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1.  Pneumococcal conjugate vaccines PREVenar13 and SynflorIX in sequence or alone in high-risk Indigenous infants (PREV-IX_COMBO): protocol of a randomised controlled trial 
BMJ Open  2015;5(1):e007247.
Introduction
Otitis media (OM) starts within weeks of birth in almost all Indigenous infants living in remote areas of the Northern Territory (NT). OM and associated hearing loss persist from infancy throughout childhood and often into adulthood. Educational and social opportunities are greatly compromised. Pneumococcus and non-typeable Haemophilus influenzae (NTHi) are major OM pathogens that densely colonise the nasopharynx and infect the middle ear from very early in life. Our hypothesis is that compared to current single vaccine schedules, a combination of vaccines starting at 1 month of age, may provide earlier, broadened protection.
Methods and analyses
This randomised outcome assessor, blinded controlled trial will recruit 425 infants between 28 and 38 days of age and randomly allocate them (1:1:1) to one of three pneumococcal conjugate vaccine (PCV) schedules: Synflorix at 2, 4, 6 months of age, Prevenar13 at 2, 4 and 6 months of age, or an investigational schedule of Synflorix at 1, 2 and 4 months plus Prevenar13 at 6 months of age. The blinded primary outcomes at 7 months of age are immunogenicity of specific vaccine antigens (geometric mean concentration (GMC) and proportion of participants with above threshold GMC of 0.35 µg/L). Secondary outcomes at all timepoints are additional immunogenicity measures and proportion of participants with nasopharyngeal carriage of vaccine-type pneumococci and NTHi, and any OM, including any tympanic membrane perforation. Parental interviews will provide data on common risk factors for OM.
Ethics and dissemination
Ethical approval has been obtained from NT Department of Health and Menzies HREC (EC00153), Central Australian HREC (EC00155) and West Australian Aboriginal Health Ethics Committee (WAAHEC- 377-12/2011). Final trial results, data analyses, interpretation and conclusions will be presented in appropriate written and oral formats to parents and guardians, participating communities, local, national and international conferences, and published in peer-reviewed open access journals.
Trial registration numbers
ACTRN12610000544077 and NCT01174849.
doi:10.1136/bmjopen-2014-007247
PMCID: PMC4298104  PMID: 25596202
IMMUNOLOGY; MICROBIOLOGY; PUBLIC HEALTH
2.  Increased GABA Contributes to Enhanced Control over Motor Excitability in Tourette Syndrome 
Current Biology  2014;24(19):2343-2347.
Summary
Tourette syndrome (TS) is a developmental neurological disorder characterized by vocal and motor tics [1] and associated with cortical-striatal-thalamic-cortical circuit dysfunction [2, 3], hyperexcitability within cortical motor areas [4], and altered intracortical inhibition [4–7]. TS often follows a developmental time course in which tics become increasingly more controlled during adolescence in many individuals [1], who exhibit enhanced control over their volitional movements [8–11]. Importantly, control over motor outputs appears to be brought about by a reduction in the gain of motor excitability [6, 7, 12, 13]. Here we present a neurochemical basis for a localized gain control mechanism. We used ultra-high-field (7 T) magnetic resonance spectroscopy to investigate in vivo concentrations of γ-aminobutyric acid (GABA) within primary and secondary motor areas of individuals with TS. We demonstrate that GABA concentrations within the supplementary motor area (SMA)—a region strongly associated with the genesis of motor tics in TS [14]—are paradoxically elevated in individuals with TS and inversely related to fMRI blood oxygen level-dependent activation. By contrast, GABA concentrations in control sites do not differ from those of a matched control group. Importantly, we also show that GABA concentrations within the SMA are inversely correlated with cortical excitability in primary motor cortex and are predicted by motor tic severity and white-matter microstructure (FA) within a region of the corpus callosum that projects to the SMA within each hemisphere. Based upon these findings, we propose that extrasynaptic GABA contributes to a form of control, based upon localized tonic inhibition within the SMA, that may lead to the suppression of tics.
Highlights
•We report a 7 T 1H MRS investigation of GABA in Tourette syndrome (TS)•GABA levels within the SMA are significantly elevated in TS•SMA GABA is negatively correlated with SMA BOLD and cortical excitability•SMA GABA is predicted by motor tic severity and corpus callosum FA values
Using magnetic resonance spectroscopy, Draper et al. find that concentrations of the neurotransmitter GABA in motor areas of the brain are associated with symptom severity in individuals with Tourette syndrome.
doi:10.1016/j.cub.2014.08.038
PMCID: PMC4188813  PMID: 25264251
3.  tDCS-induced alterations in GABA concentration within primary motor cortex predict motor learning and motor memory: A 7 T magnetic resonance spectroscopy study 
Neuroimage  2014;99(100):237-243.
Transcranial direct current stimulation (tDCS) is a non-invasive brain stimulation technique that alters cortical excitability in a polarity specific manner and has been shown to influence learning and memory. tDCS may have both on-line and after-effects on learning and memory, and the latter are thought to be based upon tDCS-induced alterations in neurochemistry and synaptic function. We used ultra-high-field (7 T) magnetic resonance spectroscopy (MRS), together with a robotic force adaptation and de-adaptation task, to investigate whether tDCS-induced alterations in GABA and Glutamate within motor cortex predict motor learning and memory. Note that adaptation to a robot-induced force field has long been considered to be a form of model-based learning that is closely associated with the computation and ‘supervised’ learning of internal ‘forward’ models within the cerebellum. Importantly, previous studies have shown that on-line tDCS to the cerebellum, but not to motor cortex, enhances model-based motor learning. Here we demonstrate that anodal tDCS delivered to the hand area of the left primary motor cortex induces a significant reduction in GABA concentration. This effect was specific to GABA, localised to the left motor cortex, and was polarity specific insofar as it was not observed following either cathodal or sham stimulation. Importantly, we show that the magnitude of tDCS-induced alterations in GABA concentration within motor cortex predicts individual differences in both motor learning and motor memory on the robotic force adaptation and de-adaptation task.
