Trajectories of otitis media and association with health determinants among Indigenous children in Australia: the Longitudinal Study of Indigenous Children.

OBJECTIVES: Indigenous children in Australia experience high burden of persistent otitis media (OM) from very early age. The aim was to identify distinct trajectories of OM in children up to age 10-12 years and examine the association with socio-economic determinants. STUDY DESIGN: A multistage clustered national panel survey. METHODS: The study analysed the birth cohort of the Longitudinal Study of Indigenous Children from 2008 to 2018, comprising 11 study waves. Group-based trajectory modelling was used to identify different trajectories of OM outcome. Multinomial logistic regression was applied to examine the relationship between trajectories and individual, household and community-level socio-economic determinants. RESULTS: This analysis included 894 children with at least three responses on OM over the 11 waves, and the baseline mean age was 15.8 months. Three different trajectories of OM were identified: non-severe OM prone, early/persistent severe OM and late-onset severe OM. Overall, 11.4% of the children had early/persistent severe OM from birth to 7.5 to nine years, while late-onset severe OM consisted of 9.8% of the children who had first OM from age 3.5 to five years. Children in communities with middle and the highest socio-economic outcomes have lower relative risk of early/persistent severe OM (adjusted relative risk ratio = 0.39, 95% confidence interval = 0.22-0.70 and adjusted relative risk ratio = 0.22, 95% confidence interval = 0.09-0.52, respectively) compared to children in communities with lowest socio-economic outcomes. CONCLUSION: Efforts to close the gap in the quality of life of Indigenous children must prioritise strategies that prevent severe ear disease (runny ears and perforation), including improved healthcare access, reduced household crowding, and better education, and more employment opportunities.

Genetic Diversity and Protective Efficacy of the RTS,S/AS01 Malaria Vaccine.

BACKGROUND: The RTS,S/AS01 vaccine targets the circumsporozoite protein of Plasmodium falciparum and has partial protective efficacy against clinical and severe malaria disease in infants and children. We investigated whether the vaccine efficacy was specific to certain parasite genotypes at the circumsporozoite protein locus. METHODS: We used polymerase chain reaction-based next-generation sequencing of DNA extracted from samples from 4985 participants to survey circumsporozoite protein polymorphisms. We evaluated the effect that polymorphic positions and haplotypic regions within the circumsporozoite protein had on vaccine efficacy against first episodes of clinical malaria within 1 year after vaccination. RESULTS: In the per-protocol group of 4577 RTS,S/AS01-vaccinated participants and 2335 control-vaccinated participants who were 5 to 17 months of age, the 1-year cumulative vaccine efficacy was 50.3% (95% confidence interval [CI], 34.6 to 62.3) against clinical malaria in which parasites matched the vaccine in the entire circumsporozoite protein C-terminal (139 infections), as compared with 33.4% (95% CI, 29.3 to 37.2) against mismatched malaria (1951 infections) (P=0.04 for differential vaccine efficacy). The vaccine efficacy based on the hazard ratio was 62.7% (95% CI, 51.6 to 71.3) against matched infections versus 54.2% (95% CI, 49.9 to 58.1) against mismatched infections (P=0.06). In the group of infants 6 to 12 weeks of age, there was no evidence of differential allele-specific vaccine efficacy. CONCLUSIONS: These results suggest that among children 5 to 17 months of age, the RTS,S vaccine has greater activity against malaria parasites with the matched circumsporozoite protein allele than against mismatched malaria. The overall vaccine efficacy in this age category will depend on the proportion of matched alleles in the local parasite population; in this trial, less than 10% of parasites had matched alleles. (Funded by the National Institutes of Health and others.).

Bayesian Networks to Compare Pest Control Interventions on Commodities Along Agricultural Production Chains.

