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Novel hearing therapeutics are rapidly progressing along the innovation pathway and into the clinical trial domain. Because these trials are new to the hearing community, they come with challenges in terms of trial design, regulation and delivery. In this paper, we address the key scientific and operational issues and outline the opportunities for interdisciplinary and international collaboration these trials offer. Vital to the future successful implementation of these therapeutics is to evaluate their potential for adoption into healthcare systems, including consideration of their health economic value. This requires early engagement with all stakeholder groups along the hearing innovation pathway. • Novel hearing loss therapies are rapidly progressing along the translational pathway. • To develop precision medicine for inner ear disorders, precision diagnosis is needed. • There is an urgent need for large-scale genotype–phenotype studies. • Clinical trials capability and capacity must increase in line with this growing field. • For implementation, it is vital to consider health economics and service impact. [ABSTRACT FROM AUTHOR]

Background: Current opinions regarding the management of acute otitis media (AOM) in children vary across Western countries. With antibiotic resistance rising and more evidence regarding the limited clinical efficacy of antibiotics becoming available, interest in managing AOM other than with antibiotics is renewed. Objectives: To compare international rates of antibiotic prescription and surgery for AOM. To provide current evidence regarding the efficacy of various treatment options for AOM and their potential complications. Methods: Qualitative (narrative) review. Results: The percentage of patients given antibiotics for AOM varies from 31% in The Netherlands to more than 90% in most other Western countries. The 1998 prevalence of penicillin-resistant S. pneumoniae strains, on the other hand, ranges from 3% in The Netherlands to 53% in France. The surgical rate for tympanostomy tubes varies from 2 per 1000 children per year in the United Kingdom to 20 per 1000 in The Netherlands. The benefit of both antibiotic and surgical therapy in AOM appears to be limited, with numbers needed to treat ranging from 8 to 25 for antibiotic therapy, depending on the definition of outcome. Conclusions: International rates of antibiotic prescription and surgery for AOM vary strongly, which can be explained largely by the lack of uniform evidence-based guidelines. International debates with the aim of overcoming cultural differences regarding the management of otitis media, and of reaching agreement on guidelines on the basis of current evidence are necessary. [Copyright &y& Elsevier]

Objective: To quantify the critical age period of first episode of acute otitis media (AOM) and its consequences for AOM recurrences and AOM health care use.Study Design: Children enrolled in the Wheezing-Illnesses-STudy-LEidsche-Rijn cohort with at least 1 episode of AOM documented in their primary care health record before 2 years of age were followed until 6 years of age. Data on episodes of AOM and associated primary care consultations, antibiotic prescriptions, and specialist referrals were retrieved. Regression models assessed the presence and shape of the associations between age of first AOM and subsequent episodes of AOM and health care use.Results: A total of 796 of 2026 children (39%) experienced a first AOM before 2 years of age. Each month decrease in age at first AOM in the first 2 years of life increased the risk of developing recurrent AOM (≥3 AOM episodes in 6 months or ≥ 4 in 1 year) linearly by 6% (adjusted risk ratio: 1.06; 95% CI: 1.02-1.10). For first AOM occurring before 9 months, the cumulative 6-year primary care consultation rate increased by 8% (adjusted incidence rate ratio: 1.08; 95% CI: 1.03-1.15) and the associated specialist referral increased by 16% (adjusted risk ratio: 1.16; 95% CI: 1.07-1.27) for each month decrease in age. No associations were found between age at first AOM and total AOM episodes or antibiotic prescriptions.Conclusions: The association between earlier age of first AOM and recurrent AOM as well as total health care use during childhood is particularly strong before 9 months of age. [ABSTRACT FROM AUTHOR]