Highlights
•Ultra-high-field (7 T) magnetic resonance spectroscopy study of the effects of tDCS.•Anodal tDCS leads to a polarity and site specific reduction in MRS-GABA.•tDCS-induced changes in MRS-GABA in M1 predict model-based motor learning/memory.
doi:10.1016/j.neuroimage.2014.05.070
PMCID: PMC4121086  PMID: 24904994
BOLD, blood-oxygen-level-dependent; fMRI, functional magnetic resonance imaging; GABA, γ-amino-butyric acid; M1, primary motor cortex; MRI, magnetic resonance imaging; MRS, magnetic resonance spectroscopy; NAA, N-acetylaspartate; NAAG, N-acetylaspartylglutamate; tDCS, transcranial direct current stimulation; TMS, transcranial magnetic stimulation; V1, primary visual cortex; Motor learning; Force adaptation; Magnetic resonance spectroscopy; tDCS; GABA
4.  Early Exercise Rehabilitation of Muscle Weakness in Acute Respiratory Failure Patients 
Acute Respiratory Failure patients experience significant muscle weakness which contributes to prolonged hospitalization and functional impairments post-hospital discharge. Based on our previous work, we hypothesize that an exercise intervention initiated early in the intensive care unit aimed at improving skeletal muscle strength could decrease hospital stay and attenuate the deconditioning and skeletal muscle weakness experienced by these patients.
Summary
Early exercise has the potential to decrease hospital length of stay and improve function in Acute Respiratory Failure patients.
doi:10.1097/JES.0b013e3182a4e67c
PMCID: PMC3792856  PMID: 23873130
Length of Stay; Physical Function; Mobility; Intensive Care Unit; Strength Training
5.  Physical and Cognitive Performance of Patients with Acute Lung Injury 1 Year after Initial Trophic versus Full Enteral Feeding. EDEN Trial Follow-up 
Rationale: We hypothesized that providing patients with acute lung injury two different protein/calorie nutritional strategies in the intensive care unit may affect longer-term physical and cognitive performance.
Objectives: To assess physical and cognitive performance 6 and 12 months after acute lung injury, and to evaluate the effect of trophic versus full enteral feeding, provided for the first 6 days of mechanical ventilation, on 6-minute-walk distance, cognitive impairment, and secondary outcomes.
Methods: A prospective, longitudinal ancillary study of the ARDS Network EDEN trial evaluating 174 consecutive survivors from 5 of 12 centers. Blinded assessments of patients’ arm anthropometrics, strength, pulmonary function, 6-minute-walk distance, and cognitive status (executive function, language, memory, verbal reasoning/concept formation, and attention) were performed.
Measurements and Main Results: At 6 and 12 months, respectively, the mean (SD) percent predicted for 6-minute-walk distance was 64% (22%) and 66% (25%) (P = 0.011 for difference between assessments), and 36 and 25% of survivors had cognitive impairment (P = 0.001). Patients performed below predicted values for secondary physical tests with small improvement from 6 to 12 months. There was no significant effect of initial trophic versus full feeding for the first 6 days after randomization on survivors’ percent predicted for 6-minute-walk distance, cognitive impairment status, and all secondary outcomes.
Conclusions: EDEN trial survivors performed below predicted values for physical and cognitive performance at 6 and 12 months, with some improvement over time. Initial trophic versus full enteral feeding for the first 6 days after randomization did not affect physical and cognitive performance.
doi:10.1164/rccm.201304-0651OC
PMCID: PMC3827703  PMID: 23805899
follow-up studies; exercise tests; muscle strength; neuropsychological tests; cognition disorders
6.  Effect of a Family-Centered, Secondhand Smoke Intervention to Reduce Respiratory Illness in Indigenous Infants in Australia and New Zealand: A Randomized Controlled Trial 
Nicotine & Tobacco Research  2014;17(1):48-57.
Introduction:
Secondhand smoke (SHS) is a significant cause of acute respiratory illness (ARI) and 5 times more common in indigenous children. A single-blind randomized trial was undertaken to determine the efficacy of a family centered SHS intervention to reduce ARI in indigenous infants in Australia and New Zealand.
Methods:
Indigenous mothers/infants from homes with ≥1 smoker were randomized to a SHS intervention involving 3 home visits in the first 3 months of the infants’ lives (plus usual care) or usual care. The primary outcome was number of ARI-related visits to a health provider in the first year of life. Secondary outcomes, assessed at 4 and 12 months of age, included ARI hospitalization rates and mothers’ report of infants’ SHS exposure (validated by urinary cotinine/creatinine ratios [CCRs]), smoking restrictions, and smoking cessation.
Results:
Two hundred and ninety-three mother/infant dyads were randomized and followed up. Three quarters of mothers smoked during pregnancy and two thirds were smoking at baseline (as were their partners), with no change for more than 12 months. Reported infant exposure to SHS was low (≥95% had smoke-free homes/cars). Infant CCRs were higher if one or both parents were smokers and if mothers breast fed their infants. There was no effect of the intervention on ARI events [471 intervention vs. 438 usual care (reference); incidence rate ratio = 1.10, 95% confidence intervals (CI) = 0.88–1.37, p = .40].
Conclusions:
Despite reporting smoke-free homes/cars, mothers and their partners continue to smoke in the first year of infants’ lives, exposing them to SHS. Emphasis needs to be placed on supporting parents to stop smoking preconception, during pregnancy, and postnatal.
doi:10.1093/ntr/ntu128
PMCID: PMC4282121  PMID: 25156527
7.  Otitis media in children vaccinated during consecutive 7-valent or 10-valent pneumococcal conjugate vaccination schedules 
BMC Pediatrics  2014;14:200.
Background
In 2001 when 7-valent pneumococcal conjugate vaccine (PCV7) was introduced, almost all (90%) young Australian Indigenous children living in remote communities had some form of otitis media (OM), including 24% with tympanic membrane perforation (TMP). In late 2009, the Northern Territory childhood vaccination schedule replaced PCV7 with 10-valent pneumococcal Haemophilus influenzae protein D conjugate vaccine (PHiD-CV10).
Methods
We conducted regular surveillance of all forms of OM in children in remote Indigenous communities between September 2008 and December 2012. This analysis compares children less than 36 months of age who received a primary course of at least two doses of PCV7 or PHiD-CV10, and not more than one dose of another pneumococcal vaccine.
Results
Mean ages of 444 PCV7- and 451 PHiD-CV10-vaccinated children were 20 and 18 months, respectively. Bilaterally normal middle ears were detected in 7% and 9% respectively. OM with effusion was diagnosed in 41% and 51% (Risk Difference 10% [95% Confidence Interval 3 to 17] p = 0.002), any suppurative OM (acute OM or any TMP) in 51% versus 39% (RD −12% [95% CI −19 to −5] p = 0.0004], and TMP in 17% versus 14% (RD −3% [95% CI −8 to 2] p = 0.2), respectively. Multivariate analyses described a similar independent negative association between suppurative OM and PHiD-CV10 compared to PCV7 (Odds Ratio = 0.6 [95% CI 0.4 to 0.8] p = 0.001). Additional children in the household were a risk factor for OM (OR = 2.4 [95% CI 2 to 4] p = 0.001 for the third additional child), and older age and male gender were associated with less disease. Other measured risk factors were non-significant. Similar clinical results were found for children who had received non-mixed PCV schedules.
