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Regional patterns in wind underpin the low-cost migratory flyways of billions of birds and insects, 1 , 2 , 3 but the effect of large-scale changes in temperature on flight is unknown. Flight costs should increase with rising temperatures because lift decreases as density decreases, whereas weight remains unchanged. The effects of density are well-established in the context of high-altitude movements and migration. 4 , 5 , 6 , 7 Here, we examine the impact of air density on low-flying birds in relation to seasonal, regional, and global changes in temperature. We deployed multi-sensor loggers on red-tailed tropicbirds (Phaethon rubricauda), a large and widely distributed seabird breeding year round in Mauritius. Seasonal changes in air density caused very small differences in flight costs (1%-2%, estimated using aeronautical models) despite being the major driver of seasonal differences in wingbeat frequency. Flight costs should vary in space as well as time, and aeronautical models predicted ≥10% variation in power across the tropicbird's range due to latitudinal temperature gradients. Changes in air density can therefore modulate flight costs across regional scales, even when birds are operating close to sea level. Indeed, creating a 20-year climatology of air density at sea level revealed that temperature gradients cause effective altitude to vary by >2 km at a global scale within a given season. This "invisible topography" at sea level could influence the biogeography of flight morphologies, particularly the distribution of birds with the highest flight costs, which generally occur in regions with relatively high air density., Competing Interests: Declaration of interests The authors declare no competing interests., (Copyright © 2024 The Authors. Published by Elsevier Inc. All rights reserved.)

SUMOylation, the covalent attachment of the small ubiquitin-like modifier (SUMO) to target proteins, and its reversal, deSUMOylation by SUMO proteases like Sentrin-specific proteases (SENPs), are crucial for initiating cellular responses to hypoxia. However, their roles in subsequent adaptation processes to hypoxia such as mitochondrial autophagy (mitophagy) remain unexplored. Here, we show that general SUMOylation, particularly SUMO2/3 modification, suppresses mitophagy under both normoxia and hypoxia. Furthermore, we identify deSUMO2/3-ylation enzyme SENP3 and mitochondrial Fission protein 1 (FIS1) as key players in hypoxia-induced mitophagy (HIM), with SUMOylatable FIS1 acting as a crucial regulator for SENP3-mediated HIM regulation. Interestingly, we find that hypoxia promotes FIS1 SUMO2/3-ylation and triggers an interaction between SUMOylatable FIS1 and Rab GTPase-activating protein Tre-2/Bub2/Cdc16 domain 1 family member 17 (TBC1D17), which in turn suppresses HIM. Therefore, we propose a novel SUMOylation-dependent pathway where the SENP3-FIS1 axis promotes HIM, with TBC1D17 acting as a fine-tuning regulator. Importantly, the SENP3-FIS1 axis plays a protective role against hypoxia-induced cell death, highlighting its physiological significance, and hypoxia-inducible FIS1-TBC1D17 interaction is detectable in primary glioma stem cell-like (GSC) cultures derived from glioblastoma patients, suggesting its disease relevance. Our findings not only provide new insights into SUMOylation/deSUMOylation regulation of HIM but also suggest the potential of targeting this pathway to enhance cellular resilience under hypoxic stress., Competing Interests: Competing interests: The authors declare no competing interests. Ethics approval and consent to participate: All methods were conducted in accordance with relevant guidelines and regulations, including the principles outlined in the Declaration of Helsinki. Informed consent was obtained from all human subjects. Ethics approval for deriving primary GSC cultures was granted by the Yorkshire & The Humber - Leeds East Research Ethics Committee (IRB protocol 11-YH-0319/STH15598). Ethics approval for deriving primary renal cell cultures was obtained from the Research Ethical Committee (REC: 20SW0193) as part of the Ex Vivo DEtermiNed Cancer Therapy (EVIDENT) trial (NCT05231655)., (© 2024. The Author(s).)

Introduction: Shortage of ear, nose, and throat specialists in public hospitals can result in delays in the detection and management of otitis media. This study introduced a new hospital-based telehealth service, named the Ear Portal, and investigated its role in improving access to specialist care., Methods: The study included 87 children (aged 6 months to 6 years) referred to a tertiary children's hospital due to otitis media-related concerns. A specialist multidisciplinary team met fortnightly to review pre-recorded data and provide care plans., Results: The service resulted in a median waiting time of 28 days to receive a diagnosis and care plan by the multidisciplinary team, compared to a mean waiting time of 450 days for a reference group receiving standard healthcare services. Most children (90.3%) received bilateral ear diagnosis. Normal findings were found in 43.9%. However, the majority required further ear, nose, and throat with or without audiology face-to-face follow-up due to a diagnosis of middle-ear disease, unknown hearing status, or concerns not related to ears. The mean time required for clinical assessments completion by research assistants and multidisciplinary team review was 37.6 and 5.1 min per participant, respectively., Discussion: Children in the Ear Portal service received a diagnosis and care plan in a median of 28 days, which is within the clinically recommended timeframes. With sufficient clinical information, this service can provide faster access to specialist care than the standard healthcare pathway. The service can reduce the time required by the specialist to provide a diagnosis and care plan which may help increase the specialists' capacity., Competing Interests: Declaration of conflicting interestsThe authors declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.

