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Inhibition of Notch signalling with a gamma-secretase inhibitor (GSI) induces mammalian hair cell regeneration and partial hearing restoration. In this proofof-concept Phase I/IIa multiple-ascending dose open-label trial (ISRCTN59733689), adults with mild-moderate sensorineural hearing loss received 3 intratympanic injections of GSI LY3056480, in 1 ear over 2 weeks. Phase I primary outcome was safety and tolerability. Phase lla primary outcome was change from baseline to 12 weeks in average pure-tone air conduction threshold across 2,4,8 kHz. Secondary outcomes included this outcome at 6 weeks and change from baseline to 6 and 12 weeks in pure-tone thresholds at individual frequencies, speech reception thresholds (SRTs), Distortion Product Otoacoustic Emissions (DPOAE) amplitudes, Signal to Noise Ratios (SNRs) and distribution of categories normal, present-abnormal, absent and Hearing Handicap Inventory for Adults/Elderly (HHIA/E). In Phase I (N = 15, 1 site) there were no severe nor serious adverse events. In Phase IIa (N = 44, 3 sites) the average pure-tone threshold across 2,4,8 kHz did not change from baseline to 6 and 12 weeks (estimated change −0.87 dB; 95% CI −2.37 to 0.63; P = 0.252 and −0.46 dB; 95% CI −1.94 to 1.03; P = 0.545, respectively), nor did the means of secondary measures. DPOAE amplitudes, SNRs and distribution of categories did not change from baseline to 6 and 12 weeks, nor did SRTs and HHIA/E scores. Intratympanic delivery of LY3056480 is safe and well-tolerated; the trial’s primary endpoint was not met. [ABSTRACT FROM AUTHOR]

Purpose: Children with Down's syndrome (DS) are prone to respiratory tract infections (RTIs) due to anatomical variation, immune system immaturity and comorbidities. However, evidence on RTI-related healthcare utilisation, especially in primary care, is incomplete. In this retrospective cohort study, we use routinely collected primary and secondary care data to quantify RTI-related healthcare utilisation in children with DS and matched controls without DS. Methods: Retrospective cohort study of 992 children with DS and 4874 matched controls attending English general practices and hospitals as identified in Clinical disease research using LInked Bespoke studies and Electronic health Records (CALIBER) from 1997 to 2010. Poisson regression was used to calculate consultation, hospitalisation and prescription rates, and rate ratios. Wald test was used to compare risk of admission following consultation. The Wilcoxon rank–sum test was used to compare length of stay by RTI type and time-to-hospitalisation. Results: RTI-related healthcare utilisation is significantly higher in children with DS than in controls in terms of GP consultations (adjusted RR 1.73; 95% CI 1.62–1.84), hospitalisations (adjusted RR 5.70; 95% CI 4.82–6.73), and antibiotic prescribing (adjusted RR 2.34; 95% CI 2.19–2.49). Two percent of children with DS presenting for an RTI-related GP consultation were subsequently admitted for an RTI-related hospitalisation, compared to 0.7% in controls. Conclusions: Children with DS have higher rates of GP consultations, hospitalisations and antibiotic prescribing compared to controls. This poses a significant burden on families. Further research is recommended to characterise healthcare behaviours and clinical decision-making, to optimise care for this at risk group. [ABSTRACT FROM AUTHOR]

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Copyright of Huisarts En Wetenschap is the property of Springer Nature and its content may not be copied or emailed to multiple sites or posted to a listserv without the copyright holder's express written permission. However, users may print, download, or email articles for individual use. This abstract may be abridged. No warranty is given about the accuracy of the copy. Users should refer to the original published version of the material for the full abstract. (Copyright applies to all Abstracts.)

We have previously found that non-typeable Haemophilus influenzae (NTHi) collected from the middle ear of children with otitis media (OM) exhibit increased levels of complement resistance compared to NTHi collected from the nasopharynx. However, it is unknown whether bacteria develop complement resistance in the middle ear, or whether resistance is present when residing in the nasopharynx. The objective of this study was to investigate whether the levels of complement resistance of isolates collected from the middle ear were similar to those of isolates from the nasopharynx with an identical MLST type. We included 62 children with recurrent acute OM, chronic OM with effusion or acute tympanostomy tube otorrhea. NTHi was simultaneously isolated from the nasopharynx and middle ear fluid. MLST, resistance to complement-mediated killing, IgG binding, IgM binding and phosphorylcholine expression was determined. In 41 children, NTHi isolated from the middle ear and nasopharynx showed to have an identical MLST type. Isolates collected from the middle ear showed a highly similar level of complement resistance and IgM binding with isolates collected from the nasopharynx, whereas this was not the case for IgG binding and phosphorylcholine incorporation into lipooligosaccharide. Resistance to complement-mediated killing and IgM binding of NTHi isolates with an identical MLST type collected from the middle ear and nasopharynx of children with OM was highly similar. [ABSTRACT FROM AUTHOR]