Abstract: Objective: To develop an easily applicable prediction rule for asthma in young adulthood using childhood characteristics. Methods: A total of 1,055 out of 1,328 members of a Dutch birth cohort were followed from 2 to 21 years of age. Univariate and multivariate logistic regression analyses were used to evaluate the predictive value of childhood characteristics on asthma at 21 years of age. A prognostic function was developed, and the area under the receiving operating characteristic (ROC) curve was used to estimate the predictive ability of the prognostic models. Results: Of the 693 responding subjects, 86 (12%) were diagnosed with asthma. Independent prognostic factors at ages 2 and 4 years were female gender (odds ratios (OR) 1.9 and 2.1; 95% confidence intervals (CI) 1.2–3.2 and 1.3–2.5), smoking mother (OR 1.6 and 1.6; CI 1.0–2.7 and 1.0–2.6), lower respiratory tract illness (OR 1.9 and 2.4; CI 1.0–3.6 and 1.4–4.0), and atopic parents (OR 2.1 and 1.9; CI 1.3–3.4 and 1.2–3.1). The predictive power of both models was poor; area under ROC curve was 0.66 and 0.68, respectively. Conclusion: Asthma in young adulthood could not be predicted satisfactorily based on childhood characteristics. Nevertheless, we propose that this method is further tested as a tool to predict development of asthma. [Copyright &y& Elsevier]

Summary: Background: Opinions about otitis media (OM) as an illness and about the need for antibiotic or surgical treatment vary internationally. It is not known how this is to be explained, whether by cultural differences or by other factors, such as variation in environmental risk factors for OM. Objectives: To report on variation in environmental risk factors for OM across Western countries, and on the organisation of health care in these countries. Methods: Main environmental risk factors for OM were identified by searching Pubmed. Data on the distribution of these risk factors and the organisation of health care across countries were obtained from the OECD and WHO websites. Results: Main risk factors for OM were day-care, number of siblings, smoking, breastfeeding, birth weight, socio-economic status (SES) and air pollution. Data were available for several European countries, the United State, Canada and Australia. Large international differences were found regarding the proportion of children attending day-care (Sweden 75% versus Italy 6%) and being breastfed at age 6 months (Norway 80% versus Poland 6%), and the rate of female smokers (Germany, France and Norway 30–40% versus Portugal <10%). Conclusion: It appears that differences in risk factor exposure between populations are often overshadowed by other culturally or demographically significant factors. Attempts to discern these factors within populations and between countries may be important in the management of OM and warrants further study. [Copyright &y& Elsevier]

Background: Fever is an important physical sign in infectious diseases in childhood. Daily assessment of fever may be used to monitor the occurrence of infections for research purposes. The infrared tympanic membrane thermometer (ITT) seems ideal for measuring central body temperature. Its accuracy, however, is still debated, and the feasibility of daily temperature measurements with an ITT has not been described. Objective: To determine the accuracy and feasibility of daily infrared tympanic membrane temperature measurements at home. Methods: Tympanic membrane temperature was measured by the Braun Pro 3000, rectal temperature by the Omron MC 63. To establish the accuracy of the ITT, rectal and tympanic membrane temperature measurements were performed in 41 children, aged 2–10 years. To establish the feasibility of daily infrared tympanic temperature measurements at home, parents of 21 children performed daily measurements for 2 weeks. Results: With fever defined as a body temperature of ≥38.0 °C, sensitivity was 93.3%, specificity 92%, positive predictive value 87.5%, negative predictive value 95.8%, and the concordance rate 92.5%. Most of the parents found the instructions for the use of the ITT clear (93%) and the ITT easy to use (86%). During the test period of 2 weeks the technique of the tympanic membrane temperature measurements remained adequate in 93% of the parents. Conclusion: The tympanic membrane temperature measured by the Braun Pro 3000 accurately reflects rectal temperature, validly assesses the presence of fever in children, and is easy to use. The Braun ITT therefore is an adequate tool to assess fever and may be used both in a clinical setting and for research purposes. [Copyright &y& Elsevier]