Background: Tonsillectomy and adenoidectomy (AT) are two of the most commonly performed ENT procedures in children, with over 500,000 cases performed annually in the United States. Whilst generally considered a safe and well-tolerated operation, it is not without its risks and complications including pain, nausea, anorexia and most importantly bleeding and post-tonsillectomy haemorrhage (PTH). Whilst tranexamic acid (TXA) has a proven benefit in reducing bleeding and transfusion requirements in patients undergoing trauma, spinal and cardiac surgery; the effectiveness, timing and safety of its application in paediatric tonsillectomy has not yet been established., Aims, Objectives & Significance: To date, there has been no published systematic review of the literature specifically looking at paediatric patients undergoing AT, despite a massive surge in popularity of the use of TXA perioperatively. The aim of this study is therefore to systematically review the current literature and collate evidence regarding the efficacy and safety of using TXA to reduce bleeding in children undergoing tonsillectomy and/or adenoidectomy., Methods: A structured search of bibliographic databases (MEDLINE, EMBASE, PubMed, CINAHL, Cochrane CENTRAL) was undertaken to retrieve randomised controlled trials, non-randomised case-control studies and ongoing clinical trials that describe the use of TXA in paediatric patients undergoing AT. The following search terms (and their variations) were used as both medical subject headings (MeSH terms) and text words: tranexamic acid, bleeding, tonsillectomy, adenoidectomy, paediatrics. To ensure that all relevant data was captured, the search did not contain any restrictions on language or publication time. Data extraction and risk of bias assessment was performed independently and in duplicate., Results: This review identified and included a total of eight studies (n = 1315). Five studies reported on the intravenous use of TXA (n = 531) whilst three studies reported on the topical use of TXA (n = 784), and these were analysed separately. The intravenous use of TXA did not reduce intraoperative blood loss significantly (95 % CI: -0.1 to 0.33 p = 0.28) and there was not enough information to analyse the effect on PTH in these studies. Topical TXA led to a significant reduction in both intraoperative blood loss (95 % CI 0.11 to 5.31, p = 0.04) and post operative bleeding rates (RR 0.04, 95 % CI 0.01 to 0.08, P = 0.02)., Conclusion: The results of this systematic review and meta-analysis suggest that TXA administered via the intravenous route does not reduce perioperative bleeding associated with AT in paediatric patients. However, when topical TXA is used intraoperatively at the surgical site in paediatric patients undergoing adenoidectomy alone, there was a significant reduction in both intraoperative blood loss and post operative bleeding. TXA appears to be a safe and well-tolerated drug in the paediatric population with no adverse effects reported in this review. Nevertheless, further large and well-designed randomised controlled trials are needed to investigate the risks and benefits of TXA in paediatric AT with a particular focus on its use topically and in association with newly developed surgical equipment., Competing Interests: Declaration of competing interest The authors declare no conflicts of interest., (Copyright © 2024 Elsevier B.V. All rights reserved.)

Competing Interests: Declaration of competing interest We confirm that there are no declarations of interest in our currently submitted manuscript.

Purpose: Despite the volume of accumulating knowledge from prospective Aboriginal cohort studies, longitudinal data describing developmental trajectories in health and well-being is limited. The linkage of child and carer cohorts from a historical cross-sectional survey with longitudinal health-service and social-service administrative data has created a unique and powerful data resource that underpins the Western Australian Aboriginal Child Health Survey (WAACHS) linked data study. This study aims to provide evidence-based information to Aboriginal communities across Western Australia, governments and non-government agencies on the heterogeneous life trajectories of Aboriginal children and families., Participants: This study comprises data from a historical cross-sectional household study of 5289 Aboriginal children from the WAACHS (2000-2002) alongside their primary (N=2113) and other (N=1040) carers, and other householders. WAACHS data were linked with Western Australia (WA) government administrative datasets up to 2020 including health, education, child protection, police and justice system contacts. The study also includes two non-Aboriginal cohorts from WA, linked with the same administrative data sources allowing comparisons of outcomes across cohorts in addition to between-group comparisons within the Aboriginal population., Findings to Date: Linked data coverage rates are presented for all WAACHS participants. Child health outcomes for the WAACHS children (Cohort 1) are described from birth into adulthood along with other outcomes including child protection and juvenile justice involvement., Future Plans: Analysis of data from both the child and carer cohorts will seek to understand the contribution of individual, family (intergenerational) and community-level influences on Aboriginal children's developmental and health pathways, identify key developmental transitions or turning points where interventions may be most effective in improving outcomes, and compare service pathways for Aboriginal and non-Aboriginal children. All research is guided by Aboriginal governance processes and study outputs will be produced with Aboriginal leadership to guide culturally appropriate policy and practice for improving health, education and social outcomes., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2024. Re-use permitted under CC BY. Published by BMJ.)