Conclusions
Otitis media remains a significant health and social issue for Australian Indigenous children despite PCV vaccination. Around 90% of young children have some form of OM. Children vaccinated in with PHiD-CV10 had less suppurative OM than children vaccinated with PCV7. Ongoing surveillance during the PCV13 era, and trials of early intervention including earlier and mixed vaccine schedules are warranted.
doi:10.1186/1471-2431-14-200
PMCID: PMC4149294  PMID: 25109288
Otitis media; Child; Indigenous; Pneumococcal vaccines; Prevalence; Public health; Surveillance; Risk factors
8.  Chronic suppurative otitis media 
Clinical Evidence  2012;2012:0507.
Introduction
Chronic suppurative otitis media (CSOM) is a common cause of hearing impairment and disability. Occasionally it can lead to fatal intracranial infections and acute mastoiditis, especially in developing countries.
Methods and outcomes
We conducted a systematic review and aimed to answer the following clinical questions: What are the effects of treatments for chronic suppurative otitis media in adults and in children? What are the effects of treatments for cholesteatoma in adults and in children? We searched: Medline, Embase, The Cochrane Library, and other important databases up to May 2010 (Clinical Evidence reviews are updated periodically, please check our website for the most up-to-date version of this review). We included harms alerts from relevant organisations such as the US Food and Drug Administration (FDA) and the UK Medicines and Healthcare products Regulatory Agency (MHRA).
Results
We found 51 systematic reviews, RCTs, or observational studies that met our inclusion criteria. We performed a GRADE evaluation of the quality of evidence for interventions.
Conclusions
In this systematic review, we present information relating to the effectiveness and safety of the following interventions: topical ear cleansing, surgery for cholesteatoma, systemic antibiotics, topical antibiotics, topical antibiotics plus topical corticosteroids, topical antiseptics, topical corticosteroids, tympanoplasty (with or without mastoidectomy).
Key Points
Chronic suppurative otitis media (CSOM) causes recurrent or persistent discharge (otorrhoea) through a perforation in the tympanic membrane, and can lead to thickening of the middle-ear mucosa and mucosal polyps. It usually occurs as a complication of persistent acute otitis media with perforation in childhood. CSOM is a common cause of hearing impairment, disability, and poor scholastic performance. Occasionally it can lead to fatal intracranial infections and acute mastoiditis, especially in developing countries.
In children with CSOM, topical antibiotics may improve symptoms compared with antiseptics. The benefits of ear cleansing are unknown, although this treatment is usually recommended for children with ear discharge.
We don't know whether topical antiseptics, topical or systemic antibiotics, or topical corticosteroids, alone or in combination with antibiotics, improve symptoms in children with CSOM compared with placebo or other treatments.
In adults with CSOM, topical antibiotics either alone or in combination with topical corticosteroids may improve symptoms compared with placebo or either treatment alone, although we found few adequate studies. There is consensus that topical antibiotics should be combined with ear cleansing so that the antibiotics are able to reach the middle ear space. We don't know whether topical antiseptics, topical corticosteroids, or systemic antibiotics are beneficial in reducing symptoms.It is possible that antibiotics against gram-negative bacteria may reduce ear discharge more than other classes of antibiotics or placebo.
We don't know whether tympanoplasty with or without mastoidectomy improves symptoms compared with no surgery or other treatments in adults or children with CSOM.
Cholesteatoma is an abnormal accumulation of squamous epithelium usually found in the middle ear cavity and mastoid process of the temporal bone. Granulation tissue and ear discharge are often associated with secondary infection of the desquamating epithelium.
Cholesteatoma can be either congenital (behind an intact tympanic membrane) or acquired. If untreated, it may progressively enlarge and erode the surrounding structures. We don't know the beneficial effects of surgery, whether surgery can be delayed, or which surgical techniques are associated with the best outcomes in children or adults with cholesteatoma.
PMCID: PMC3412293  PMID: 23870746
9.  Absence of an Important Vaccine and Diagnostic Target in Carriage- and Disease-Related Nontypeable Haemophilus influenzae 
Nontypeable Haemophilus influenzae (NTHi)-associated disease is a major health problem globally. Whole-genome sequence analysis identified the absence of hpd genes encoding Haemophilus protein D in 3 of 16 phylogenetically distinct NTHi isolates. This novel finding is of potential clinical significance, as protein D and hpd represent important NTHi vaccine antigen and diagnostic targets, respectively.
doi:10.1128/CVI.00632-13
PMCID: PMC3910944  PMID: 24285816
10.  Does function fit structure? A ground truth for non-invasive neuroimaging 
Neuroimage  2014;94(100):89-95.
There are now a number of non-invasive methods to image human brain function in-vivo. However, the accuracy of these images remains unknown and can currently only be estimated through the use of invasive recordings to generate a functional ground truth. Neuronal activity follows grey matter structure and accurate estimates of neuronal activity will have stronger support from accurate generative models of anatomy. Here we introduce a general framework that, for the first time, enables the spatial distortion of a functional brain image to be estimated empirically. We use a spherical harmonic decomposition to modulate each cortical hemisphere from its original form towards progressively simpler structures, ending in an ellipsoid. Functional estimates that are not supported by the simpler cortical structures have less inherent spatial distortion. This method allows us to compare directly between magnetoencephalography (MEG) source reconstructions based upon different assumption sets without recourse to functional ground truth.
Highlights
•We use spherical harmonics to create generative cortical surface models.•Accurate functional estimates will be best supported by veridical cortical models.•The method provides spatial confidence bounds for non-invasive functional images.
doi:10.1016/j.neuroimage.2014.02.033
PMCID: PMC4073649  PMID: 24636880
11.  Moving from Outsider to Insider: Peer Status and Partnerships between Electricity Utilities and Residential Consumers 
PLoS ONE  2014;9(6):e101189.