This Review outlines the development of DNA-based therapeutics for treatment of hearing loss, and in particular, considers the potential to utilize the properties of recombinant neurotrophins to improve cochlear auditory (spiral ganglion) neuron survival and repair. This potential to reduce spiral ganglion neuron death and indeed re-grow the auditory nerve fibres has been the subject of considerable pre-clinical evaluation over decades with the view of improving the neural interface with cochlear implants. This provides the context for discussion about the development of a novel means of using cochlear implant electrode arrays for gene electrotransfer. Mesenchymal cells which line the cochlear perilymphatic compartment can be selectively transfected with (naked) plasmid DNA using array - based gene electrotransfer, termed 'close-field electroporation'. This technology is able to drive expression of brain derived neurotrophic factor (BDNF) in the deafened guinea pig model, causing re-growth of the spiral ganglion peripheral neurites towards the mesenchymla cells, and hence into close proximity with cochlear implant electrodes within scala tympani. This was associated with functional enhancement of the cochlear implant neural interface (lower neural recruitment thresholds and expanded dynamic range, measured using electrically - evoked auditory brainstem responses). The basis for the efficiency of close-field electroporation arises from the compression of the electric field in proximity to the ganged cochlear implant electrodes. The regions close to the array with highest field strength corresponded closely to the distribution of bioreporter cells (adherent human embryonic kidney (HEK293)) expressing green fluorescent reporter protein (GFP) following gene electrotransfer. The optimization of the gene electrotransfer parameters using this cell-based model correlated closely with in vitro and in vivo cochlear gene delivery outcomes. The migration of the cochlear implant electrode array-based gene electrotransfer platform towards a clinical trial for neurotrophin-based enhancement of cochlear implants is supported by availability of a novel regulatory compliant mini-plasmid DNA backbone (pFAR4; plasmid Free of Antibiotic Resistance v.4) which could be used to package a 'humanized' neurotrophin expression cassette. A reporter cassette packaged into pFAR4 produced prominent GFP expression in the guinea pig basal turn perilymphatic scalae. More broadly, close-field gene electrotransfer may lend itself to a spectrum of potential DNA therapeutics applications benefitting from titratable, localised, delivery of naked DNA, for gene augmentation, targeted gene regulation, or gene substitution strategies. • Cochlear mesenchymal cells can be targeted for gene electrotransfer via electric field compression using cochlear implants. • Regeneration of cochlear peripheral neurites after neurotrophin gene augmentation via bionic array-based electrotransfer. • Local recombinant neurotrophin expression enhances neural recruitment and electrically evoked auditory brainstem responses. • Bionic array directed gene electrotransfer requires low voltages albeit higher than existing cochlear implant capabilities. • Regulatory-permissive mini-plasmids free of antibiotic resistance genes achieve efficient gene expression in the cochlea. [ABSTRACT FROM AUTHOR]

Highlights • Pneumococcal conjugate vaccination (PCV) in infancy is widely implemented globally. • PCV may impact pneumococcal AOM episodes occurring during early childhood. • Our study suggests that PCV postpones the onset and reduces the risk of first AOM. • PCV however did not affect AOM recurrences in children up to the age of four years. Abstract Background It has been hypothesized that widespread implementation of pneumococcal conjugate vaccination (PCV) in infancy reduces early AOM and thereby prevents further AOM episodes and associated health care resource use. Methods We tested this hypothesis by applying an extension of the original Cox proportional hazards model (Prentice, Williams and Petersons' total time) to individual AOM episodes recorded in pseudonymised primary care electronic health records of 18,237 Dutch children born between 2004 and 2015. Children were assigned to three groups: no-PCV (January 2004-March 2006), PCV7 (April 2006-February 2011) and PCV10 (March 2011-February 2015). Results Of the 18,237 newborns, 6967 (38%) experienced at least one GP-diagnosed AOM episode up to the age of four years (median age at first AOM: 12 months, interquartile range: 12; total number of AOM episodes: 14,689). Time-to-first AOM was longest in the PCV10 group compared with the PCV7 and no-PCV groups (log rank test: P < 0.001); in these groups 30% had experienced a first AOM at 20, 17 and 15 months, respectively. Children in the PCV10 group had a 21% lower risk of experiencing a first AOM episode than those in the no-PCV group (hazard ratio (HR): 0.79, 95% confidence interval (CI): 0.72–0.86), while the effect was less pronounced for the PCV7 group (HR: 0.94, 95% CI: 0.87–1.02). Neither PCV7 nor PCV10 reduced the risk of AOM recurrences. Compared to no-PCV, HRs for overall AOM were 1.00 (95% CI: 0.95–1.06) and 0.89 (95% CI: 0.84–0.95) for PCV7 and PCV10, respectively. Conclusion Our cohort study suggests that PCV postpones the onset and reduces the risk of first AOM without affecting recurrences. The impact of PCV on overall AOM in children up to the age of four years seems therefore largely attributable to the prevention of a first AOM episode. [ABSTRACT FROM AUTHOR]