Objective: Describe the ear and hearing outcomes in Aboriginal infants in an Australian urban area., Design: Aboriginal infants enrolled in the Djaalinj Waakinj prospective cohort study had ear health screenings at ages 2-4, 6-8 and 12-18 months and audiological assessment at ∼12 months of age. Sociodemographic, environmental characteristics, otoscopy, otoacoustic emissions, tympanometry and visual reinforcement audiometry data were collected., Study Sample: 125 infants were enrolled in the study; 67 completed audiological assessment, 62, 54, and 58 of whom attended ear screenings at 2-4, 6-8 and 12-18 months., Results: Of the children that attended the audiological assessment, 36.5%, 50% and 64.3% of infants had otitis media (OM) at 2-4, 6-8 and 12-18 months. Using a 10 dB correction factor, 44.8% of infants had hearing loss (HL) (≥ 25 dB HL) at ∼ 12 months of age. More males (X 2 =5.4 (1df, p = 0.02)) and infants with OM at audiological assessment (X 2 =5.8 (1df, p = 0.02)) had HL. More infants that used a pacifier at 12-18 months of age had HL (X 2 =4.7 (1df, p = 0.03))., Conclusion: Aboriginal infants in an urban area have high rates of HL and OM, which requires early surveillance and timely treatment to reduce the medical and developmental impacts of OM and HL.

The development of architecturally unique molecular nanocarbons by bottom-up organic synthesis is essential for accessing functional organic materials awaiting technological developments in fields such as energy, electronics, and biomedicine. Herein, we describe the design and synthesis of a triptycene-based three-dimensional (3D) nanocarbon, GFN-1 , with geometrical flexibility on account of its three peripheral π-panels being capable of interconverting between two curved conformations. An effective through-space electronic communication among the three π-panels of GFN-1 has been observed in its monocationic radical form, which exhibits an extensively delocalized spin density over the entire 3D π-system as revealed by electron paramagnetic resonance and UV-vis-NIR spectroscopies. The flexible 3D molecular architecture of GFN-1 , along with its densely packed superstructures in the presence of fullerenes, is revealed by microcrystal electron diffraction and single-crystal X-ray diffraction, which establish the coexistence of both propeller and tweezer conformations in the solid state. GFN-1 exhibits strong binding affinities for fullerenes, leading to host-guest complexes that display rapid photoinduced electron transfer within a picosecond. The outcomes of this research could pave the way for the utilization of shape and electronically complementary nanocarbons in the construction of functional coassemblies.

Objectives: There is limited but consistent evidence that suggests prenatal factors, including maternal stress, may contribute to susceptibility for otitis media. We aimed to determine the effect of multiple life stress events during pregnancy on risk of acute and recurrent otitis media in offspring at three and five years of age., Methods: Exposure data on stressful life events were collected from pregnant women in a longitudinal prospective pregnancy cohort study, at 18 and 34 weeks' gestation. We used longitudinal regression models stratified by offspring sex to examine associations between the number, type and timing of maternal prenatal stress events and the likelihood of any OM in addition to recurrent OM infection at age three and five years, adjusting for pre-specified prenatal sociodemographic and environmental confounders., Results: Each additional stressful life event in pregnancy was associated with increased risk of any OM at both ages (3 years: OR = 1.07, 95%CI = 1.02, 1.12; 5 years: OR = 1.07, 95%CI = 1.02, 1.12), with larger effect sizes for recurrent otitis media (3 years: OR = 1.11, 95%CI = 1.05, 1.17; 5 years: OR = 1.09, 95%CI = 1.04, 1.14). Risk of offspring otitis media did not differ with timing of stress nor by offspring sex. Specific types of stress (pregnancy and relationship problems, issues with other children) were each associated with increased risk of recurrent OM at age three and five years., Conclusions: We observed a dose-response relationship between maternal stressful life events in pregnancy and the risk for offspring otitis media in the preschool years, most marked for recurrent otitis media., Competing Interests: Declaration of competing interest none., (Copyright © 2024 Elsevier B.V. All rights reserved.)

Controlled modulation of electronic and magnetic properties in stimuli-responsive materials provides valuable insights for the design of magnetoelectric or multiferroic devices. This paper demonstrates the modulation of electrical and magnetic properties of a semiconductive, paramagnetic metal-organic framework (MOF) Cu 3 (C 6 O 6 ) 2 with small gaseous molecules, NH 3 , H 2 S, and NO. This study merges chemiresistive and magnetic tests to reveal that the MOF undergoes simultaneous changes in electrical conductance and magnetization that are uniquely modulated by each gas. The features of response, including direction, magnitude, and kinetics, are modulated by the physicochemical properties of the gaseous molecules. This study advances the design of multifunctional materials capable of undergoing simultaneous changes in electrical and magnetic properties in response to chemical stimuli., (© 2024 Wiley-VCH GmbH.)

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.)

Objective: Investigating the impact of early childhood ventilation tube insertion (VTI) on long-term language outcomes., Design: Longitudinal cohort study., Setting: A total of 2900 pregnant women participated in the Raine Study between 1989 and 1991 in Western Australia, and 2868 children have been followed up., Participants: Based on parental reports, 314 children had a history of recurrent otitis media but did not undergo VTI (rOM group); another 94 received VTI (VTI group); while 1735 had no history of rOM (reference group) in the first 3 years of childhood. Children with data on outcomes and confounders were included in analyses of PPVT-R at ages 6 (n = 1567) and 10 years (n = 1313) and CELF-III at 10 years (n = 1410) (approximately 5% in the VTI group and 15% in the rOM group)., Main Outcome Measures: Peabody Picture Vocabulary Test-Revised edition and Clinical Evaluation of Language Fundamentals® Preschool-3., Results: At 6 years, mean PPVT-R scores were significantly lower in the VTI group than the reference group (β = -3.3; 95% CI [-6.5 to -0.04], p = .047). At 10 years, while the difference between the VTI and reference groups was less pronounced for PPVT-R scores, there was a small but consistent trend of lower measures, on average, across CELF-III scores (expressive: β = -3.4 [-7.1 to 0.27], p = .069; receptive: β = -4.1 [-7.9 to -0.34], p = .033; total: β = -3.9 [-7.5 to -0.21], p = .038). There was no evidence to suggest that language outcomes in the rOM group differed from the reference group., Conclusion: Lower scores of language outcomes in school-aged children who received VTI in early childhood may suggest a long-term risk which should be considered alongside the potential benefits of VTI., (© 2023 The Authors. Clinical Otolaryngology published by John Wiley & Sons Ltd.)