The production of an agricultural commodity involves a sequence of processes: planting/growing, harvesting, sorting/grading, postharvest treatment, packing, and exporting. A Bayesian network has been developed to represent the level of potential infestation of an agricultural commodity by a specified pest along an agricultural production chain. It reflects the dependency of this infestation on the predicted level of pest challenge, the anticipated susceptibility of the commodity to the pest, the level of impact from pest control measures as designed, and any variation from that due to uncertainty in measure efficacy. The objective of this Bayesian network is to facilitate agreement between national governments of the exporters and importers on a set of phytosanitary measures to meet specific phytosanitary measure requirements to achieve target levels of protection against regulated pests. The model can be used to compare the performance of different combinations of measures under different scenarios of pest challenge, making use of available measure performance data. A case study is presented using a model developed for a fruit fly pest on dragon fruit in Vietnam; the model parameters and results are illustrative and do not imply a particular level of fruit fly infestation of these exports; rather, they provide the most likely, alternative, or worst-case scenarios of the impact of measures. As a means to facilitate agreement for trade, the model provides a framework to support communication between exporters and importers about any differences in perceptions of the risk reduction achieved by pest control measures deployed during the commodity production chain.

Nasopharyngeal carriage and macrolide resistance in Indigenous children with bronchiectasis randomized to long-term azithromycin or placebo.

Although long-term azithromycin decreases exacerbation frequency in bronchiectasis, increased macrolide resistance is concerning. We investigated macrolide resistance determinants in a secondary analysis of a multicenter randomized controlled trial. Indigenous Australian children living in remote regions and urban New Zealand Maori and Pacific Islander children with bronchiectasis were randomized to weekly azithromycin (30 mg/kg) or placebo for up to 24 months and followed post-intervention for up to 12 months. Nurses administered and recorded medications given and collected nasopharyngeal swabs 3-6 monthly for culture and antimicrobial susceptibility testing. Nasopharyngeal carriage of Haemophilus influenzae and Moraxella catarrhalis was significantly lower in azithromycin compared to placebo groups, while macrolide-resistant Streptococcus pneumoniae and Staphylococcus aureus carriage was significantly higher. Australian children, compared to New Zealand children, had higher carriage overall, significantly higher carriage of macrolide-resistant bacteria at baseline (16/38 versus 2/40 children) and during the intervention (69/152 versus 22/239 swabs), and lower mean adherence to study medication (63 % versus 92 %). Adherence ≥70 % (versus <70 %) in the Australian azithromycin group was associated with lower carriage of any pathogen [odds ratio (OR) 0.19, 95 % confidence interval (CI) 0.07-0.53] and fewer macrolide-resistant pathogens (OR 0.34, 95 % CI 0.14-0.81). Post-intervention (median 6 months), macrolide resistance in S. pneumoniae declined significantly in the azithromycin group, from 79 % (11/14) to 7 % (1/14) of positive swabs, but S. aureus strains remained 100 % macrolide resistant. Azithromycin treatment, the Australian remote setting, and adherence <70 % were significant independent determinants of macrolide resistance in children with bronchiectasis. Adherence to treatment may limit macrolide resistance by suppressing carriage.

Diversity of nontypeable Haemophilus influenzae strains colonizing Australian Aboriginal and non-Aboriginal children.

Nontypeable Haemophilus influenzae (NTHI) strains are responsible for respiratory-related infections which cause a significant burden of disease in Australian children. We previously identified a disparity in NTHI culture-defined carriage rates between Aboriginal and non-Aboriginal children (42% versus 11%). The aim of this study was to use molecular techniques to accurately determine the true NTHI carriage rates (excluding other culture-identical Haemophilus spp.) and assess whether the NTHI strain diversity correlates with the disparity in NTHI carriage rates. NTHI isolates were cultured from 595 nasopharyngeal aspirates collected longitudinally from asymptomatic Aboriginal (n=81) and non-Aboriginal (n=76) children aged 0 to 2 years living in the Kalgoorlie-Boulder region, Western Australia. NTHI-specific 16S rRNA gene PCR and PCR ribotyping were conducted on these isolates. Confirmation of NTHI by 16S rRNA gene PCR corrected the NTHI carriage rates from 42% to 36% in Aboriginal children and from 11% to 9% in non-Aboriginal children. A total of 75 different NTHI ribotypes were identified, with 51% unique to Aboriginal children and 13% unique to non-Aboriginal children (P<0.0001). The strain richness (proportion of different NTHI ribotypes) was similar for Aboriginal (19%, 65/346) and non-Aboriginal children (19%, 37/192) (P=0.909). Persistent carriage of the same ribotype was rare in the two groups, but colonization with multiple NTHI strains was more common in Aboriginal children than in non-Aboriginal children. True NTHI carriage was less than that estimated by culture. The Aboriginal children were more likely to carry unique and multiple NTHI strains, which may contribute to the chronicity of NTHI colonization and subsequent disease.