While pneumococcal conjugate vaccines have shown to be highly effective against invasive pneumococcal disease, their potential effectiveness against acute otitis media (AOM) might become a major economic driver for implementing these vaccines in national immunization programmes. However, the relationship between the costs and benefits of available vaccines remains a controversial topic. Our objective is to systematically review the literature on the cost effectiveness of pneumococcal conjugate vaccination against AOM in children. We searched PubMed, Cochrane and the Centre for Reviews and Dissemination databases (Database of Abstracts of Reviews of Effects [DARE], NHS Economic Evaluation Database [NHS EED] and Health Technology Assessment database [HTA]) from inception until 18 February 2010. We used the following keywords with their synonyms: 'otitis media', 'children', 'cost-effectiveness', 'costs' and 'vaccine'. Costs per AOM episode averted were calculated based on the information in this literature. A total of 21 studies evaluating the cost effectiveness of pneumococcal conjugate vaccines were included. The quality of the included studies was moderate to good. The cost per AOM episode averted varied from €168 to €4214, and assumed incidence rates varied from 20 952 to 118 000 per 100 000 children aged 0-10 years. Assumptions regarding direct and indirect costs varied between studies. The assumed vaccine efficacy of the 7-valent pneumococcal CRM197-conjugate vaccine was mainly adopted from two trials, which reported 6-8% efficacy. However, some studies assumed additional effects such as herd immunity or only took into account AOM episodes caused by serotypes included in the vaccine, which resulted in efficacy rates varying from 12% to 57%. Costs per AOM episode averted were inversely related to the assumed incidence rates of AOM and to the estimated costs per AOM episode. The median costs per AOM episode averted tended to be lower in industry-sponsored studies. Key assumptions regarding the incidence and costs of AOM episodes have major implications for the estimated cost effectiveness of pneumococcal conjugate vaccination against AOM. Uniform methods for estimating direct and indirect costs of AOM should be agreed upon to reliably compare the cost effectiveness of available and future pneumococcal vaccines against AOM. [ABSTRACT FROM AUTHOR]

Copyright of Huisarts En Wetenschap is the property of Springer Nature and its content may not be copied or emailed to multiple sites or posted to a listserv without the copyright holder's express written permission. However, users may print, download, or email articles for individual use. This abstract may be abridged. No warranty is given about the accuracy of the copy. Users should refer to the original published version of the material for the full abstract. (Copyright applies to all Abstracts.)

In this study the reliability and validity of generic and disease-specific questionnaires has been assessed focusing on responsiveness. This is part of a study on the effects of recurrent acute otitis media (rAOM) on functional health status (FHS) and health-related quality of life (HRQoL) in 383 children with rAOM participating in a randomized clinical trial. The following generic questionnaires were studied: 1. RAND general health rating index, 2. Functional Status Questionnaire (FSQ Generic and FSQ Specific), 3. TNO-AZL Infant Quality of Life (TAIQOL), and the following disease-specific questionnaires: 1. Otitis Media-6 (OM-6), 2. Numerical rating scales (NRS) for child and caregiver (NRS Child and NRS Caregiver), and 3. a new Family Functioning Questionnaire (FFQ). Reliability was good to excellent (Cronbach’s α range 0.80–0.90, intraclass correlation coefficient range 0.76–0.93). Moderate to strong correlations were found between the questionnaires as well as between questionnaires and relevant clinical indicators ( r = 0.29–0.49), demonstrating construct validity. Discriminant validity for children with few versus frequent episodes of acute otitis media per year was good for most questionnaires ( P < 0.004) but poor for the otitis media-related subscales of the TAIQOL ( P = 0.10–0.97) and both NRS ( P = 0.22 and 0.48). Except for the TAIQOL subscales, change scores were significant ( P < 0.003) for generic and disease-specific questionnaires. Effect sizes were somewhat higher for disease-specific compared to generic questionnaires (0.55–0.95 versus 0.32–0.60) except for the TAIQOL subscales, which showed very poor sensitivity to change. Anchor-based methods resulted in a somewhat larger range of estimates of MCID than distribution-based methods. Combining distribution-based and anchor-based methods resulted in similar ranges for the minimally clinical important differences for generic and disease-specific questionnaires: 2–15 points on a 0–100 scale. Apart from the generic TAIQOL subscales, both generic and disease-specific questionnaires used in this study showed good psychometric qualities and responsiveness for use in clinical studies on children with rAOM. [ABSTRACT FROM AUTHOR]

Pneumococcal vaccines may be effective in preventing or decreasing the burden of disease related to otitis media. In study reported here, we investigated the effectiveness of pneumococcal vaccination on otitis media with effusion (OME) in children ( n = 383 children aged 1–7 years) with a history of recurrent otitis media within the framework of a randomized double blind placebo controlled trial. Children were randomized to be immunized with either a 7-valent pneumococcal conjugate vaccine followed by the 23-valent pneumococcal polysaccharide vaccine, or by hepatitis A or B vaccines. The proportion of children diagnosed with OME at the scheduled follow-up visits – 7, 14, 20 and 26 months after randomization – was then calculated. OME was diagnosed according to an algorithm combining tympanometry and otoscopy. The percentage of children diagnosed with OME was similar in the pneumococcal vaccination group and control group at both baseline and the follow-up visits at 7, 14, 20 and 26 months – 52.9 versus 52.7, 44.9 versus 44.2, 34.9 versus 31.5, 40.8 versus 32.2 and 31.4 versus 26.1, respectively (corresponding to p-values of 0.96, 0.89, 0.51, 0.13 and 0.36, respectively). We conclude that the combined pneumococcal conjugate and the polysaccharide vaccination have no beneficial effect on OME in children aged 1 year or older with a history of recurrent otitis media. Therefore, these vaccinations are not indicated in the prevention of OME in these children. [ABSTRACT FROM AUTHOR]

Copyright of Huisarts En Wetenschap is the property of Springer Nature and its content may not be copied or emailed to multiple sites or posted to a listserv without the copyright holder's express written permission. However, users may print, download, or email articles for individual use. This abstract may be abridged. No warranty is given about the accuracy of the copy. Users should refer to the original published version of the material for the full abstract. (Copyright applies to all Abstracts.)

The original version of this article unfortunately contained an omission. [ABSTRACT FROM AUTHOR]