Does otitis media in early childhood affect later behavioural development? Results from the Western Australian Pregnancy Cohort (Raine) Study.

OBJECTIVES: To examine the relationship between early life episodes of otitis media and later behavioural development with adjustment for confounders. DESIGN: Longitudinal cohort study. SETTING: The Western Australian Pregnancy Cohort (Raine) Study recruited 2900 pregnant women from King Edward Memorial Hospital (KEMH) in Perth, Western Australia, between 1989 and 1991. PARTICIPANTS: Data from the children born were collected at both the Year 3 and Year 5 follow-up. At Year 3, n = 611 were diagnosed with recurrent otitis media through parent-report and clinical examination. At Year 5, n = 299 were considered exposed to otitis media based upon tympanometry results. MAIN OUTCOME MEASURES: Performance in the Child Behaviour Checklist (CBCL), a questionnaire completed by the primary caregiver at Year 10. RESULTS: Significant associations were found between recurrent otitis media at Year 3 and internalising behaviours (P = .011), and the somatic (P = .011), withdrawn (P = .014), attention (P = .003) and thought problems domains (P = .021), and the total CBCL score (P = .010). A significant association was also found between exposure to otitis media at Year 5 and externalising behaviours (P = .026). CONCLUSIONS: A modest association was seen between recurrent otitis media at Year 3 and exposure to otitis media at Year 5 and a number of behaviour domains at Year 10.

Associations between cardiovascular disease and its risk factors with hearing loss-A cross-sectional analysis.

OBJECTIVES: To investigate the relationship between hearing loss and cardiovascular disease risk factors. DESIGN: Cross-sectional study. METHODS: Participants were recruited between May 2010 and December 2015 and answered a health and risk factor questionnaire. Physical and biochemical assessments were performed. SETTING: A community-based population. PARTICIPANTS: A total of 5107 participants born within the years 1946-1964 enrolled in the Busselton Healthy Ageing Study. MAIN OUTCOME MEASURES: Hearing was assessed behaviourally through the best ear pure-tone average (500, 1000, 2000, 4000 Hz), low-frequency average (250, 500, 1000 Hz) and high-frequency average (4000, 8000 Hz). Self-reported hearing loss, tinnitus and hyperacusis were assessed via questionnaire. Cardiovascular risk factors were assessed via a patient-completed questionnaire and objective measurements including blood pressure, body mass index, waist circumference, lipid profile and glycated haemoglobin. RESULTS: Of the participants, 54% were female, with the mean age of 58 years (range 45-69 years). Age, sex and family history of hearing loss were consistently strong determinants of hearing loss outcomes. After adjusting for these, obesity, current smoking, peripheral arterial disease and history of cardiovascular disease were significantly associated with pure-tone, low-frequency and high-frequency hearing loss. In addition, high blood pressure, triglyceride and glycated haemoglobin were significantly associated with low-frequency hearing loss. There was a graded association between hearing loss and Framingham Risk Score for cardiovascular risk (P<0.001). CONCLUSIONS: Established cardiovascular disease and individual and combined cardiovascular disease risk factors were found to be associated with hearing loss. Future research should prospectively investigate whether targeting cardiovascular disease can prevent hearing loss.

A population-based study of the association between dysglycaemia and hearing loss in middle age.

AIMS: To investigate the independent associations between hearing loss and dysglycaemia in a sample of middle-aged adults, including separate analysis of those aged < 60 years. METHODS: The first 2023 participants in the cross-sectional Busselton Health Ageing Survey were assessed for hearing loss ≥ 26 dB (better ear) for four-frequency average (4FA) of pure-tone thresholds at 500, 1000, 2000 and 4000 Hz, and high-frequency average (HFA) of pure-tone thresholds at 4000 and 8000 Hz. RESULTS: Valid data from 1864 participants in the Busselton Health Ageing Survey [92.1%; mean ± sd age 56.2 ± 5.5 years, 46.0% men, 120 (7.0%) with diabetes, 274 (14.7%) with prediabetes] were analysed, of whom 103 (5.5%) had four-frequency average hearing loss and 561 (30.1%) had high-frequency average hearing loss. In multivariable analyses, glycaemic status was not independently associated with four-frequency or high-frequency average hearing loss. In the 1286 participants aged < 60 years, there was no relationship between dysglycaemia and high-frequency average hearing loss, but the prevalence of four-frequency average hearing loss increased from 2.3% (95% CI 1.5-3.4) in participants with normoglycaemia to 5.7% (95% CI 3.0-10.6) in those with prediabetes and 10.2% (4.2-21.5) in those with diabetes (trend P = 0.003). In multivariable analysis with normoglycaemia as reference, the odds ratios for four-frequency average hearing loss were 2.84 (95% CI 1.29-6.27) for prediabetes and 5.93 (95% CI 1.67-21.05) for diabetes (P ≤ 0.01) in the < 60 year age group. CONCLUSIONS: There was progressively increasing mid-range hearing loss with worsening glucose tolerance in younger individuals, suggesting dysglycaemia-associated early-onset presbycusis.