An electricity demand reduction project based on comprehensive residential consumer engagement was established within an Australian community in 2008. By 2011, both the peak demand and grid supplied electricity consumption had decreased to below pre-intervention levels. This case study research explored the relationship developed between the utility, community and individual consumer from the residential customer perspective through qualitative research of 22 residential households. It is proposed that an energy utility can be highly successful at peak demand reduction by becoming a community member and a peer to residential consumers and developing the necessary trust, access, influence and partnership required to create the responsive environment to change. A peer-community approach could provide policymakers with a pathway for implementing pro-environmental behaviour for low carbon communities, as well as peak demand reduction, thereby addressing government emission targets while limiting the cost of living increases from infrastructure expenditure.
doi:10.1371/journal.pone.0101189
PMCID: PMC4076285  PMID: 24979234
12.  Mobile phones support adherence and retention of indigenous participants in a randomised controlled trial: strategies and lessons learnt 
BMC Public Health  2014;14:622.
Background
Ensuring adherence to treatment and retention is important in clinical trials, particularly in remote areas and minority groups. We describe a novel approach to improve adherence, retention and clinical review rates of Indigenous children.
Methods
This descriptive study was nested within a placebo-controlled, randomised trial (RCT) on weekly azithromycin (or placebo) for 3-weeks. Indigenous children aged ≤24-months hospitalised with acute bronchiolitis were recruited from two tertiary hospitals in northern Australia (Darwin and Townsville). Using mobile phones embedded within a culturally-sensitive approach and framework, we report our strategies used and results obtained. Our main outcome measure was rates of adherence to medications, retention in the RCT and self-presentation (with child) to clinic for a clinical review on day-21.
Results
Of 301 eligible children, 76 (21%) families declined participation and 39 (13%) did not have access to a mobile phone. 186 Indigenous children were randomised and received dose one under supervision in hospital. Subsequently, 182 (99%) children received dose two (day-7), 169 (93%) dose three (day-14) and 180 (97%) attended their clinical review (day-21). A median of 2 calls (IQR 1–3) were needed to verify adherence. Importantly, over 97% of children remained in the RCT until their clinical endpoint at day-21.
Conclusions
In our setting, the use of mobile phones within an Indigenous-appropriate framework has been an effective strategy to support a clinical trial involving Australian Indigenous children in urban and remote Australia. Further research is required to explore other applications of this approach, including the impact on clinical outcomes.
Trial registration
ACTRN12608000150347 (RCT component).
doi:10.1186/1471-2458-14-622
PMCID: PMC4067523  PMID: 24943961
Mobile phones; SMS; Adherence; Randomised controlled trial; ALRTI; Bronchiolitis; Indigenous
13.  The Posterior Cricoarytenoid Muscle Is Spared from MuRF1-Mediated Muscle Atrophy in Mice with Acute Lung Injury 
PLoS ONE  2014;9(1):e87587.
Background
Skeletal muscle wasting in acute lung injury (ALI) patients increases the morbidity and mortality associated with this critical illness. The contribution of laryngeal muscle wasting to these outcomes is unknown, though voice impairments and aspiration are common in intensive care unit (ICU) survivors. We evaluated the intrinsic laryngeal abductor (PCA, posterior cricoarytenoid), adductor (CT, cricothyroid) and limb (EDL, extensor digitorum longus) muscles in a mouse model of ALI.
Methods
Escherichia coli lipopolysaccharides were instilled into the lungs of adult male C57Bl6J mice (ALI mice). Limb and intrinsic laryngeal muscles were analyzed for fiber size, type, protein expression and myosin heavy chain (MyHC) composition by SDS-PAGE and mass spectroscopy.
Results
Marked muscle atrophy occurred in the CT and EDL muscles, while the PCA was spared. The E3 ubiquitin ligase muscle ring finger-1 protein (MuRF1), a known mediator of limb muscle atrophy in this model, was upregulated in the CT and EDL, but not in the PCA. Genetic inhibition of MuRF1 protected the CT and EDL from ALI-induced muscle atrophy. MyHC-Extraocular (MyHC-EO) comprised 27% of the total MyHC in the PCA, distributed as hybrid fibers throughout 72% of PCA muscle fibers.
Conclusion
The vocal cord abductor (PCA) contains a large proportion of fibers expressing MyHC-EO and is spared from muscle atrophy in ALI mice. The lack of MuRF1 expression in the PCA suggests a previously unrecognized mechanism whereby this muscle is spared from atrophy. Atrophy of the vocal cord adductor (CT) may contribute to the impaired voice and increased aspiration observed in ICU survivors. Further evaluation of the sparing of muscles involved in systemic wasting diseases may lead to potential therapeutic targets for these illnesses.
doi:10.1371/journal.pone.0087587
PMCID: PMC3909200  PMID: 24498144
14.  Pulmonary MRI contrast using Surface Quadrupolar Relaxation (SQUARE) of hyperpolarized 83Kr☆ 
Magnetic Resonance Imaging  2014;32(1):48-53.
Hyperpolarized 83Kr has previously been demonstrated to enable MRI contrast that is sensitive to the chemical composition of the surface in a porous model system. Methodological advances have lead to a substantial increase in the 83Kr hyperpolarization and the resulting signal intensity. Using the improved methodology for spin exchange optical pumping of isotopically enriched 83Kr, internal anatomical details of ex vivo rodent lung were resolved with hyperpolarized 83Kr MRI after krypton inhalation. Different 83Kr relaxation times were found between the main bronchi and the parenchymal regions in ex vivo rat lungs. The T1 weighted hyperpolarized 83Kr MRI provided a first demonstration of surface quadrupolar relaxation (SQUARE) pulmonary MRI contrast.
doi:10.1016/j.mri.2013.08.007
PMCID: PMC3898897  PMID: 24144493
83Kr; Krypton-83; Kr-83 hyperpolarization; Hyperpolarized; Noble gas MRI; Spin polarization; Cryogenic separation; Spin-exchange optical pumping; Nuclear electric quadrupole moment; Quadrupolar relaxation; Surface sensitive contrast; Pre-clinical MRI; Pulmonary MRI; Lung surfactant
15.  Dominance of Haemophilus influenzae in ear discharge from Indigenous Australian children with acute otitis media with tympanic membrane perforation 
Background
Indigenous Australian children living in remote communities experience high rates of acute otitis media with tympanic membrane perforation (AOMwiP). Otitis media in this population is associated with dense nasopharyngeal colonization of three primary otopathogens; Haemophilus influenzae, Streptococcus pneumoniae and Moraxella catarrhalis. Little is known about the relative abundance of these pathogens during infection. The objective of this study was to estimate the abundance and concordance of otopathogens in ear discharge and paired nasopharyngeal swabs from children with AOMwiP (discharge of not more than 6 weeks’ duration and perforation size <2%).