Objective To provide recommendations for the workup of hearing loss in the pediatric patient. Methods Expert opinion by the members of the International Pediatric Otolaryngology Group. Results Consensus recommendations include initial screening and diagnosis as well as the workup of sensorineural, conductive and mixed hearing loss in children. The consensus statement discusses the role of genetic testing and imaging and provides algorithms to guide the workup of children with hearing loss. Conclusion The workup of children with hearing loss can be guided by the recommendations provided herein. [ABSTRACT FROM AUTHOR]

Objective To provide recommendations for the comprehensive management of young infants who present with signs or symptoms concerning for laryngomalacia. Methods Expert opinion by the members of the International Pediatric Otolaryngology Group (IPOG). Results Consensus recommendations include initial care and triage recommendations for health care providers who commonly evaluate young infants with noisy breathing. The consensus statement also provides comprehensive care recommendations for otolaryngologists who manage young infants with laryngomalacia including: evaluation and treatment considerations for commonly debated issues in laryngomalacia, initial work-up of infants presenting with inspiratory stridor, treatment recommendations based on disease severity, management of the infant with feeding difficulties, post-surgical treatment management recommendations, and suggestions for acid suppression therapy. Conclusion Laryngomalacia care consensus recommendations are aimed at improving patient-centered care in infants with laryngomalacia. [ABSTRACT FROM AUTHOR]

Objectives To develop consensus recommendations for peri-operative tracheotomy care in pediatric patients. Methods Expert opinion by the members of the International Pediatric Otolaryngology Group (IPOG). The mission of the IPOG is to develop expertise-based consensus recommendations for the management of pediatric otolaryngologic disorders with the goal of improving patient care. The consensus recommendations herein represent the first publication by the group. Results Consensus recommendations including pre-operative, intra-operative, and post-operative considerations, as well as sedation and nutrition management are described. These recommendations are based on the collective opinion of the IPOG members and are targeted to (i) otolaryngologists who perform tracheotomies on pediatric patients, (ii) intensivists who are involved in the shared-care of these patients, and (iii) allied health professionals. Conclusion Pediatric peri-operative tracheotomy care consensus recommendations are aimed at improving patient-centered care in this patient population. [ABSTRACT FROM AUTHOR]

Abstract: Objective: (a) To establish whether disease-related, child-related, and physician-related factors are independently associated with specialist referral in young children with recurrent RTI, and (b) to evaluate whether general practitioners (GPs) follow current guidelines regarding these referrals. Methods: Electronic GP records of children under 24month of age, born 2002–2008, were reviewed for RTI episodes using ICPC codes. Child-related factors were extracted from the prospective WHISTLER birth-cohort in which a considerable part of children had been enrolled. To evaluate guideline adherence, referral data were compared to national guideline recommendations. Results: Consultations for 2532 RTI episodes (1041 children) were assessed. Seventy-eight children were referred for recurrent RTI (3.1% of RTI episodes; 7.5% of children). Disease factors were the main determinants of referral: number (OR 1.7 [CI 1.7–1.7]) and severity of previous RTI episodes (OR 2.2 [CI 1.6–2.8]), and duration of RTI episode (OR 1.7 [CI 1.7–1.8]). The non-disease factors daycare attendance (OR 1.3 [CI 1.0–1.7]) and 5–10 years working experience as a GP compared with <5 years (OR 0.37 [CI 0.27–0.50]) were also associated. Fifty-seven percent of referrals for recurrent RTI were made in accordance with national guidelines. Conclusions: Referral of children for recurrent RTI was primarily determined by frequency, severity, and duration of RTIs; the influence of non-disease factors was limited. Just over half of referrals were made in accordance with guidelines. [Copyright &y& Elsevier]