Protective benefit of predominant breastfeeding against otitis media may be limited to early childhood: results from a prospective birth cohort study.

OBJECTIVES: To examine the long-term effects of predominant breastfeeding on incidence of otitis media. DESIGN: Prospective birth cohort study. SETTING: The West Australian Pregnancy Cohort (Raine) Study recruited 2900 mothers through antenatal clinics at the major tertiary obstetric hospital in Perth, Western Australia, between 1989 and 1992. PARTICIPANTS: In total, 2237 children participated in a 6-year cohort follow-up, and a subset of 1344 were given ear and hearing assessments. MAIN OUTCOME MEASURES: OM diagnosis at 6 years of age (diagnosed by low-compliance tympanograms, 0-0.1 mmho). This was compared to OM diagnosed at the 3-year cohort follow-up using parent-report measures. Main exposure measures were duration of predominant breastfeeding (defined as the age other milk was introduced) and duration of partial (any) breastfeeding (defined as the age breastfeeding was stopped). RESULTS: There was a significant, independent association between predominant breastfeeding (OR = 1.33 [1.04, 1.69]; P = 0.02) and OM, and breastfeeding duration (OR = 1.35 [1.08, 1.68]; P = 0.01) with OM at 3 years of age. However, at 6 years of age, this relationship was no longer statistically significant (predominant breastfeeding OR = 0.78 [0.48, 1.06]; P = 0.09; duration of breastfeeding, OR = 1.34 [0.81, 2.23]; P = 0.25). CONCLUSIONS: Our findings are in line with a number of epidemiological studies which show a positive association between breastfeeding and OM in early childhood. However, the long-term follow-up of these children revealed that by 6 years of age, there was no significant influence of breastfeeding on presence of OM. These results suggest that the protective effect of predominant breastfeeding for at least 6 months does not extend to school-age children, where other social and environmental factors may be stronger predictors of OM.

The relationship between hearing impairment and cognitive function: a meta-analysis in adults.

OBJECTIVE: Hearing loss affects over 1.23 billion people globally. It has been proposed that hearing impairment negatively impacts on cognition. Some studies have demonstrated a faster rate of decline in cognition, and increased risk of incident all-cause dementia. This finding is not ubiquitous. This study used meta-analysis to examine the evidence-base regarding the relationship between hearing and cognition. DESIGN: A systematic review of the literature and meta-analyses of study findings were conducted. Published and grey literature was reviewed. Papers were included if they studied the relationship between hearing and cognition in adults with and without hearing impairment. MAIN OUTCOME MEASURES: Meta-analyses examined evidence for and against seven questions. Is cognition poorer in individuals with normal hearing compared to (i) untreated or (ii) treated hearing impairment, is cognition associated with degree of hearing impairment in (iii) untreated and/or (iv) treated hearing, is cognition (v) different in untreated compared to treated hearing impairment, (vii) does cognition improve after intervention, and (vii) how is hearing impairment differentially associated with cognitive ability across six domains of cognition? RESULTS: The 33 included studies contributed 40 samples, with a total of 602 participants with untreated hearing impairment, 672 participants with treated hearing impairment, 176 healthy controls, and 4260 individuals with a range of hearing impairment with/without treatment. The results demonstrated that cognition is significantly poorer in (i) individuals with untreated hearing and remains poorer in (ii) treated hearing impairment compared to normal hearers. The degree of cognitive deficit is significantly associated with the degree of hearing impairment in both (iii) untreated and (iv) treated hearing impairment. Furthermore, (v) hearing intervention significantly improves cognition. Finally, (vii) hearing impairment impacted on all domains of cognition. CONCLUSIONS: This meta-analysis suggests that hearing impairment is associated with cognitive problems. However, due to diversity within studies, small sample sizes, the failure to control for premorbid and other health factors, this conclusion may be premature.

Safety, tolerability, and effect of a single aural dose of Dornase alfa at the time of ventilation tube surgery for otitis media: A Phase 1b double randomized control trial.