Methods
Culture and quantitative PCR (qPCR) estimation of H. influenzae, S. pneumoniae, M. catarrhalis and total bacterial load were performed on paired nasopharyngeal and ear discharge swabs from 55 Indigenous children with AOMwiP aged 3.5 – 45.6 months and resident in remote communities.
Results
By culture, H. influenzae, S. pneumoniae, and M. catarrhalis were detected in 80%, 84% and 91% of nasopharyngeal swabs, and 49%, 33% and 4% of ear discharge swabs, respectively. Using qPCR, H. influenzae, S. pneumoniae, and M. catarrhalis were detected in 82%, 82%, and 93% of nasopharyngeal swabs, and 89%, 41% and 18% of ear discharge swabs, respectively. Relative abundance of H. influenzae in ear discharge swabs was 0-68% of the total bacterial load (median 2.8%); whereas S. pneumoniae and M. catarrhalis relative abundances were consistently <2% of the total bacterial load. S. pneumoniae and M. catarrhalis abundances were significantly lower in ear discharge compared with nasopharyngeal swabs (p = 0.001, p < 0.001); no significant difference was observed in H. influenzae mean abundance at the two sites.
Conclusions
H. influenzae was the dominant otopathogen detected in ear discharge swabs collected from children with AOMwiP. High prevalence and abundance of S. pneumoniae and M. catarrhalis in the nasopharynx did not predict ear discharge prevalence and abundances of these pathogens. PCR was substantially more sensitive than culture for ear discharge, and a necessary adjunct to standard microbiology. Quantitative methods are required to understand species abundance in polymicrobial infections and may be needed to measure accurately the microbiological impact of interventions and to provide a better understanding of clinical failure in these children.
doi:10.1186/1472-6815-13-12
PMCID: PMC3852835  PMID: 24099576
Otitis media; Haemophilus influenzae; Moraxella catarrhalis; Streptococcus pneumoniae; Bacterial load; Abundance; Relative abundance; qPCR
16.  A Single Dose of Azithromycin Does Not Improve Clinical Outcomes of Children Hospitalised with Bronchiolitis: A Randomised, Placebo-Controlled Trial 
PLoS ONE  2013;8(9):e74316.
Objective
Bronchiolitis, one of the most common reasons for hospitalisation in young children, is particularly problematic in Indigenous children. Macrolides may be beneficial in settings where children have high rates of nasopharyngeal bacterial carriage and frequent prolonged illness. The aim of our double-blind placebo-controlled randomised trial was to determine if a large single dose of azithromycin (compared to placebo) reduced length of stay (LOS), duration of oxygen (O2) and respiratory readmissions within 6 months of children hospitalised with bronchiolitis. We also determined the effect of azithromycin on nasopharyngeal microbiology.
Methods
Children aged ≤18 months were randomised to receive a single large dose (30 mg/kg) of either azithromycin or placebo within 24 hrs of hospitalisation. Nasopharyngeal swabs were collected at baseline and 48hrs later. Primary endpoints (LOS, O2) were monitored every 12 hrs. Hospitalised respiratory readmissions 6-months post discharge was collected.
Results
97 children were randomised (n = 50 azithromycin, n = 47 placebo). Median LOS was similar in both groups; azithromycin = 54 hours, placebo = 58 hours (difference between groups of 4 hours 95%CI -8, 13, p = 0.6). O2 requirement was not significantly different between groups; Azithromycin = 35 hrs; placebo = 42 hrs (difference 7 hours, 95%CI -9, 13, p = 0.7). Number of children re-hospitalised was similar 10 per group (OR = 0.9, 95%CI 0.3, 2, p = 0.8). At least one virus was detected in 74% of children. The azithromycin group had reduced nasopharyngeal bacterial carriage (p = 0.01) but no difference in viral detection at 48 hours.
Conclusion
Although a single dose of azithromycin reduces carriage of bacteria, it is unlikely to be beneficial in reducing LOS, duration of O2 requirement or readmissions in children hospitalised with bronchiolitis. It remains uncertain if an earlier and/or longer duration of azithromycin improves clinical and microbiological outcomes for children. The trial was registered with the Australian and New Zealand Clinical Trials Register. Clinical trials number: ACTRN12608000150347. http://www.anzctr.org.au/TrialSearch.aspx.
doi:10.1371/journal.pone.0074316
PMCID: PMC3783434  PMID: 24086334
17.  Does a 10-valent pneumococcal-Haemophilus influenzae protein D conjugate vaccine prevent respiratory exacerbations in children with recurrent protracted bacterial bronchitis, chronic suppurative lung disease and bronchiectasis: protocol for a randomised controlled trial 
Trials  2013;14:282.
Background
Recurrent protracted bacterial bronchitis (PBB), chronic suppurative lung disease (CSLD) and bronchiectasis are characterised by a chronic wet cough and are important causes of childhood respiratory morbidity globally. Haemophilus influenzae and Streptococcus pneumoniae are the most commonly associated pathogens. As respiratory exacerbations impair quality of life and may be associated with disease progression, we will determine if the novel 10-valent pneumococcal-Haemophilus influenzae protein D conjugate vaccine (PHiD-CV) reduces exacerbations in these children.
Methods
A multi-centre, parallel group, double-blind, randomised controlled trial in tertiary paediatric centres from three Australian cities is planned. Two hundred six children aged 18 months to 14 years with recurrent PBB, CSLD or bronchiectasis will be randomised to receive either two doses of PHiD-CV or control meningococcal (ACYW135) conjugate vaccine 2 months apart and followed for 12 months after the second vaccine dose. Randomisation will be stratified by site, age (<6 years and ≥6 years) and aetiology (recurrent PBB or CSLD/bronchiectasis). Clinical histories, respiratory status (including spirometry in children aged ≥6 years), nasopharyngeal and saliva swabs, and serum will be collected at baseline and at 2, 3, 8 and 14 months post-enrolment. Local and systemic reactions will be recorded on daily diaries for 7 and 30 days, respectively, following each vaccine dose and serious adverse events monitored throughout the trial. Fortnightly, parental contact will help record respiratory exacerbations. The primary outcome is the incidence of respiratory exacerbations in the 12 months following the second vaccine dose. Secondary outcomes include: nasopharyngeal carriage of H. influenzae and S. pneumoniae vaccine and vaccine- related serotypes; systemic and mucosal immune responses to H. influenzae proteins and S. pneumoniae vaccine and vaccine-related serotypes; impact upon lung function in children aged ≥6 years; and vaccine safety.