Aim: Children with early-life recurrent otitis media (OM) will often endure pain, sleep disturbances, and other developmental setbacks that impact the surrounding family system. The aim of this study was to investigate the psychological well-being and family functioning of caregivers of children with early-life recurrent OM (rOM)., Methods: Data from a longitudinal pregnancy cohort were used to categorize children into two groups: those with a history of recurrent OM (rOM group) and those without a history of rOM (reference group) by the age of 3 years. The psychological well-being of caregivers and the family functioning status were assessed using the Affect Balance Scale and the General Functioning Scale of the McMaster Family Assessment Device (FAD-GF), respectively, at the three-, five-, and eight-year follow-up appointments. Multiple linear regression models were used to analyze the data and were adjusted for potential confounding variables., Results: There were significant associations between having a child with an early history of rOM and the Affect Balance Scale of caregivers for the negative affects subscale at the three- (p < 0.001) and five- (p = 0.018) year follow-ups, and the Affect Balance subscale at the three-year (p = 0.007) and the five-year follow-ups (p = 0.047). There were no significant associations measured during the 8-year follow-up period for the FAD-GF., Conclusion: The findings of this study further highlight the impact of caring for a child with rOM in early childhood on caregivers' psychological well-being in the first five years of a child's life. The impact, however, did not appear to influence the longer-term functioning of the family as a whole., Level of Evidence: 3 Laryngoscope, 134:1445-1449, 2024., (© 2023 The American Laryngological, Rhinological and Otological Society, Inc.)

Glioblastoma is an aggressive, incurable brain cancer with poor five-year survival rates of around 13% despite multimodal treatment with surgery, DNA-damaging chemoradiotherapy and the recent addition of Tumour Treating Fields (TTFields). As such, there is an urgent need to improve our current understanding of cellular responses to TTFields using more clinically and surgically relevant models, which reflect the profound spatial heterogeneity within glioblastoma, and leverage these biological insights to inform the rational design of more effective therapeutic strategies incorporating TTFields. We have recently reported the use of preclinical TTFields using the inovitro TM system within 2D glioma stem-like cell (GSC) models and demonstrated significant cytotoxicity enhancement when co-applied with a range of therapeutically approved and preclinical DNA damage response inhibitors (DDRi) and chemoradiotherapy. Here we report the development and optimisation of preclinical TTFields delivery within more clinically relevant 3D scaffold-based primary GSC models of spatial heterogeneity, and highlight some initial enhancement of TTFields potency with temozolomide and clinically approved PARP inhibitors (PARPi). These studies, therefore, represent an important platform for further preclinical assessment of TTFields-based therapeutic strategies within clinically relevant 3D GSC models, aimed towards accelerating clinical trial implementation and the ultimate goal of improving the persistently dire survival rates for these patients.

Objective: Telemedicine, particularly real time video-otoscopy in rural and remote Australia holds great potential in assessing and managing otology conditions. There is good evidence of store and forward images for assessment, however limited evidence exists for the use of real-time video-otoscopy. The objective of this study was to assess the validity of using real time video-otoscopy, compared to standard store and forward still image otoscopy, in a paediatric population., Method: Fifty-two paediatric tympanic membranes in 27 patients were examined and photographed by a telehealth facilitator with prior otoscope training. This occurred at two rural Western Australian health centre sites. These images were stored and forwarded to a tertiary paediatric hospital for otolaryngology department assessment on the day of real-time video-otoscopy consultation. During this consultation the same twenty-seven patients underwent real-time video-otoscopy assessment, which was recorded. Across six domains including, image quality, focus, light, cerumen amount, field of view and tympanic membrane landmarks, real-time video-otoscopy was compared against still image capture. The recording of each real-time video-otoscopy and still image tympanic membrane was assessed by two otology specialists for the ability to diagnose each as either normal or abnormal. An inter-rater reliability agreement was then calculated., Results: There was greater image adequacy across five of the six domains for real time video-otoscopy compared to standard store and forward otoscopy images. Substantial agreement in diagnosing each tympanic membrane as either normal or abnormal between each rater was evident., Conclusion: This study supports the use of real time video-otoscopy during telemedicine consultation. With greater image quality, focus, light, field of view and identification of tympanic membrane landmarks video-otoscopy compared to still images has broad clinical applications. This includes primary assessment of the tympanic membrane and post operative follow-up clinical settings. Video-otoscopy offers a promising new way to over-come barriers in delivering ear health care in rural populations., Competing Interests: Declaration of competing interest No potential conflict of interest was reported by the author(s)., (Crown Copyright © 2024. Published by Elsevier B.V. All rights reserved.)