Abstract: Objective: To analyse which strategies are used to promote evidence based interventions in the management of children with upper respiratory tract infections (URTIs) in daily practice. To assess the effectiveness of these interventions, and when more are effective – which works best. And to analyse the costs associated with these interventions. Methods: We systematically searched Pubmed, Embase and CENTRAL bibliographies for studies on the effectiveness of strategies aimed at changing health care professionals’ behavior in the management of children with URTIs. Results: The search yielded 11,788 references, of which 18 studies were eligible, and 10 met the inclusion criteria. Most strategies were aimed at changing antibiotic prescribing behavior in children with acute otitis media. All strategies used (i.e. computer interventions, educational sessions with or without education materials, collaborative development of guidelines and a training video in combination with a risk factor checklist) were effective in changing health care professionals practice regarding children with URTIs. Multifaceted and computer strategies work best. Computer interventions reduced antibiotic prescribing by 4% and 34% and increased guideline compliance by 41%. Educational sessions combined with education materials reduced inappropriate antibiotic prescription by 2% and 17% and increased knowledge of compliance enhancing strategies by 28% and 29%. Collaborative guideline development combined with educational materials reduced inappropriate antibiotic prescription by 24% and 40%. Finally, by a combination of a training video and a risk factor checklist appropriate referrals by the GP to the otolaryngologist increased by 37%. Since the costs associated with the interventions were not explicitly mentioned in the articles, no conclusion on cost-effectiveness can be drawn. Conclusion: Multifaceted and computer strategies appear to be most effective to put evidence into practice in the area of URTIs in children. [Copyright &y& Elsevier]

Abstract: IgG2 antibodies are the main antibody subclass produced after pneumococcal polysaccharide vaccination. For these antibodies to be effective, interaction with FcγIIa receptors on phagocytic cells is necessary. FcγRIIa displays a functional polymorphism with either a histidine (H) or arginine (R) at position 131. Interaction of IgG2 antibodies depends on the H131 allele, whereas this interaction is low to absent with the R131 allele. We tested the clinical efficacy of combined pneumococcal conjugate and pneumococcal polysaccharide vaccination according to FcγIIa-H/R131 genotype in a randomized double blind placebo controlled vaccination trial in children with a history of acute otitis media. We found a decisive role for the FcγIIa-H/R131 polymorphism on the clinical vaccine efficacy of combined pneumococcal conjugate and polysaccharide vaccinations. RR homozygotes showed a significant increase in recurrence of acute otitis media after pneumococcal vaccinations. This cannot be explained by differences in the pneumococcal specific antibody response or differences in nasopharyngeal pneumococcal carriage, but may be explained by less efficient interaction of FcγRIIa with polysaccharide-induced IgG2 anti-pneumococcal antibodies in RR homozygotes. Our data show that the genetic make-up of individuals or populations under study should be considered while evaluating vaccine efficacy trials. [Copyright &y& Elsevier]

Summary: Objectives: Chronic suppurative otitis media (CSOM) remains one of the most common childhood chronic infectious diseases worldwide. Although microbial, immunological, and genetically determined factors, as well as Eustachian tube characteristics, are supposed to be involved in the pathogenesis of CSOM, many aspects of the pathogenesis of CSOM still need to be clarified. Optimal treatment strategy has not been established yet. The objective of this review is to present and evaluate the current state of knowledge of CSOM. Design: Systematic narrative review. Methods: A PubMed search (1966–January 2005) was performed for studies on epidemiology, pathogenesis, clinical management, and complications of CSOM. All included articles were categorized according to level of evidence. Results: Five hundred and fifty papers were identified, of which 79 were found to be relevant for this review. The definition of CSOM was found to vary. CSOM is a multifactorial disease. Regarding management of CSOM, there is no consensus as to what the optimal management strategy should entail. No convincing evidence is available for most medical and surgical therapies. Topical quinolones have proven effective, but need further monitoring regarding adverse effects. Conclusions and recommendations: Important goals in research of CSOM should be achieving consensus about the definition of CSOM and gaining more in-depth knowledge of the pathogenesis of CSOM, especially the role of innate and adaptive immunity. There is also a need for further well-designed studies on the effectiveness of various management strategies for CSOM. [Copyright &y& Elsevier]