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.

The evolution of the Indian Ocean parrots (Psittaciformes): extinction, adaptive radiation and eustacy.

Parrots are among the most recognisable and widely distributed of all bird groups occupying major parts of the tropics. The evolution of the genera that are found in and around the Indian Ocean region is particularly interesting as they show a high degree of heterogeneity in distribution and levels of speciation. Here we present a molecular phylogenetic analysis of Indian Ocean parrots, identifying the possible geological and geographical factors that influenced their evolution. We hypothesise that the Indian Ocean islands acted as stepping stones in the radiation of the Old-World parrots, and that sea-level changes may have been an important determinant of current distributions and differences in speciation. A multi-locus phylogeny showing the evolutionary relationships among genera highlights the interesting position of the monotypic Psittrichas, which shares a common ancestor with the geographically distant Coracopsis. An extensive species-level molecular phylogeny indicates a complex pattern of radiation including evidence for colonisation of Africa, Asia and the Indian Ocean islands from Australasia via multiple routes, and of island populations 'seeding' continents. Moreover, comparison of estimated divergence dates and sea-level changes points to the latter as a factor in parrot speciation. This is the first study to include the extinct parrot taxa, Mascarinus mascarinus and Psittacula wardi which, respectively, appear closely related to Coracopsis nigra and Psittacula eupatria.

Indirect population dynamic benefits of altered life-history trade-offs in response to egg harvesting.

Variations in demographic rates due to differential resource allocation between individuals are important considerations in the development of accurate population dynamic models. Systematic harvesting can alter age structure and/or reduce population density, conferring indirect positive benefits on the source population as a result of a consequent redistribution of resources between the remaining individuals. Independently of effects mediated through changes in density and competition, demographic rates can also be influenced by within-individual competition for resources. Harvesting dependent life stages can reduce an individual's current reproductive costs, allowing increased investment in its future fecundity and survival. Although such changes in demographic rates are well known, there has been little exploration of the potential impact on population dynamics. We use empirical data collected from a successfully reintroduced population of the Mauritius kestrel Falco punctatus to explore the population consequences of manipulating reproductive effort through harvesting. Consequent increases in an individual's future fecundity and survival allow source populations to withstand longer and more intensive harvesting regimes without being exposed to an increase in extinction risk, increasing maximum sustainable yields. These effects may also buffer populations against the impacts of stochastic events, but directional shifts in environmental conditions that increase reproductive costs may have detrimental population-level effects.

Herbivory in rocks and the weathering of a desert.

Two species of snail, Euchondrus albulus and Euchondrus desertorum, eat endolithic lichens growing under the surface of limestone rocks in the Negev Desert, Israel. This unusual type of herbivory has the unexpected and major impact of weathering this rocky desert at a rate of 0.7 to 1.1 metric tons per hectare per year. The biotic weathering contributes to the process of soil formation at a rate that is similar to wind-borne dust deposition. These findings demonstrate that herbivores can have a significant regulatory impact on ecosystem processes, even in cases where the total amount of primary production consumed is small.

Chain reactions linking acorns to gypsy moth outbreaks and Lyme disease risk.

In eastern U.S. oak forests, defoliation by gypsy moths and the risk of Lyme disease are determined by interactions among acorns, white-footed mice, moths, deer, and ticks. Experimental removal of mice, which eat moth pupae, demonstrated that moth outbreaks are caused by reductions in mouse density that occur when there are no acorns. Experimental acorn addition increased mouse density. Acorn addition also increased densities of black-legged ticks, evidently by attracting deer, which are key tick hosts. Mice are primarily responsible for infecting ticks with the Lyme disease agent. The results have important implications for predicting and managing forest health and human health.

Assessment of tumour response with (18)F-fluorodeoxyglucose positron emission tomography using three-dimensional measures compared to SUVmax--a phantom study.

