoring board for the Novavax COVID-19 vaccine. JB provided a report to MSD Australia. All other authors declare no competing interests., (Copyright © 2022 Elsevier Ltd. All rights reserved.)

Introduction: Otitis media (OM) is a common childhood illness, often resolving without intervention and acute and long-term complications are rare. However, Australian Aboriginal and Torres Strait Islander infants and children experience a high burden of OM and are at high risk of complications (tympanic membrane perforation and chronic infections). Bacterial OM is commonly associated with Streptococcus pneumoniae , non-typeable Haemophilus influenzae , and Moraxella catarrhalis . BIGDATA is a data asset combining over 25 years of microbiology and OM surveillance research from the Ear Health Research Program at Menzies School of Health Research (Northern Territory, Australia), including 11 randomized controlled trials, four cohort studies, eight surveys in over 30 remote communities (including data from Western Australia), and five surveys of urban childcare centers including Aboriginal and Torres Strait Islander and non-Indigenous children. Outcome measures include clinical examinations (focusing on OM), antibiotic prescriptions, pneumococcal vaccination, modifiable risk factors such as smoking and household crowding, and nasopharyngeal and ear discharge microbiology including antimicrobial resistance testing., Methods and Analysis: The initial series of projects are planned to address the following key knowledge gaps: (i) otitis media prevalence and severity over pre pneumococcal conjugate vaccines (PCVs) and three eras of increasing PCV valency; (ii) impact of increasing valency PCVs on nasopharyngeal carriage dynamics of pneumococcal serotypes, and antimicrobial resistance; (iii) impact of increasing valency PCVs on nasopharyngeal carriage dynamics and antimicrobial resistance of other otopathogens; and (iv) serotype specific differences between children with acute OM and OM with effusion or without OM. These data will be utilized to identify research gaps, providing evidence-based prioritization for ongoing research., Ethics and Dissemination: Data asset creation and priority analyses were approved by the Human Research Ethics Committee of Northern Territory Department of Health and Menzies School of Health Research (EC00153, 18-3281), the Child and Adolescent Health Service Human Research Ethics Committee and Western Australian Aboriginal Health Ethics Committee. Dissemination will be through peer review publication and conference presentations., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Beissbarth, Smith-Vaughan, Cheng, Morris and Leach.)

Objective: To better understand how to undertake valuable, ethical and sustainable randomised controlled clinical trial (RCT) research within Aboriginal and Torres Strait Islander primary health services., Design: In a qualitative approach, we utilised data collected between 2013 and 2020 during the planning and implementation of two RCTs. The data comprised agreed records of research meetings, and semistructured interviews with clinical trial stakeholders. The stakeholders were parents/carers of child participants, and site-based research officers, healthcare providers and community advisory groups. Our thematic analysis was informed by constructivist grounded theory., Setting: The RCTs investigated the management of otitis media in Aboriginal and Torres Strait Islander children, with the first RCT commencing recruitment in 2014 and the second in 2017. They took place in Aboriginal Medical Services (AMSs), large primary health services for Aboriginal and Torres Strait Islander people, based in urban and regional communities across two Australian states and one territory., Results: We analysed data from 56 meetings and 67 interviews, generating themes on making research valuable and undertaking ethical and sustainable RCTs. Aboriginal and Torres Strait Islander leadership, and support of AMSs in their service delivery function were critical. The broad benefits of the trials were considered important to sustainability, including workforce development, enhanced ear healthcare and multidirectional research capacity building. Participants emphasised the long-term responsibility of research teams to deliver benefits to AMSs and communities regardless of RCT outcomes, and to focus on relationships, reciprocity and creating positive experiences of research., Conclusion: We identify principles and strategies to assist in undertaking ethical and sustainable RCTs within Aboriginal and Torres Strait Islander primary health services. Maintaining relationships with AMSs and focusing on mutual workforce development and capacity building creates opportunities for long-term benefits so that health research and RCTs work for Aboriginal and Torres Strait Islander peoples, services, communities and researchers., Trial Registration Number: ACTRN12613001068752 (Pre-results); ACTRN12617001652369 (Pre-results)., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2021. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Maternal urogenital human papillomavirus (HPV) infection may place neonates at risk of HPV acquisition and subsequently lower respiratory infections as HPV can influence development of immunity. The respiratory HPV prevalence is not known in remote-dwelling Aboriginal infants, who are at high risk of respiratory infection and where the population prevalence of urogenital HPV in women is high. These data are necessary to inform HPV vaccination regimens. A retrospective analysis using PCR specific for HPV was performed on 64 stored nasopharyngeal swabs from remote-dwelling Aboriginal infants < 6 months of age, with and without hospitalised pneumonia. HPV DNA was not detected in any specimen. Despite the negative result, we cannot exclude a role for HPV in respiratory infections affecting infants in this population; however, our data do not support HPV as an important contributor to acute respiratory infection in remote-dwelling Aboriginal children., Competing Interests: None., (© 2021 Chinese Medical Association. Pediatric Investigation published by John Wiley & Sons Australia, Ltd on behalf of Futang Research Center of Pediatric Development.)