Summary: Background:: Growing interest in health-related quality of life (HRQoL) in children with otitis media has brought the need to study the currently available HRQoL instruments with respect to their results and their applicability in clinical practice and research of otitis media. Objective:: To review existing literature on health-related quality of life research in children with otitis media with respect to: (1) the measured impact of otitis media on HRQoL; and (2) the applicability of HRQoL instruments used in research and clinical practice based on their characteristics and contents. Methods:: A search was performed in EMBASE (1988–November 2004) and on NLM Gateway (1966–November 2004) for studies assessing health-related quality of life or functional health status by means of disease-specific or generic questionnaires in children aged 0–18 years with chronic or recurrent otitis media with effusion or acute otitis media. The bibliographies of the selected articles were searched manually. Results:: Only 13 of the 141 retrieved articles retrieved fulfilled the criteria for inclusion. In these studies, physical suffering (pain, high fever, etc.), difficulties with hearing or speech, behavioural problems, or emotional distress were reported to be the most important problems experienced by children with otitis media. Almost all instruments applied in these studies measure functional health status instead of health-related quality of life. Data on validity and reliability of these instruments are incomplete. Conclusions:: Recurrent or chronic otitis media is reported to have a substantial and negative effect on various domains of functional health status and health-related quality of life of children. The OM-6 appears to be the best available instrument to assess functional health status in children with OM in a research setting. However, the lack of true HRQoL instruments as well as incomplete data on their reliability and validity, limit both our current knowledge of HRQoL in OM and the application of current instruments in both research and clinical practice. [Copyright &y& Elsevier]

Background: Knowledge about the effect of recurrent acute otitis media (rAOM) and its treatment on health-related quality of life (HRQoL) and functional health status (FHS) in children with rAOM is limited. The current study aims to assess the effect of pneumococcal vaccination on HRQoL and FHS in children aged 1–7 years with rAOM. Methods: In a double-blind randomized controlled trial, 383 children aged 1–7 years with rAOM were vaccinated with either heptavalent pneumococcal conjugate vaccine followed by pneumococcal polysaccharide vaccine (pneumococcal group, n=190), or hepatitis A or B vaccine (control group, n=193). At baseline, age-adjusted HRQoL and FHS scores of all children were compared to those of reference populations. Subsequently, scores of the pneumococcal and control vaccine group were compared at baseline and at 7, 14, and 26 months follow-up. Data are presented for two instruments, NRS Child and FSQ Generic, assessing HRQoL and FHS, respectively. Results: Scores on the FSQ Generic of children with rAOM were lower than those of healthy children and comparable to those of children with asthma. After vaccination, no differences on the FSQ Generic or NRS Child were found between the pneumococcal and the control group at baseline and during follow-up. Conclusions: Recurrent acute otitis media has a considerable impact on the HRQoL and FHS of children; however, pneumococcal vaccination had no beneficial effect on their HRQoL and FHS. [Copyright &y& Elsevier]

To summarize recently published key articles on the topics of biomedical engineering, biotechnology and new models in relation to otitis media (OM). Electronic databases: PubMed, Ovid Medline, Cochrane Library and Clinical Evidence (BMJ Publishing). Articles on biomedical engineering, biotechnology, material science, mechanical and animal models in OM published between May 2015 and May 2019 were identified and subjected to review. A total of 132 articles were ultimately included. New imaging technologies for the tympanic membrane (TM) and the middle ear cavity are being developed to assess TM thickness, identify biofilms and differentiate types of middle ear effusions. Artificial intelligence (AI) has been applied to train software programs to diagnose OM with a high degree of certainty. Genetically modified mice models for OM have further investigated what predisposes some individuals to OM and consequent hearing loss. New vaccine candidates protecting against major otopathogens are being explored and developed, especially combined vaccines, targeting more than one pathogen. Transcutaneous vaccination against non-typeable Haemophilus influenzae has been successfully tried in a chinchilla model. In terms of treatment, novel technologies for trans-tympanic drug delivery are entering the clinical domain. Various growth factors and grafting materials aimed at improving healing of TM perforations show promising results in animal models. New technologies and AI applications to improve the diagnosis of OM have shown promise in pre-clinical models and are gradually entering the clinical domain. So are novel vaccines and drug delivery approaches that may allow local treatment of OM. IMPLICATIONS FOR PRACTICE : New diagnostic methods, potential vaccine candidates and the novel trans-tympanic drug delivery show promising results, but are not yet adapted to clinical use. [ABSTRACT FROM AUTHOR]