Otitis media at 6-monthly assessments of Australian First Nations children between ages 12-36 months: Findings from two randomised controlled trials of combined pneumococcal conjugate vaccines.

OBJECTIVES: In remote communities of northern Australia, First Nations children with hearing loss are disproportionately at risk of poor school readiness and performance compared to their peers with no hearing loss. The aim of this trial is to prevent early childhood persisting otitis media (OM), associated hearing loss and developmental delay. To achieve this, we designed a mixed pneumococcal conjugate vaccine (PCV) schedule that could maximise immunogenicity and thereby prevent bacterial otitis media (OM) and a trajectory of educational and social disadvantage. METHODS: In two sequential parallel, open-label, randomised controlled trials, eligible infants were first allocated 1:1:1 to standard or mixed PCV primary schedules at age 28-38 days, then at age 12 months to a booster dose (1:1) of 13-valent PCV, PCV13 (Prevenar13®, +P), or 10-valent pneumococcal non-typeable Haemophilus influenzae protein D conjugated vaccine, PHiD-CV10 (Synflorix®, +S). Here we report findings of standardised ear assessments conducted six-monthly from age 12-36 months, by booster dose. RESULTS: From March 2013 to September 2018, 261 children were allocated to booster + P (n = 131) or + S (n = 130). There were no significant differences in prevalence of any OM diagnosis by booster dose or when stratified by primary schedule. We found high, almost identical prevalence of OM in both boost groups at each age (for example 88% of 129 and 91% of 128 children seen, respectively, at primary endpoint age 18 months, difference -3% [95% Confidence Interval -11, 5]). At each age prevalence of bilateral OM was 52%-78%, and tympanic membrane perforation was 10%-18%. CONCLUSION: Despite optimal pneumococcal immunisation, the high prevalence of OM persists throughout early childhood. Novel approaches to OM prevention are needed, along with improved early identification strategies and evaluation of expanded valency PCVs.

Culture and PCR detection of Haemophilus influenzae and Haemophilus haemolyticus in Australian Indigenous children with bronchiectasis.

A PCR for protein D (hpd#3) was used to differentiate nontypeable Haemophilus influenzae (NTHI) from Haemophilus haemolyticus. While 90% of nasopharyngeal specimens and 100% of lower-airway specimens from 84 Indigenous Australian children with bronchiectasis had phenotypic NTHI isolates confirmed as H. influenzae, only 39% of oropharyngeal specimens with phenotypic NTHI had H. influenzae. The nasopharynx is therefore the preferred site for NTHI colonization studies, and NTHI is confirmed as an important lower-airway pathogen.

Nasopharyngeal carriage of otitis media pathogens in infants receiving 10-valent non-typeable Haemophilus influenzae protein D conjugate vaccine (PHiD-CV10), 13-valent pneumococcal conjugate vaccine (PCV13) or a mixed primary schedule of both vaccines: A randomised controlled trial.