Discussion
As H. influenzae is the most common bacterial pathogen associated with these chronic respiratory diseases in children, a novel pneumococcal conjugate vaccine that also impacts upon H. influenzae and helps prevent respiratory exacerbations would assist clinical management with potential short- and long-term health benefits. Our study will be the first to assess vaccine efficacy targeting H. influenzae in children with recurrent PBB, CSLD and bronchiectasis.
Trial registration
Australia and New Zealand Clinical Trials Registry (ANZCTR) number: ACTRN12612000034831.
doi:10.1186/1745-6215-14-282
PMCID: PMC3846146  PMID: 24010917
Bronchiectasis; Child; Chronic suppurative lung disease; Non-typeable Haemophilus influenzae; Pneumococcal conjugate vaccines; Protracted bacterial bronchitis; Randomised controlled trial; Respiratory exacerbations; Streptococcus pneumoniae
18.  L-arginine and Vitamin D Adjunctive Therapies in Pulmonary Tuberculosis: A Randomised, Double-Blind, Placebo-Controlled Trial 
PLoS ONE  2013;8(8):e70032.
Background
Vitamin D (vitD) and L-arginine have important antimycobacterial effects in humans. Adjunctive therapy with these agents has the potential to improve outcomes in active tuberculosis (TB).
Methods
In a 4-arm randomised, double-blind, placebo-controlled factorial trial in adults with smear-positive pulmonary tuberculosis (PTB) in Timika, Indonesia, we tested the effect of oral adjunctive vitD 50,000 IU 4-weekly or matching placebo, and L-arginine 6.0 g daily or matching placebo, for 8 weeks, on proportions of participants with negative 4-week sputum culture, and on an 8-week clinical score (weight, FEV1, cough, sputum, haemoptysis). All participants with available endpoints were included in analyses according to the study arm to which they were originally assigned. Adults with new smear-positive PTB were eligible. The trial was registered at ClinicalTrials.gov NCT00677339.
Results
200 participants were enrolled, less than the intended sample size: 50 received L-arginine + active vitD, 49 received L-arginine + placebo vit D, 51 received placebo L-arginine + active vitD and 50 received placebo L-arginine + placebo vitD. According to the factorial model, 99 people received arginine, 101 placebo arginine, 101 vitamin D, 99 placebo vitamin D. Results for the primary endpoints were available in 155 (4-week culture) and 167 (clinical score) participants. Sputum culture conversion was achieved by week 4 in 48/76 (63%) participants in the active L-arginine versus 48/79 (61%) in placebo L-arginine arms (risk difference −3%, 95% CI −19 to 13%), and in 44/75 (59%) in the active vitD versus 52/80 (65%) in the placebo vitD arms (risk difference 7%, 95% CI −9 to 22%). The mean clinical outcome score also did not differ between study arms. There were no effects of the interventions on adverse event rates including hypercalcaemia, or other secondary outcomes.
Conclusion
Neither vitD nor L-arginine supplementation, at the doses administered and with the power attained, affected TB outcomes.
Registry
ClinicalTrials.gov. Registry number: NCT00677339
doi:10.1371/journal.pone.0070032
PMCID: PMC3743888  PMID: 23967066
19.  Longitudinal Nasopharyngeal Carriage and Antibiotic Resistance of Respiratory Bacteria in Indigenous Australian and Alaska Native Children with Bronchiectasis 
PLoS ONE  2013;8(8):e70478.
Background
Indigenous children in Australia and Alaska have very high rates of chronic suppurative lung disease (CSLD)/bronchiectasis. Antibiotics, including frequent or long-term azithromycin in Australia and short-term beta-lactam therapy in both countries, are often prescribed to treat these patients. In the Bronchiectasis Observational Study we examined over several years the nasopharyngeal carriage and antibiotic resistance of respiratory bacteria in these two PCV7-vaccinated populations.
Methods
Indigenous children aged 0.5–8.9 years with CSLD/bronchiectasis from remote Australia (n = 79) and Alaska (n = 41) were enrolled in a prospective cohort study during 2004–8. At scheduled study visits until 2010 antibiotic use in the preceding 2-weeks was recorded and nasopharyngeal swabs collected for culture and antimicrobial susceptibility testing. Analysis of respiratory bacterial carriage and antibiotic resistance was by baseline and final swabs, and total swabs by year.
Results
Streptococcus pneumoniae carriage changed little over time. In contrast, carriage of Haemophilus influenzae declined and Staphylococcus aureus increased (from 0% in 2005–6 to 23% in 2010 in Alaskan children); these changes were associated with increasing age. Moraxella catarrhalis carriage declined significantly in Australian, but not Alaskan, children (from 64% in 2004–6 to 11% in 2010). While beta-lactam antibiotic use was similar in the two cohorts, Australian children received more azithromycin. Macrolide resistance was significantly higher in Australian compared to Alaskan children, while H. influenzae beta-lactam resistance was higher in Alaskan children. Azithromycin use coincided significantly with reduced carriage of S. pneumoniae, H. influenzae and M. catarrhalis, but increased carriage of S. aureus and macrolide-resistant strains of S. pneumoniae and S. aureus (proportion of carriers and all swabs), in a ‘cumulative dose-response’ relationship.
Conclusions
Over time, similar (possibly age-related) changes in nasopharyngeal bacterial carriage were observed in Australian and Alaskan children with CSLD/bronchiectasis. However, there were also significant frequency-dependent differences in carriage and antibiotic resistance that coincided with azithromycin use.
doi:10.1371/journal.pone.0070478
PMCID: PMC3734249  PMID: 23940582
20.  Investigating the metabolic changes due to visual stimulation using functional proton magnetic resonance spectroscopy at 7 T 
Proton magnetic resonance spectroscopy (1H-MRS) has been used to demonstrate metabolic changes in the visual cortex on visual stimulation. Small (2% to 11%) but significant stimulation induced increases in lactate, glutamate, and glutathione were observed along with decreases in aspartate, glutamine, and glycine, using 1H-MRS at 7 T during single and repeated visual stimulation. In addition, decreases in glucose and increases in γ-aminobutyric acid (GABA) were seen but did not reach significance. Changes in glutamate and aspartate are indicative of increased activity of the malate–aspartate shuttle, which taken together with the opposite changes in glucose and lactate, reflect the expected increase in brain energy metabolism. These results are in agreement with those of Mangia et al. In addition, increases in glutamate and GABA coupled with the decrease in glutamine can be interpreted in terms of increased activity of the neurotransmitter cycles. An entirely new observation is the increase of glutathione during prolonged visual stimuli. The similarity of its time course to that of glutamate suggests that it may be a response to the increased release of glutamate or to the increased production of reactive oxygen species. Together, these observations constitute the most detailed analysis to date of functional changes in human brain metabolites.