SUVmax is currently the most common semi-quantitative method of response assessment on FDG PET. By defining the tumour volume of interest (VOI), a measure of total glycolytic volume (TGV) may be obtained. We aimed to comprehensively examine, in a phantom setting, the accuracy of TGV in reflecting actual lesion activity and to compare TGV with SUVmax for response assessment. The algorithms for VOI generation from which TGV was derived included fixed threshold techniques at 50% of maximum (MAX50), 70% of maximum (MAX70), an adaptive threshold of 50% of (maximum + background)/2 (BM50) and a semi-automated iterative region-growing algorithm, GRAB. Comparison with both actual lesion activity and response scenarios was performed. SUVmax correlated poorly with actual lesion activity (r = 0.651) and change in lesion activity (r = 0.605). In a response matrix scenario SUVmax performed poorly when all scenarios were considered, but performed well when only clinically likely scenarios were included. The TGV derived using MAX50 and MAX70 algorithms performed poorly in evaluation of lesion change. The TGV derived from BM50 and GRAB algorithms however performed extremely well in correlation with actual lesion activity (r = 0.993 and r = 0.982, respectively), change in lesion activity (r = 0.972 and r = 0.963, respectively) and in the response scenario matrix. TGV(GRAB) demonstrated narrow confidence bands when modelled with actual lesion activity. Measures of TGV generated by iterative algorithms such as GRAB show potential for increased sensitivity of metabolic response monitoring compared to SUVmax, which may have important implications for improved patient care.

Trichomonas gallinae in Mauritian columbids: implications for an endangered endemic.

Although well known as a widespread parasitic disease of columbids and birds of prey, there have been few studies of trichomonosis in populations of wild birds. In Mauritius, trichomonosis has been highlighted as a major threat to an endangered endemic, the Pink Pigeon (Neosoenas [Columba] mayeri). In this study, we examined the role that populations of other columbids in Mauritius might be playing as infectious reservoirs of the causal flagellate protozoan, Trichomonas gallinae. We screened 296 wild individuals of three columbid species (Madagascan Turtle Dove [Streptopelia picturata], Spotted Dove [Streptopelia chinensis], and Zebra Dove [Geopelia striata]) between September 2002 and April 2004. Prevalence varied significantly among species (ranging from 19% in S. chinensis to 59% in G. striata) and between S. picturata sampled from upland and coastal sites; S. picturata from upland sites (>500 m) were significantly less likely to be infected with T. gallinae than those from lowland sites (<50 m; 62% and 27% prevalence, respectively). There was no significant difference in the prevalence of T. gallinae at sites where Pink Pigeons were also present compared to those sampled at sites without Pink Pigeons. We show that T. gallinae infection prevalence is higher at sites and times of warmer temperatures and lower rainfall.

Pattern of expression and characteristics of a cysteine proteinase cDNA from germinating seeds of pea (Pisum sativum L.).

A thiol proteinase cDNA clone with homology to barley aleurain and rice oryzain gamma and mammalian cathepsin H was isolated from a germinating pea (Pisum saticum L.) cotyledon library. The corresponding mRNA was present in late developing seeds, decreased in dry seeds and rose considerably as germination proceeded.

The effect of interleukin-8 and granulocyte macrophage colony stimulating factor on the response of neutrophils to formyl methionyl leucyl phenylalanine.

Neutrophils isolated from patients with chronic bronchitis and emphysema have been shown to have enhanced responses to formyl peptides when assessed in vitro compared to age, sex matched controls. It is currently unclear whether the observed differences are due to a 'priming' effect by a second agent in vivo, or whether this is a primary difference in the neutrophils. We have studied the effects of interleukin-8, which is thought to be one of the major pro-inflammatory cytokines in chronic lung disease and granulocyte macrophage colony stimulating factor (GMCSF), in order to assess their effects on neutrophil chemotaxis and connective tissue degradation. In addition, we have assessed the effect of preincubation of these agents with neutrophils for 30 min followed by stimulation with F-Met-Leu-Phe (FMLP) to investigate any possible 'priming' effect that may be relevant to our clinical data. We report suppression of neutrophil chemotaxis to FMLP following incubation of the neutrophils with both IL-8 and GMCSF. However, we have observed an additive effect of IL-8 and FMLP for neutrophil degranulation leading to fibronectin degradation. The results suggest that IL-8 does not 'prime' neutrophils for subsequent FMLP stimulation as observed in vivo. Although the results for GMCSF were similar for the chemotactic response, the agent also had a synergistic effect on connective tissue degradation. However, it is concluded that neither agent could explain the enhanced neutrophil responses seen in our patients.

The effect of the Z mutation on the ability of alpha 1-antitrypsin to prevent neutrophil mediated tissue damage.