BACKGROUND: Aboriginal children in Northern Australia have a high burden of otitis media, driven by early and persistent nasopharyngeal carriage of otopathogens, including non-typeable Haemophilus influenzae (NTHi) and Streptococcus pneumoniae (Spn). In this context, does a combined mixed primary series of Synflorix and Prevenar13 provide better protection against nasopharyngeal carriage of NTHi and Spn serotypes 3, 6A and 19A than either vaccine alone? METHODS: Aboriginal infants (n = 425) were randomised to receive Synflorix™ (S, PHiD-CV10) or Prevenar13™ (P, PCV13) at 2, 4 and 6 months (_SSS or _PPP, respectively), or a 4-dose early mixed primary series of PHiD-CV10 at 1, 2 and 4 months and PCV13 at 6 months of age (SSSP). Nasopharyngeal swabs were collected at 1, 2, 4, 6 and 7 months of age. Swabs of ear discharge were collected from tympanic membrane perforations. FINDINGS: At the primary endpoint at 7 months of age, the proportion of nasopharyngeal (Np) swabs positive for PCV13-only serotypes 3, 6A, or 19A was 0%, 0.8%, and 1.5% in the _PPP, _SSS, and SSSP groups respectively, and NTHi 55%, 52%, and 52% respectively, and no statistically significant vaccine group differences in other otopathogens at any age. The most common serotypes (in order) were 16F, 11A, 10A, 7B, 15A, 6C, 35B, 23B, 13, and 15B, accounting for 65% of carriage. Ear discharge swabs (n = 108) were culture positive for NTHi (52%), S. aureus (32%), and pneumococcus (20%). CONCLUSIONS: Aboriginal infants experience nasopharyngeal colonisation and tympanic membrane perforations associated with NTHi, non-PCV13 pneumococcal serotypes and S. aureus in the first months of life. Nasopharyngeal carriage of pneumococcus or NTHi was not significantly reduced in the early 4-dose combined SSSP group compared to standard _PPP or _SSS schedules at any time point. Current pneumococcal conjugate vaccine formulations do not offer protection from early onset NTHi and pneumococcal colonisation in this high-risk population.

A novel fuel cell design foroperandoenergy-dispersive x-ray absorption measurements.

A polymer electrolyte fuel cell has been designed to allowoperandox-ray absorption spectroscopy (XAS) measurements of catalysts. The cell has been developed to operate under standard fuel cell conditions, with elevated temperatures and humidification of the gas-phase reactants, both of which greatly impact the catalyst utilisation. X-ray windows in the endplates of the cell facilitate collection of XAS spectra during fuel cell operation while maintaining good compression in the area of measurement. Results of polarisation curves and cyclic voltammograms showed that theoperandocell performs well as a fuel cell, while also providing XAS data of suitable quality for robust XANES analysis. The cell has produced comparable XAS results when performing a cyclic voltammogram to an establishedin situcell when measuring the Pt LIII edge. Similar trends of Pt oxidation, and reduction of the formed Pt oxide, have been presented with a time resolution of 5 s for each spectrum, paving the way for time-resolved spectral measurements of fuel cell catalysts in a fully-operating fuel cell.

The nonserotypeable pneumococcus: phenotypic dynamics in the era of anticapsular vaccines.

Nonserotypeable pneumococci (NSP) are commonly carried by Australian Indigenous children in remote communities. The purpose of this study was to characterize carriage isolates of NSP from Indigenous children vaccinated with the seven-valent pneumococcal conjugate vaccine (PCV7) and to use these data to guide decisions on reporting of NSP. A total of 182 NSP were characterized by BOX typing, antibiogram analysis, and multilocus sequence typing (MLST) of common BOX types. NSP positive for the wzg capsule gene were analyzed by a multiplex PCR-based reverse line blot hybridization assay (mPCR/RLB-H) targeting capsule genes to determine the serotype. Among 182 NSP, 49 BOX types were identified. MLST of 10 representative isolates found 7 STs, including ST448 (which accounted for 11% of NSP). Non-penicillin susceptibility was evident in 51% of the isolates. Pneumococcal wzg sequences were detected in only 23 (13%) NSP, including 10 that contained an approximately 1.2-kb insert in the region. mPCR/RLB-H identified serotype 14 wzy sequences in all 10 NSP, and 1 also contained a serotype 3-specific wze sequence. Among the remaining 13 wzg-positive NSP, few belonged to the serotypes represented in PCV7. It appears that most NSP identified in Australian Indigenous children are from a true nonencapsulated lineage. Few NSP represented serotypes in PCV7 that suppress capsular expression. High rates of carriage and penicillin resistance and the occasional presence of capsule genes suggest a role for NSP in the maintenance and survival of capsulated pneumococci. To avoid the inflation of pneumococcal carriage and antibiotic resistance rates, in clinical trials, we recommend separate reporting of rates of capsular strains and NSP and the exclusion of data for NSP from primary analyses.