doi:10.1038/jcbfm.2012.33
PMCID: PMC3421086  PMID: 22434070
antioxidants; energy metabolism; lactate; MR spectroscopy; neurotransmitters
21.  Secretory phospholipase A2 mediated depletion of phosphatidylglycerol in early Acute Respiratory Distress Syndrome 
Background
Secretory phospholipases A2 (sPLA2) hydrolyze phospholipids in cell membranes and extracellular structures such as pulmonary surfactant. This study tests the hypothesis that sPLA2 are elevated in human lungs during acute respiratory distress syndrome (ARDS) and that sPLA2 levels are associated with surfactant injury by hydrolysis of surfactant phospholipids.
Methods
Bronchoalveolar lavage (BAL) fluid was obtained from 18 patients with early ARDS (<72 hours) and compared to samples from 10 healthy volunteers. Secreted phospholipase A2 were measured (enzyme activity and enzyme immunoassay) in conjunction with ARDS subjects’ surfactant abnormalities including surfactant phospholipid composition, large and small aggregates distribution, and surface tension function.
Results
BAL sPLA2 enzyme activity was markedly elevated in ARDS samples relative to healthy subjects when measured by ex vivo hydrolysis of both phosphatidylglycerol (PG) and phosphatidylcholine (PC). Enzyme immunoassay identified increased PLA2G2A protein in the ARDS BAL fluid, which was strongly correlated with the sPLA2 enzyme activity against PG. Of particular interest, we demonstrated an average depletion of 69% of the PG in the ARDS sample large aggregates relative to the normal controls. Furthermore, the sPLA2 enzyme activity against PG and PC ex vivo correlated with the BAL recovery of in vivo PG and PC, respectively, and also correlated with the altered distribution of the large and small surfactant aggregates.
Conclusions
These results support the hypothesis that sPLA2-mediated hydrolysis of surfactant phospholipid, especially PG by PLA2G2A, contributes to surfactant injury during early ARDS.
doi:10.1097/MAJ.0b013e318239c96c
PMCID: PMC3307942  PMID: 22173044
Acute Lung Injury; Adult Respiratory Distress Syndrome; Secretory Phospholipase A2; Pulmonary Surfactant; Phosphatidylglycerol
22.  Bronchiectasis exacerbation study on azithromycin and amoxycillin-clavulanate for respiratory exacerbations in children (BEST-2): study protocol for a randomized controlled trial 
Trials  2013;14:53.
Background
Bronchiectasis unrelated to cystic fibrosis (CF) is being increasingly recognized in children and adults globally, both in resource-poor and in affluent countries. However, high-quality evidence to inform management is scarce. Oral amoxycillin-clavulanate is often the first antibiotic chosen for non-severe respiratory exacerbations, because of the antibiotic-susceptibility patterns detected in the respiratory pathogens commonly associated with bronchiectasis. Azithromycin has a prolonged half-life, and with its unique anti-bacterial, immunomodulatory, and anti-inflammatory properties, presents an attractive alternative. Our proposed study will test the hypothesis that oral azithromycin is non-inferior (within a 20% margin) to amoxycillin-clavulanate at achieving resolution of non-severe respiratory exacerbations by day 21 of treatment in children with non-CF bronchiectasis.
Methods
This will be a multicenter, randomized, double-blind, double-dummy, placebo-controlled, parallel group trial involving six Australian and New Zealand centers. In total, 170 eligible children will be stratified by site and bronchiectasis etiology, and randomized (allocation concealed) to receive: 1) azithromycin (5 mg/kg daily) with placebo amoxycillin-clavulanate or 2) amoxycillin-clavulanate (22.5 mg/kg twice daily) with placebo azithromycin for 21 days as treatment for non-severe respiratory exacerbations. Clinical data and a parent-proxy cough-specific quality of life (PC-QOL) score will be obtained at baseline, at the start and resolution of exacerbations, and on day 21. In most children, blood and deep-nasal swabs will also be collected at the same time points. The primary outcome is the proportion of children whose exacerbations have resolved at day 21. The main secondary outcome is the PC-QOL score. Other outcomes are: time to next exacerbation; requirement for hospitalization; duration of exacerbation, and spirometry data. Descriptive viral and bacteriological data from nasal samples and blood inflammatory markers will be reported where available.
Discussion
Currently, there are no published randomized controlled trials (RCT) to underpin effective, evidence-based management of acute respiratory exacerbations in children with non-CF bronchiectasis. To help address this information gap, we are conducting two RCTs. The first (bronchiectasis exacerbation study; BEST-1) evaluates the efficacy of azithromycin and amoxycillin-clavulanate compared with placebo, and the second RCT (BEST-2), described here, is designed to determine if azithromycin is non-inferior to amoxycillin-clavulanate in achieving symptom resolution by day 21 of treatment in children with acute respiratory exacerbations.
Trial registration
Australia and New Zealand Clinical Trials Register (ANZCTR) number http://ACTRN12612000010897. http://www.anzctr.org.au/trial_view.aspx?id=347879
doi:10.1186/1745-6215-14-53
PMCID: PMC3586343  PMID: 23421781
Amoxycillin-clavulanate; Azithromycin; Bronchiectasis; Placebo; Pulmonary exacerbations; Randomized controlled trial
23.  Food subsidy programs and the health and nutritional status of disadvantaged families in high income countries: a systematic review 
BMC Public Health  2012;12:1099.
Background
Less healthy diets are common in high income countries, although proportionally higher in those of low socio-economic status. Food subsidy programs are one strategy to promote healthy nutrition and to reduce socio-economic inequalities in health. This review summarises the evidence for the health and nutritional impacts of food subsidy programs among disadvantaged families from high income countries.
Methods
Relevant studies reporting dietary intake or health outcomes were identified through systematic searching of electronic databases. Cochrane Public Health Group guidelines informed study selection and interpretation. A narrative synthesis was undertaken due to the limited number of studies and heterogeneity of study design and outcomes.