Recent studies have shown that alpha 1-antitrypsin (alpha 1-AT) from Z antitrypsin deficiency subjects has a slightly lower association rate constant with neutrophil elastase (NE) than alpha 1-AT from normal subjects, although it is unknown whether this is of clinical importance. We have purified alpha 1-AT from a normal (M alpha 1-AT) and from a deficient (Z alpha 1-AT) subject and have confirmed that the association rate constants for NE are different (5.28; S.E. 0.06.10(7) M-1 s-1 and 1.2; S.E. 0.2.10(7) M-1 s-1, respectively). We have assessed the ability of both of these proteins to inhibit neutrophil mediated fibronectin (FN) degradation in vitro. Both proteins inhibited FN degradation in a dose dependant manner although Z alpha 1-AT was less effective than M alpha 1-AT at equivalent concentrations of active inhibitor (P < 0.05). Inhibition by M alpha 1-AT was 28.5% S.E. 3.9 at 0.01 microM; 35.5% S.E. 7.3 at 0.1 microM and 37% S.E. 8.4 at 0.5 microM, whereas inhibition by Z alpha 1-AT was 9.25% S.E. 3.9; 19.25% S.E. 7.7 and 21.2% S.E. 9.7, respectively. When the time course of inhibition of FN degradation was studied the difference (although less at 1.0 microM) became greater over the 3 h period of the assay. These results suggest that Z alpha 1-AT is less able than the M phenotype to inhibit connective tissue degradation by neutrophils at equivalent concentrations. This is probably due to the lower association rate constant although the reduced stability of the Z molecule may play a role. The differences, together with the reduced plasma concentration, may accentuate the susceptibility of deficient subjects to the development of emphysema.

Phenotypic changes in neutrophils related to anti-inflammatory therapy.

Previous work from the group has shown that non-steroidal anti-inflammatory agents given to volunteers and patients inhibit PMN function possibly by affecting the developing neutrophil during the differentiation process. In this study indomethacin treatment in vivo reduced neutrophil chemotaxis and proteolytic degradation of fibronectin, with a maximal effect after 14 days. Stimulated neutrophil adherence to fibronectin was also reduced but this was not due to quantitative changes in beta(2) integrin expression or function. L-Selectin expression on resting and stimulated neutrophils was increased after 14 days and there was a small decrease in plasma levels of soluble L-selectin. These effects, however, could not be reproduced by treatment of neutrophils with indomethacin in vitro, suggesting they are due to effects on differentiating/maturing PMNs. In an attempt to interpret these changes, studies were performed with dexamethasone, which is known to alter neutrophil function and kinetics. Dexamethasone treatment reduced chemotaxis and increased superoxide generation after 1 day and was associated with increased expression of activated beta(2) integrins and reduced L-selectin expression on resting neutrophils. This suggests the appearance of mainly 'activated' cells as a result of demargination and indicates that the effects of indomethacin are distinctive and not related to changes in compartmentalisation.

Unrelated donor bone marrow transplantation for children and adolescents with Philadelphia-positive acute lymphoblastic leukemia.

PURPOSE: Few patients with Philadelphia-positive acute lymphoblastic leukemia (Ph-positive ALL) have been cured by chemotherapy alone. Registry figures show that 38% of patients who have a matched-sibling bone marrow transplant (BMT) are disease-free 2 years after transplant, but the majority of patients lack a sibling donor. Most modern ALL protocols recommend unrelated donor (UD) BMT for patients with Ph-positive ALL in first complete remission (CR1), but the outcome of this is unknown. PATIENTS AND METHODS: We report the results of 15 children and adolescents who had a T-cell depleted UD-BMT for Ph-positive ALL. Thirteen of 15 had been previously treated on United Kingdom ALL protocols. Nine were in CR1 and six had more advanced disease. Eleven donor recipient pairs were matched at HLA-A, HLA-B, HLA-DR, and HLA-DQ, and four were mismatched at one or two HLA loci. RESULTS: The incidence of greater than grade I acute and chronic graft-versus-host disease (GVHD) was low (13% and 8%, respectively). Six patients have relapsed and seven patients survive at a median of 21 months post-BMT; six of seven are disease free. All seven survivors are in full-time education or work. The 2-year overall and disease-free survivals are 44% +/- 13% and 37% +/- 13% (+/- SE). None of four patients who had mismatched donors survived, but seven of 11 matched recipients survive (P < .05). CONCLUSION: UD-BMT can produce prolonged disease-free survival in young patients with Ph-positive ALL who otherwise would have an extremely poor outlook.

Conservation of small-airway function by tacrolimus/cyclosporine conversion in the management of bronchiolitis obliterans following lung transplantation.

We studied serial lung function in 11 patients with bronchiolitis obliterans syndrome who were treated with tacrolimus conversion following lung or heart-lung transplantation. Our results show that tacrolimus conversion slows the decline of lung function in bronchiolitis obliterans syndrome. The attenuation continues for at least 1 year following conversion.