A comprehensive approach to health promotion for the reduction of dental caries in remote Indigenous Australian children: a clustered randomised controlled trial.

AIM: To evaluate the effect of a community-oriented primary health care (CPHC) intervention on oral health behaviours of Indigenous preschool children living in remote communities of Australia's Northern Territory. METHODS: The study was a community-clustered randomised controlled trial over two years, set in 30 remote Indigenous communities in the Northern Territory of Australia. Children aged 18-47 months at baseline were enrolled in the study. The intervention included fluoride varnish applications, training of primary care workers, and health promotion for oral health at an individual, family and community level. Intervention communities received six-monthly visits over two years and control communities were visited at baseline and two years later with no contact in the intervening period. The outcome measures reported in this paper are the impact of the intervention on two secondary endpoints: oral health promotion activities in the community and personal oral health practice of children. RESULTS: The intervention did not produce any significant change in oral health behaviours, clinical measures of oral hygiene, or community programmes promoting oral health. Dental caries can be reduced but will continue to be a problem among young remote Indigenous children while they experience major social disadvantage.

[The malaria vaccine candidate RTS,S/AS is in phase III clinical trials]. / Le candidat vaccin antipaludique RTS,S/AS est entré en essais cliniques de phase III.

This review paper describes the development of the RTS,S/AS vaccine, from concept to phase III testing. The rationale for selection of the circumsporozoite protein (CSP) as the target antigen and the preclinical development history of the vaccine are described. The RTS,S/AS candidate vaccine has been evaluated in multiple phase I/II studies and was shown to have a favorable safety profile and to be well tolerated in both adults and children. Consistent and significant efficacy has been observed in the target population of infants and children against Plasmodium falciparum infection and disease in different transmission settings, in different age groups, with or without Expanded Program of Immunization (EPI) vaccine co-administration. The RTS,S/AS01(E) malaria vaccine candidate has recently entered phase III testing. Reaching this important milestone is the culmination of more than 20 years of research and development by GlaxoSmithKline, their partners and collaborators. If the phase III results confirm the observations made during phase II testing, the RTS,S/AS01(E) vaccine, when broadly implemented and judiciously integrated with other malaria-prevention measures, would have a major public-health impact in sub-Saharan Africa.

Preventative and medical treatment of ear disease in remote or resource-constrained environments.

BACKGROUND: Important ear problems can affect the outer ear, the middle ear and the inner ear. Globally, the greatest burden of disease is due to ear conditions that are associated with otorrhoea and hearing loss. METHODS: This study reviewed the literature on the prevention and treatment of common ear conditions that are most relevant to settings with high rates of ear disease and limited resources. The grading of recommendations assessment, development and evaluation ('GRADE') approach was utilised to assess interventions. RESULTS: Accurate diagnosis of ear disease is challenging. Much of the preventable burden of ear disease is associated with otitis media. Nine otitis media interventions for which there is moderate to high certainty of effect were identified. While most interventions only provide modest benefit, the impact of treatment is more substantial in children with acute otitis media with perforation and chronic suppurative otitis media. CONCLUSION: Disease prevention through good hygiene practices, breastfeeding, reducing smoke exposure, immunisation and limiting noise exposure is recommended. Children with acute otitis media with perforation, chronic suppurative otitis media, complications of otitis media, and significant hearing loss should be prioritised for medical treatment.

Switching from suppressive protease inhibitor-based regimens to nevirapine-based regimens: a meta-analysis of randomized controlled trials.