Results
Fourteen studies were included, with most reporting on the Special Supplemental Nutrition Program for Women, Infants and Children in the USA. Food subsidy program participants, mostly pregnant or postnatal women, were shown to have 10–20% increased intake of targeted foods or nutrients. Evidence for the effectiveness of these programs for men or children was lacking. The main health outcome observed was a small but clinically relevant increase in mean birthweight (23–29g) in the two higher quality WIC studies.
Conclusions
Limited high quality evidence of the impacts of food subsidy programs on the health and nutrition of adults and children in high income countries was identified. The improved intake of targeted nutrients and foods, such as fruit and vegetables, could potentially reduce the rate of non-communicable diseases in adults, if the changes in diet are sustained. Associated improvements in perinatal outcomes were limited and most evident in women who smoked during pregnancy. Thus, food subsidy programs for pregnant women and children should aim to focus on improving nutritional status in the longer term. Further prospective studies and economic analyses are needed to confirm the health benefits and justify the investment in food subsidy programs.
doi:10.1186/1471-2458-12-1099
PMCID: PMC3559269  PMID: 23256601
Food subsidy; Disadvantaged families; Health outcomes; Dietary intake; Nutritional status
24.  Quantitative PCR of ear discharge from Indigenous Australian children with acute otitis media with perforation supports a role for Alloiococcus otitidis as a secondary pathogen 
Background
Otitis media is endemic in remote Indigenous communities of Australia’s Northern Territory. Alloiococcus otitidis is an outer ear commensal and putative middle ear pathogen that has not previously been described in acute otitis media (AOM) in this population. The aims of this study were to determine the presence, antibiotic susceptibility and bacterial load of A. otitidis in nasopharyngeal and ear discharge swabs collected from Indigenous Australian children with AOM with perforation.
Methods
Paired nasopharyngeal and ear discharge swabs from 27 children with AOM with perforation were tested by A. otitidis quantitative PCR (qPCR). Positive swabs were cultured for 21 days. Total and respiratory pathogen bacterial loads in A. otitidis-positive swabs were determined by qPCR.
Results
A. otitidis was detected by qPCR in 11 ear discharge swabs from 10 of 27 (37%) children, but was not detected in paired nasopharyngeal swabs. A. otitidis was cultured from 5 of 11 qPCR-positive swabs from four children. All A. otitidis isolates had minimum inhibitory concentrations consistent with macrolide resistance. All A. otitidis qPCR-positive swabs were culture-positive for other bacteria. A. otitidis bacterial load ranged from 2.2 × 104-1.1 × 108 cells/swab (median 1.8 × 105 cells/swab). The relative abundance of A. otitidis ranged from 0.01% to 34% of the total bacterial load (median 0.7%). In 6 of 11 qPCR-positive swabs the A. otitidis relative abundance was <1% and in 5 of 11 it was between 2% and 34%. The A. otitidis bacterial load and relative abundance measures were comparable to that of Haemophilus influenzae.
Conclusions
A. otitidis can be a dominant species in the bacterial communities present in the ear discharge of Indigenous children with AOM with perforation. The absence of A. otitidis in nasopharyngeal swabs suggests the ear canal as the likely primary reservoir. The significance of A. otitidis at low relative abundance is unclear; however, at higher relative abundance it may be contributing to the associated inflammation. Further studies to better understand A. otitidis as a secondary otopathogen are warranted, particularly in populations at high-risk of progression to chronic suppurative otitis media and where macrolide therapies are being used.
doi:10.1186/1472-6815-12-11
PMCID: PMC3546424  PMID: 23033913
Alloiococcus otitidis; Otitis media; Acute otitis media with perforation; Indigenous Australian children; Bacterial load
25.  Antibiotics for bronchiectasis exacerbations in children: rationale and study protocol for a randomised placebo-controlled trial 
Trials  2012;13:156.
Background
Despite bronchiectasis being increasingly recognised as an important cause of chronic respiratory morbidity in both indigenous and non-indigenous settings globally, high quality evidence to inform management is scarce. It is assumed that antibiotics are efficacious for all bronchiectasis exacerbations, but not all practitioners agree. Inadequately treated exacerbations may risk lung function deterioration. Our study tests the hypothesis that both oral azithromycin and amoxicillin-clavulanic acid are superior to placebo at improving resolution rates of respiratory exacerbations by day 14 in children with bronchiectasis unrelated to cystic fibrosis.
Methods
We are conducting a bronchiectasis exacerbation study (BEST), which is a multicentre, randomised, double-blind, double-dummy, placebo-controlled, parallel group trial, in five centres (Brisbane, Perth, Darwin, Melbourne, Auckland). In the component of BEST presented here, 189 children fulfilling inclusion criteria are randomised (allocation-concealed) to receive amoxicillin-clavulanic acid (22.5 mg/kg twice daily) with placebo-azithromycin; azithromycin (5 mg/kg daily) with placebo-amoxicillin-clavulanic acid; or placebo-azithromycin with placebo-amoxicillin-clavulanic acid for 14 days. Clinical data and a paediatric cough-specific quality of life score are obtained at baseline, at the start and resolution of exacerbations, and at day 14. In most children, blood and deep nasal swabs are also collected at the same time points. The primary outcome is the proportion of children whose exacerbations have resolved at day 14. The main secondary outcome is the paediatric cough-specific quality of life score. Other outcomes are time to next exacerbation; requirement for hospitalisation; duration of exacerbation; and spirometry data. Descriptive viral and bacteriological data from nasal samples and blood markers will also be reported.
Discussion
Effective, evidence-based management of exacerbations in people with bronchiectasis is clinically important. Yet, there are few randomised controlled trials (RCTs) in the neglected area of non-cystic fibrosis bronchiectasis. Indeed, no published RCTs addressing the treatment of bronchiectasis exacerbations in children exist. Our multicentre, double-blind RCT is designed to determine if azithromycin and amoxicillin-clavulanic acid, compared with placebo, improve symptom resolution on day 14 in children with acute respiratory exacerbations. Our planned assessment of the predictors of antibiotic response, the role of antibiotic-resistant respiratory pathogens, and whether early treatment with antibiotics affects duration and time to the next exacerbation, are also all novel.
Trial registration
Australia and New Zealand Clinical Trials Register (ANZCTR) number ACTRN12612000011886.
doi:10.1186/1745-6215-13-156
PMCID: PMC3488323  PMID: 22937736
Amoxicillin-clavulanic acid; Azithromycin; Bronchiectasis; Placebo; Pulmonary exacerbations; Randomised controlled trial

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