Background: Almost all Aboriginal children in remote communities have persistent bilateral otitis media affecting hearing and learning throughout early childhood and school years, with consequences for social and educational outcomes, and later employment opportunities. Current primary health care and specialist services do not have the resources to meet the complex needs of these children., Method/design: This stepped-wedge cluster randomised trial will allocate 18 communities to one of five 6-monthly intervention start dates. Stratification will be by region and population size. The intervention (Hearing for Learning Initiative, HfLI) consists of six 20-h weeks of training (delivered over 3 months) that includes Certificate II in Aboriginal Primary Health Care (3 modules) and competencies in ear and hearing data collection (otoscopy, tympanometry and hearScreen), plus 3 weeks of assisted integration into the health service, then part-time employment as Ear Health Facilitators to the end of the trial. Unblinding will occur 6 months prior to each allocated start date, to allow Community Reference Groups to be involved in co-design of the HfLI implementation in their community. Relevant health service data will be extracted 6-monthly from all 18 communities. The primary outcome is the difference in proportion of children (0 to 16 years of age) who have at least one ear assessment (diagnosis) documented in their medical record within each 6-month period, compared to control periods (no HfLI). Secondary outcomes include data on sustainability, adherence to evidence-based clinical guidelines for otitis media, including follow-up and specialist referrals, and school attendance. Structured interviews with staff working in health and education services, Ear Health Trainees, Ear Health Facilitators and families will assess process outcomes and the HfLI broader impact., Discussion: The impact of training and employment of Ear Health Facilitators on service enhancement will inform the health, education and employment sectors about effectiveness of skills and job creation that empowers community members to contribute to addressing issues of local importance, in this instance ear and hearing health of children., Trial Registration: ClinicalTrials.gov NCT03916029 . Registered on 16 April 2019.

Background: Aboriginal children in Northern Australia have a high burden of otitis media, driven by early and persistent nasopharyngeal carriage of otopathogens, including non-typeable Haemophilus influenzae (NTHi) and Streptococcus pneumoniae (Spn). In this context, does a combined mixed primary series of Synflorix and Prevenar13 provide better protection against nasopharyngeal carriage of NTHi and Spn serotypes 3, 6A and 19A than either vaccine alone?, Methods: Aboriginal infants (n = 425) were randomised to receive Synflorix™ (S, PHiD-CV10) or Prevenar13™ (P, PCV13) at 2, 4 and 6 months (&#95;SSS or &#95;PPP, respectively), or a 4-dose early mixed primary series of PHiD-CV10 at 1, 2 and 4 months and PCV13 at 6 months of age (SSSP). Nasopharyngeal swabs were collected at 1, 2, 4, 6 and 7 months of age. Swabs of ear discharge were collected from tympanic membrane perforations., Findings: At the primary endpoint at 7 months of age, the proportion of nasopharyngeal (Np) swabs positive for PCV13-only serotypes 3, 6A, or 19A was 0%, 0.8%, and 1.5% in the &#95;PPP, &#95;SSS, and SSSP groups respectively, and NTHi 55%, 52%, and 52% respectively, and no statistically significant vaccine group differences in other otopathogens at any age. The most common serotypes (in order) were 16F, 11A, 10A, 7B, 15A, 6C, 35B, 23B, 13, and 15B, accounting for 65% of carriage. Ear discharge swabs (n = 108) were culture positive for NTHi (52%), S. aureus (32%), and pneumococcus (20%)., Conclusions: Aboriginal infants experience nasopharyngeal colonisation and tympanic membrane perforations associated with NTHi, non-PCV13 pneumococcal serotypes and S. aureus in the first months of life. Nasopharyngeal carriage of pneumococcus or NTHi was not significantly reduced in the early 4-dose combined SSSP group compared to standard &#95;PPP or &#95;SSS schedules at any time point. Current pneumococcal conjugate vaccine formulations do not offer protection from early onset NTHi and pneumococcal colonisation in this high-risk population., Competing Interests: Declaration of Competing Interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: Authors JB, NW, BA, MJB, VMO, KL, ASB, HCSV, ACC, have nothing to declare. EKM has received support for OPA assays for a completed PCV trial in Vietnam and has an ongoing collaboration with Pfizer on pneumonia in Mongolian adults. AJL received a donation of assay reagents for immunogenicity assays from GlaxoSmithKline., (Copyright © 2021 The Author(s). Published by Elsevier Ltd.. All rights reserved.)