OBJECTIVES: We performed a meta-analysis to assess the efficacy and safety of switching from protease inhibitor (PI)- to nevirapine (NVP)-based regimens in HIV-infected patients in whom virological suppression had been achieved. METHODS: Six trials (550 patients) were analysed. The demographics showed that 11-48% of participants were female and 40-53% had hepatitis C or B virus infection, and the mean CD4 lymphocyte count was >500 cells/microL at study entry. RESULTS: NVP-based regimens showed noninferiority compared with continuation of PI therapy to maintain virological suppression in 'intention to treat' (80 vs. 78%; P=0.35) and 'on treatment' analyses (91 vs. 89%; P=0.10). Overall rates of discontinuation because of adverse events were similar in the two groups (11 vs. 10%; P=0.79). However, NVP-based therapies caused more discontinuations because of liver toxicity than PI-based therapies (7 vs. 0%; P=0.0009). At the end of follow-up there was no statistical difference in CD4, cholesterol, triglyceride and body shape measurements between the two groups. Two studies reported greater improvement in quality of life in patients who were switched to the NVP group. CONCLUSIONS: Switching from suppressive PI- to NVP-based regimens is virologically and immunologically safe; however, the risk of liver toxicity requires monitoring of clinical symptoms and liver chemistry during NVP therapy.

Pesticide Environmental Accounting: a method for assessing the external costs of individual pesticide applications.

The Pesticide Environmental Accounting (PEA) tool provides a monetary estimate of environmental and health impacts per hectare-application for any pesticide. The model combines the Environmental Impact Quotient method and a methodology for absolute estimates of external pesticide costs in UK, USA and Germany. For many countries resources are not available for intensive assessments of external pesticide costs. The model converts external costs of a pesticide in the UK, USA and Germany to Mediterranean countries. Economic and policy applications include estimating impacts of pesticide reduction policies or benefits from technologies replacing pesticides, such as sterile insect technique. The system integrates disparate data and approaches into a single logical method. The assumptions in the system provide transparency and consistency but at the cost of some specificity and precision, a reasonable trade-off for a method that provides both comparative estimates of pesticide impacts and area-based assessments of absolute impacts.

WITHDRAWN: Antibiotics for persistent nasal discharge (rhinosinusitis) in children.

BACKGROUND: Nasal discharge (rhinosinusitis) is extremely common in children. It is the result of inflammation of the mucosa of the upper respiratory tract, and is usually due to either infection or allergy. Infections may be caused by bacteria. OBJECTIVES: To determine the effectiveness of antibiotics versus placebo or standard therapy in treating children with persistent nasal discharge (rhinosinusitis) for at least 10 days. SEARCH STRATEGY: In this updated review, we searched the Cochrane Central Register of Controlled Trials (CENTRAL) (The Cochrane Library Issue 1, 2005) which includes the ARI Group's specialised trials register; MEDLINE (1966 to April Week 3, 2005) EMBASE (1997 to December 2004), and the references of relevant articles were searched. Authors and pharmaceutical companies were contacted. SELECTION CRITERIA: All randomised controlled trials that compared antibiotics versus placebo or standard therapy. Trials which included the use of other medications were included if all participants were allowed equal access to such medications or if the additional or alternative therapies were regarded as ineffective. Trials that only combined or compared antibiotics with surgery, or sinus puncture and lavage, were not included in the review. DATA COLLECTION AND ANALYSIS: Data were extracted by a single author for the following eight outcomes: overall clinical failure (primary outcome), failure to cure, failure to improve, clinical improvement, time to resolution, complications, side-effects and bacteriologic failure. For the dichotomous outcome variables of each individual study, proportional and absolute risk reductions were calculated using a modified intention-to-treat analysis. The summary weighted risk ratio and 95% confidence interval (CI) (fixed effect model) were calculated using the inverse of the variance of each study result for weighting (Cochrane statistical package, RevMan version 4.2). MAIN RESULTS: A total of six studies involving 562 children compared antibiotics with placebo or standard therapy. All studies were randomised but most were still susceptible to bias. Five of the studies were conducted in emergency, allergy or ENT clinics. Four of the studies required children to have x-ray changes consistent with sinusitis. Only the primary outcome (overall clinical failure) was reported in all studies. Around 40% of all randomised children did not have a clinical success documented when reviewed two to six weeks after randomisation. The control event rate varied from to 22 to 71% (mean 46%). The risk ratio estimated using a fixed effects model was 0.75 (95% CI 0.61 to 0.92). There was no evidence of statistical heterogeneity. Side effects (sufficient to cease treatment) occurred in 4 of 189 control group children (four studies). More children treated with antibiotics had side effects (17 of 330), but this difference was not statistically significant (RR 1.75, 95% CI 0.63 to 4.82). AUTHORS' CONCLUSIONS: For children with persistent nasal discharge or older children with radiographically confirmed sinusitis, the available evidence suggests that antibiotics will reduce the probability of persistence in the short to medium-term. The benefits appear to be modest and around eight children must be treated in order to achieve one additional cure (number needed to treat (NNT) 8, 95% CI 5 to 29). No long term benefits have been documented. These conclusions are based on a small number of small randomised controlled trials and may require revision as additional data become available.