Background: One third of children require repeat ventilation tube insertion (VTI) for otitis media. Disease recurrence is associated with persistent middle ear bacterial biofilms. With demonstration that Dornase alfa (a DNase) disrupts middle ear effusion biofilms ex vivo, we identified potential for this as an anti-biofilm therapy to prevent repeat VTI. First, safety and tolerability needed to be measured., Methods: This was a phase 1B double-blinded randomized control trial conducted in Western Australia. Children between 6 months and 5 years undergoing VTI for bilateral middle ear effusion were recruited between 2012 and 2014 and followed for two years. Children's ears were randomized to receive either Dornase alfa (1 mg/mL) or 0.9 % sodium chloride (placebo) at time of surgery. Children were followed up at 2 weeks post-VTI and at 3-monthly intervals for 2 years. Outcomes assessed were: 1) safety and tolerability, 2) otorrhoea frequency, 3) blocked or extruded ventilation tube (VT) frequency, 4) time to blockage or extrusion, 5) time to infection recurrence and/or need for repeat VTI., Results: Sixty children (mean age 2.3 years) were enrolled with 87 % reaching study endpoint. Treatment did not change otorrhoea frequency. Hearing improved in all children following VTI, with no indication of ototoxicity. Dornase alfa had some effect on increasing time until VT extrusion (p = 0.099); and blockage and/or extrusion (p = 0.122). Frequency of recurrence and time until recurrence were similar. Fourteen children required repeat VTI within the follow-up period., Conclusion: A single application of Dornase alfa into the middle ear at time of VTI was safe, non-ototoxic, and well-tolerated., Trial Registration: ACTRN12623000504617., Competing Interests: Declaration of competing interest There are no financial interests. Prof. Richmond serves on scientific advisory boards, and together with A/Prof Kirkham has received institutional funding for investigator-initiated grants, from GSK, Pfizer and MSD – all are unrelated to this work., (Copyright © 2024 The Authors. Published by Elsevier B.V. All rights reserved.)

Two novel cyclometallated iridium(III) complexes have been prepared with one bidentate or two monodentate imidazole-based ligands, 1 and 2, respectively. The complexes showed intense emission with long lifetimes of the excited state. Femtosecond transient absorption experiments established the nature of the lowest excited state as 3 IL state. Singlet oxygen generation with good yields (40% for 1 and 82% for 2) was established by detecting 1 O 2 directly, through its emission at 1270 nm. Photostability studies were also performed to assess the viability of the complexes as photosensitizers (PS) for photodynamic therapy (PDT). Complex 1 was selected as a good candidate to investigate light-activated killing of cells, whilst complex 2 was found to be toxic in the dark and unstable under light. Complex 1 demonstrated high phototoxicity indexes (PI) in the visible region, PI > 250 after irradiation at 405 nm and PI > 150 at 455 nm, in EJ bladder cancer cells., (© 2024. The Author(s).)

Aim: The purpose of this study is to explore the effectiveness of a hospital-based asynchronous ear, nose, and throat (ENT) telehealth service (the Ear Portal) in reducing cost and improving access for children with otitis media., Methods: Participants were recruited to the Ear Portal from a tertiary hospital ENT waiting list. Ear and hearing assessments were conducted during appointments by the Ear Portal research assistant, and data was stored for an asynchronous review by the Ear Portal multidisciplinary team. A cost-minimisation analysis was conducted for the Ear Portal and the standard care pathways. Waiting times to provide care for both pathways were calculated for children with semi-urgent (i.e. Category 2) and non-urgent (i.e. Category 3) referrals., Results: The running cost for the Ear Portal was $67.70 for initial appointments and $37.34 for follow-up appointments. Conversely, the running cost for the standard care pathway was $154.65 for initial appointments and $86.10 for follow-up appointments. A total of 223 appointments were required to offset the initial Ear Portal investment of $19,384.00. The median waiting time for the Ear Portal from initial contact to care plan delivery was <30 days, whereas the median waiting times for children in the standard care pathway were 291 days (interquartile range (IQR) = 117) for Category 2 and 371 days (IQR = 311) for Category 3 referrals., Conclusion: Under the current circumstances, the Ear Portal service can reduce costs for the health care system by reducing marginal costs per patient in addition to providing ENT specialist care within the clinically recommended timeframes., Competing Interests: Declaration of conflicting interestsThe author(s) declared no potential conflicts of interest with respect to the research, authorship and/or publication of this article.

Aim: To investigate the long-term effects of early-life recurrent otitis media (OM) and subsequent behavioural problems in children at the age of 10 years., Methods: Data from the Raine Study, a longitudinal pregnancy cohort, were used to categorise children into those with three or more episodes of OM (rOM group) and those without a history of recurrent OM in the first 3 years of life (reference group). The parent report Strengths and Difficulties Questionnaire was used to assess child behaviour at the age of 10 years. Parental questionnaires were used to report past and present diagnoses of various mental health and developmental conditions, including attention, anxiety, depression, learning, and speech-language problems. Multiple linear and logistic models were used to analyse the data and were adjusted for a fixed set of key confounding variables., Results: The linear regression analysis revealed significant, independent associations between a history of recurrent OM and higher Strengths and Difficulties Questionnaire scores, including total, internalising, externalising, emotional, attention/hyperactivity and peer problems subscales. Logistic regression analyses revealed an independent increased likelihood for children in the rOM group to have a diagnosis of attention, anxiety, learning and speech-language problems., Conclusion: Children at 10 years of age with an early history of recurrent OM are more likely to exhibit attentional and behavioural problems when compared to children without a history of recurrent OM. These findings highlight the association between early-life recurrent OM and later behavioural problems that may require professional allied health-care interventions., (© 2023 The Authors. Journal of Paediatrics and Child Health published by John Wiley & Sons Australia, Ltd on behalf of Paediatrics and Child Health Division (The Royal Australasian College of Physicians).)

Background: Developmental language disorder (DLD) is one of the most common neurodevelopmental conditions. Due to variable rates of language growth in children under 5 years, the early identification of children with DLD is challenging. Early indicators are often outlined by speech pathology regulatory bodies and other developmental services as evidence to empower caregivers in the early identification of DLD., Aims: To test the predictive relationship between parent-reported early indicators and the likelihood of children meeting diagnostic criteria for DLD at 10 years of age as determined by standardized assessment measures in a population-based sample., Methods: Data were leveraged from the prospective Raine Study (n = 1626 second-generation children: n = 104 with DLD; n = 1522 without DLD). These data were transformed into 11 predictor variables that reflect well-established early indicators of DLD from birth to 3 years, including if the child does not smile or interact with others, does not babble, makes only a few sounds, does not understand what others say, says only a few words, says words that are not easily understood, and does not combine words or put words together to make sentences. Family history (mother and father) of speech and language difficulties were also included as variables. Regression analyses were planned to explore the predictive relationship between this set of early indicator variables and likelihood of meeting DLD diagnostic criteria at 10 years., Results: No single parent-reported indicator uniquely accounted for a significant proportion of children with DLD at 10 years of age. Further analyses, including bivariate analyses testing the predictive power of a cumulative risk index of combined predictors (odds ratio (OR) = 0.95, confidence interval (CI) = 0.85-1.09, p = 0.447) and the moderating effect of sex (OR = 0.89, CI = 0.59-1.32, p = 0.563) were also non-significant., Conclusions: Parent reports of early indicators of DLD are well-intentioned and widely used. However, data from the Raine Study cohort suggest potential retrospective reporting bias in previous studies. We note that missing data for some indicators may have influenced the results. Implications for the impact of using early indicators as evidence to inform early identification of DLD are discussed., What This Paper Adds: What is already known on the subject DLD is a relatively common childhood condition; however, children with DLD are under-identified and under-served. Individual variability in early childhood makes identification of children at risk of DLD challenging. A range of 'red flags' in communication development are promoted through speech pathology regulatory bodies and developmental services to assist parents to identify if their child should access services. What this paper adds to the existing knowledge No one parent-reported early indicator, family history or a cumulation of indicators predicted DLD at 10 years in the Raine study. Sex (specifically, being male) did not moderate an increased risk of DLD at 10 years in the Raine study. Previous studies reporting on clinical samples may be at risk of retrospective reporting bias. What are the potential or actual clinical implications of this work? The broad dissemination and use of 'red flags' is well-intentioned; however, demonstrating 'red flags' alone may not reliably identify those who are at later risk of DLD. Findings from the literature suggest that parent concern may be complemented with assessment of linguistic behaviours to increase the likelihood of identifying those who at risk of DLD. Approaches to identification and assessment should be considered alongside evaluation of functional impact to inform participation-based interventions., (© 2023 The Authors. International Journal of Language & Communication Disorders published by John Wiley & Sons Ltd on behalf of Royal College of Speech and Language Therapists.)

The structural determination of natural products (NPs) can be arduous because of sample heterogeneity. This often demands iterative purification processes and characterization of complex molecules that may be available only in miniscule quantities. Microcrystal electron diffraction (microED) has recently shown promise as a method to solve crystal structures of NPs from nanogram quantities of analyte. However, its implementation in NP discovery remains hampered by sample throughput and purity requirements, akin to traditional NP-discovery workflows. In the methods described herein, we leverage the resolving power of transmission electron microscopy (TEM) and the miniaturization capabilities of deoxyribonucleic acid (DNA) microarray technology to address these challenges through the establishment of an NP screening platform, array electron diffraction (ArrayED). In this workflow, an array of high-performance liquid chromatography (HPLC) fractions taken from crude extracts was deposited onto TEM grids in picoliter-sized droplets. This multiplexing of analytes on TEM grids enables 1200 or more unique samples to be simultaneously inserted into a TEM instrument equipped with an autoloader. Selected area electron diffraction analysis of these microarrayed grids allows for the rapid identification of crystalline metabolites. In this study, ArrayED enabled structural characterization of 14 natural products, including four novel crystal structures and two novel polymorphs, from 20 crude extracts. Moreover, we identify several chemical species that would not be detected by standard mass spectrometry (MS) or ultraviolet-visible (UV/vis) spectroscopy and crystal forms that would not be characterized using traditional methods., Competing Interests: The authors declare no competing financial interest., (© 2023 The Authors. Published by American Chemical Society.)