Microbiology of otitis media in Indigenous Australian children: review.

OBJECTIVES: To review research addressing the polymicrobial aetiology of otitis media in Indigenous Australian children in order to identify research gaps and inform best practice in effective prevention strategies and therapeutic interventions. METHODS: Literature review. RESULTS: Studies of aspirated middle-ear fluid represented a minor component of the literature reviewed. Most studies relied upon specimens from middle-ear discharge or the nasopharynx. Culture-based middle-ear discharge studies have found that non-typeable Haemophilus influenzae and Streptococcus pneumoniae predominate, with Moraxella catarrhalis, Staphylococcus aureus and Streptococcus pyogenes isolated in a lower proportion of samples. Alloiococcus otitidis was detected in a number of studies; however, its role in otitis media pathogenesis remains controversial. Nasopharyngeal colonisation is a risk factor for otitis media in Indigenous infants, and bacterial load of otopathogens in the nasopharynx can predict the ear state of Indigenous children. CONCLUSION: Most studies have used culture-based methods and specimens from middle-ear discharge or the nasopharynx. Findings from these studies are consistent with international literature, but reliance on culture may incorrectly characterise the microbiology of this condition. Advances in genomic technologies are now providing microbiologists with the ability to analyse the entire mixed bacterial communities ('microbiomes') of samples obtained from Indigenous children with otitis media.

Efficacy of nine-valent pneumococcal conjugate vaccine against pneumonia and invasive pneumococcal disease in The Gambia: randomised, double-blind, placebo-controlled trial.

BACKGROUND: Pneumonia is estimated to cause 2 million deaths every year in children. Streptococcus pneumoniae is the most important cause of severe pneumonia. We aimed to assess the efficacy of a nine-valent pneumococcal conjugate vaccine in children. METHODS: We undertook a randomised, placebo-controlled, double-blind trial in eastern Gambia. Children age 6-51 weeks were randomly allocated three doses of either pneumococcal conjugate vaccine (n=8718) or placebo (8719), with intervals of at least 25 days between doses. Our primary outcome was first episode of radiological pneumonia. Secondary endpoints were clinical or severe clinical pneumonia, invasive pneumococcal disease, and all-cause admissions. Analyses were per protocol and intention to treat. FINDINGS: 529 children assigned vaccine and 568 allocated placebo were not included in the per-protocol analysis. Results of per-protocol and intention-to-treat analyses were similar. By per-protocol analysis, 333 of 8189 children given vaccine had an episode of radiological pneumonia compared with 513 of 8151 who received placebo. Pneumococcal vaccine efficacy was 37% (95% CI 27-45) against first episode of radiological pneumonia. First episodes of clinical pneumonia were reduced overall by 7% (95% CI 1-12). Efficacy of the conjugate vaccine was 77% (51-90) against invasive pneumococcal disease caused by vaccine serotypes, 50% (21-69) against disease caused by all serotypes, and 15% (7-21) against all-cause admissions. We also found an efficacy of 16% (3-28) against mortality. 110 serious adverse events arose in children given the pneumococcal vaccine compared with 131 in those who received placebo. INTERPRETATION: In this rural African setting, pneumococcal conjugate vaccine has high efficacy against radiological pneumonia and invasive pneumococcal disease, and can substantially reduce admissions and improve child survival. Pneumococcal conjugate vaccines should be made available to African infants.

Antibiotics for the prevention of acute and chronic suppurative otitis media in children.

BACKGROUND: Acute otitis media (AOM) is a common childhood illness. These middle ear infections may be frequent and painful. AOM may be associated with perforation of the tympanic membrane and can progress to chronic suppurative otitis media (CSOM). OBJECTIVES: To determine the effectiveness of long-term antibiotics (for longer than six weeks) in preventing any AOM, AOM with perforation and CSOM. SEARCH STRATEGY: We searched the Cochrane Central Register of Controlled Trials (CENTRAL) (The Cochrane Library Issue 1, 2006), MEDLINE (January 1966 to March Week 3 2006), OLD MEDLINE (1950 to 1965), EMBASE (1990 to December 2005) and the references of relevant studies. SELECTION CRITERIA: All randomised controlled trials of long-term (longer than six weeks) antibiotics versus placebo or no treatment for the prevention of AOM, AOM with perforation, or CSOM were eligible. DATA COLLECTION AND ANALYSIS: Two authors independently extracted the data for: any AOM; episodes of AOM; any recurrent AOM; episodes of illness; any side effects; any antibiotic resistance, as well as outcomes at end of intervention (any AOM); and following cessation of intervention (any AOM). For dichotomous outcomes, the summary risk ratio (fixed and random-effects models) was calculated. For rate outcomes, the summary incidence rate ratio was calculated. MAIN RESULTS: Sixteen studies involving 1483 children met our inclusion criteria. All studies enrolled children at increased risk of AOM, and in seven studies the children were prone to otitis media. The majority of studies were high quality and most (15 studies) reported data for our primary outcomes. None reported AOM with perforation or CSOM. Long-term antibiotics reduced any episode of AOM (13 studies, 1358 children, risk ratio (RR) 0.62, 95% CI 0.52 to 0.75; random-effects model) and number of episodes of AOM (12 studies, 1112 children, incidence rate ratio (IRR) 0.48, 95% CI 0.37 to 0.62; random-effects model). Approximately five children would need to be treated long term to prevent one child experiencing AOM whilst on treatment. Antibiotics prevented 1.5 episodes of AOM for every 12 months of treatment per child. Statistical heterogeneity was explored. Long-term antibiotics were not associated with a significant increase in adverse events (11 studies, 714 children, RR 1.99, 95% CI 0.25 to 15.89; random-effects model). AUTHORS' CONCLUSIONS: For children at risk, antibiotics given once or twice daily will reduce the probability of AOM while the child is on treatment. Antibiotics will reduce the number of episodes of AOM per year from around three to around 1.5. We believe that larger absolute benefits are likely in high-risk children. These conclusions were not affected by sensitivity analyses.

Exercise echocardiography after coronary artery bypass surgery: correlation with coronary angiography.

OBJECTIVES: Our aim was to assess, in patients after coronary artery bypass surgery, how well exercise echocardiography predicts the presence of vascular compromise on angiography. BACKGROUND: Because late graft failure frequently occurs after bypass surgery, a reliable noninvasive technique is needed to identify those patients who would benefit from angiographic study. METHODS: In 182 patients, a total of 213 symptom-limited treadmill exercise electrocardiograms (ECGs) and exercise echocardiograms were performed in association with coronary and bypass angiography 2 weeks to 21 years after bypass surgery. RESULTS: There were more inconclusive exercise ECGs (28%) than exercise echocardiograms (9%). The positive predictive value was 85% for the exercise echocardiogram versus 62% for the exercise ECG; the corresponding negative predictive values were 81% versus 52%. The accuracy of the exercise echocardiogram was linked to the degree of underlying vascular compromise. After excluding cases with nondiagnostic results, due to either submaximal stress or poor image quality, the exercise echocardiogram detected 46 of the 60 cases with vascular compromise in one region (sensitivity 77%) and 47 of the 49 cases with compromise in two or three regions (sensitivity 96%). Similarly, an abnormal exercise echocardiogram had a positive predictive value of 71% for vascular compromise in one region and 98% for compromise in two or three regions. Most false negative exercise echocardiographic results were associated with posterolateral single-region vascular compromise on angiography. CONCLUSIONS: This study confirms a high positive and negative predictive value of exercise echocardiography in the detection of vascular compromise in patients after bypass surgery. It is clearly superior to exercise electrocardiography in predicting which patients will have angiographically significant graft or arterial lesions, and it can be used to obtain a better selection of patients for angiographic study.