Aim: Children with otitis media (OM) experience long waiting times to access Australia's public hospitals due to limited capacity. The aim of this article is to utilize an Ear, Nose, and Throat (ENT) telehealth service (the Ear Portal) to examine whether delayed access to specialist care is associated with poorer behavioral outcomes for children with OM., Methods: Participants in the study included 45 children who were referred to ENT specialists due to recurrent and persistent OM. Children were triaged as semiurgent with a target time-to-assessment of 90 days or nonurgent with a target time-to-assessment of 365 days. The behavioral outcomes of children were assessed using the parent report Strengths and Difficulties Questionnaire (SDQ). Descriptive statistics and adjusted multiple linear regression models were used to compare children who received access to the service within the time-to-assessment target of their triage category ("on-boundary"; n  = 17) and outside the time-to-assessment target ("off-boundary"; n  = 28). Spearman correlation analysis was used to explore the relationship between the internalizing, externalizing, and total SDQ scores as a function of waiting times in days., Results: Borderline or abnormal SDQ scores ranged from 24.4% to 42.2% across the study participants. The regression analysis showed a statistically significant association between the off-boundary group and higher scores (i.e., poorer) on the peer, emotional, conduct, internalizing, and total problems subscales. Further, lengthy waiting times were significantly correlated with higher internalizing problems. These findings indicate that longer waiting times may lead to poorer behavioral outcomes for children with OM., Clinical Trial Registration: (ACTRN1269000039189p)., Conclusion: Children with recurrent and persistent OM referred to ENT outpatient care were found to have significantly more behavioral difficulties if their waiting times exceeded the recommended timeframes for their triaged referrals. Additionally, they experienced more internalizing problems that correlated with longer waiting times. This highlights the calls for alterations in current clinical practice given the lengthy waiting times in Australia's public hospitals., Competing Interests: No competing financial interests exist., (© Ali A.H. Altamimi et al., 2023; Published by Mary Ann Liebert, Inc.)

Background: Chronic tinnitus during childhood/adolescence can be associated with impaired quality of life. Guidelines for managing paediatric tinnitus recommend assessment and interventions are often based upon the experiences and opinions of guideline committee members., Objective: To examine patient response tools used for the assessment and management of childhood tinnitus and how interventions had been evaluated., Design: A structured scoping review (i) identifying and critically appraising patient response measures (PRMs) assessing tinnitus in children/adolescents, and (ii) critically appraising evidence supporting reported interventions. Original papers written in English, involving paediatric participants ≤19 years, reporting (i) application of established PRMs to assess the experience of chronic tinnitus or (ii) application and evaluation of tinnitus interventions were included., Study Sample: Papers written in English, identifying, or assessing the experience of chronic tinnitus (>3 months) as a primary complaint during childhood/adolescence in participants ≤19 years of age using a PRM and studies evaluating the application of non-pharmaceutical interventions for tinnitus in children/adolescents., Results: Six studies involving the assessment of tinnitus during childhood/adolescence using a PRM were identified and evaluated. Three established (previously named, described, and published) PRMs were applied of which none were developed specifically for children/adolescents. Three behavioural tinnitus interventions and three combination intervention strategies (coupling of psychological intervention with sound enrichment) had been applied to and evaluated within paediatric populations., Conclusions: Although clinicians are seeing children/adolescents with tinnitus, they are evaluating and managing children's distress without appropriate PRMs, and little evidence exists to support clinical interventions.

Background: High-grade gliomas are primary brain cancers with unacceptably low and persistent survival rates of 10-16 months for WHO grade 4 gliomas over the last 40 years, despite surgical resection and DNA-damaging chemo-radiotherapy. More recently, tumour-treating fields therapy (TTFields) has demonstrated modest survival benefit and been clinically approved in several countries. TTFields is thought to mediate anti-cancer activity by primarily disrupting mitosis. However, recent data suggest that TTFields may also attenuate DNA damage repair and replication fork dynamics, providing a potential platform for therapeutic combinations incorporating standard-of-care treatments and targeted DNA damage response inhibitors (DDRi)., Methods: We have used patient-derived, typically resistant, glioma stem-like cells (GSCs) in combination with the previously validated preclinical Inovitro™ TTFields system together with a number of therapeutic DDRi., Results: We show that TTFields robustly activates PARP- and ATR-mediated DNA repair (including PARylation and CHK1 phosphorylation, respectively), whilst combining TTFields with PARP1 or ATR inhibitor treatment leads to significantly reduced clonogenic survival. The potency of each of these strategies is further enhanced by radiation treatment, leading to increased amounts of DNA damage with profound delay in DNA damage resolution., Conclusion: To our knowledge, our findings represent the first report of TTFields applied with clinically approved or in-trial DDRi in GSC models and provides a basis for translational studies toward multimodal DDRi/TTFields-based therapeutic strategies for patients with these currently incurable tumours., (© 2023. The Author(s).)

Objectives: To identify and review key research advances from the literature published between 2019 and 2023 on the diagnosis and microbiology of otitis media (OM) including acute otitis media (AOM), recurrent AOM (rAOM), otitis media with effusion (OME), chronic suppurative otitis media (CSOM) and AOM complications (mastoiditis)., Data Sources: PubMed database of the National Library of Medicine., Review Methods: All relevant original articles published in Medline in English between July 2019 and February 2023 were identified. Studies that were reviews, case studies, relating to OM complications (other than mastoiditis), and studies focusing on guideline adherence, and consensus statements were excluded. Members of the panel drafted the report based on these search results., Main Findings: For the diagnosis section, 2294 unique records screened, 55 were eligible for inclusion. For the microbiology section 705 unique records were screened and 137 articles were eligible for inclusion. The main themes that arose in OM diagnosis were the need to incorporate multiple modalities including video-otoscopy, tympanometry, telemedicine and artificial intelligence for accurate diagnoses in all diagnostic settings. Further to this, was the use of new, cheap, readily available tools which may improve access in rural and lowmiddle income (LMIC) settings. For OM aetiology, PCR remains the most sensitive method for detecting middle ear pathogens with microbiome analysis still largely restricted to research use. The global pandemic response reduced rates of OM in children, but post-pandemic shifts should be monitored., Implication for Practice and Future Research: Cheap, easy to use multi-technique assessments combined with artificial intelligence and/or telemedicine should be integrated into future practice to improve diagnosis and treatment pathways in OM diagnosis. Longitudinal studies investigating the in-vivo process of OM development, timings and in-depth interactions between the triad of bacteria, viruses and the host immune response are still required. Standardized methods of collection and analysis for microbiome studies to enable inter-study comparisons are required. There is a need to target underlying biofilms if going to effectively prevent rAOM and OME and possibly enhance ventilation tube retention., Competing Interests: Declaration of competing interest No conflict., (Copyright © 2023 Elsevier B.V. All rights reserved.)

Plastic pollution is distributed patchily around the world's oceans. Likewise, marine organisms that are vulnerable to plastic ingestion or entanglement have uneven distributions. Understanding where wildlife encounters plastic is crucial for targeting research and mitigation. Oceanic seabirds, particularly petrels, frequently ingest plastic, are highly threatened, and cover vast distances during foraging and migration. However, the spatial overlap between petrels and plastics is poorly understood. Here we combine marine plastic density estimates with individual movement data for 7137 birds of 77 petrel species to estimate relative exposure risk. We identify high exposure risk areas in the Mediterranean and Black seas, and the northeast Pacific, northwest Pacific, South Atlantic and southwest Indian oceans. Plastic exposure risk varies greatly among species and populations, and between breeding and non-breeding seasons. Exposure risk is disproportionately high for Threatened species. Outside the Mediterranean and Black seas, exposure risk is highest in the high seas and Exclusive Economic Zones (EEZs) of the USA, Japan, and the UK. Birds generally had higher plastic exposure risk outside the EEZ of the country where they breed. We identify conservation and research priorities, and highlight that international collaboration is key to addressing the impacts of marine plastic on wide-ranging species., (© 2023. The Author(s).)

Introduction: Video otoscopy plays an important role in improving access to ear health services. This study investigated the clinician-rated quality of video otoscopy recordings and still images, and compared their suitability for asynchronous diagnosis of middle-ear disease., Methods: Two hundred and eighty video otoscopy image-recording pairs were collected from 150 children (aged six months to 15 years) by an ear, nose, and throat (ENT) specialist, audiologists, and trained research assistants, and independently rated by an audiologist and ENT surgeon. On a five-point scale, clinicians rated the cerumen amount, field of view, quality, focus, light, and gave an overall rating, and asked whether they could make an accurate diagnosis for both still images and recordings., Results: More video otoscopy recordings were rated as 'good' or 'excellent' compared to still images across all domains. The mean difference between the two otoscopic procedures ratings was significant across almost all domains ( p  < 0.05), except 'cerumen amount'. The suitability to make a diagnosis significantly improved when using recordings (p<0.05). Younger participant age was found to have a significant, negative impact on the ratings across all domains ( p  < 0.03). The role of the tester conducting video otoscopy did not have a significant impact on the ratings., Discussion: Video otoscopy recordings were found to provide clearer views of the tympanic membrane and increase the ability to make diagnoses, compared to still images, for both audiologists and ENT surgeons. Research assistants with limited practice were able to obtain video otoscopy images and recordings that were comparable to the ones obtained by clinicians.

Aspergillus fumigatus is a serious human pathogen causing life-threatening Aspergillosis in immunocompromised patients. Secondary metabolites (SMs) play an important role in pathogenesis, but the products of many SM biosynthetic gene clusters (BGCs) remain unknown. In this study, we have developed a heterologous expression platform in Aspergillus nidulans , using a newly created genetic dereplication strain, to express a previously unknown BGC from A. fumigatus and determine its products. The BGC produces sartorypyrones, and we have named it the spy BGC. Analysis of targeted gene deletions by HRESIMS, NMR, and microcrystal electron diffraction (MicroED) enabled us to identify 12 products from the spy BGC. Seven of the compounds have not been isolated previously. We also individually expressed the polyketide synthase (PKS) gene spyA and demonstrated that it produces the polyketide triacetic acid lactone (TAL), a potentially important biorenewable platform chemical. Our data have allowed us to propose a biosynthetic pathway for sartorypyrones and related natural products. This work highlights the potential of using the A. nidulans heterologous expression platform to uncover cryptic BGCs from A. fumigatus and other species, despite the complexity of their secondary metabolomes., Competing Interests: The authors declare no conflicts of interest., (This journal is © The Royal Society of Chemistry.)