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Purpose Low diffusing capacity of the lung for carbon monoxide (DLCO) and spirometry values are associated with increased mortality risk. However, associations between mortality risk and cardiovascular disease with the transfer coefficient of the lung for carbon monoxide (KCO) and alveolar volume (VA) are unknown. This cohort study: (i) evaluated whether DLCO, KCO, and VA abnormalities are independently associated with cardiovascular morbidity and/or elevated mortality risk and, (ii) compared these associations with those using spirometry values. Methods Gas-diffusing capacity and spirometry data of 1165 adults seen at specialist respiratory outreach clinics over an 8-year period (241 with cardiovascular disease; 108 deceased) were analysed using multivariable Cox and logistic regression. Results DLCO, KCO, and VA values below the lower limit of normal (Z-scores) were associated with elevated cardiovascular disease prevalence [respective odds ratios of 1.83 (95% CI 1.31–2.55), 1.56 (95% CI 1.08–2.25), 2.20 (95% CI 1.60–3.01)] and increased all-cause mortality risk [respective hazard ratios of 2.99 (95% CI 1.83–4.90), 2.14 (95% CI 1.38–3.32), 2.75 (95% CI 1.18–2.58)], after adjustment for factors including age, personal smoking, and respiratory disease. Compared to similar levels of spirometry abnormality, DLCO, KCO, and VA were associated with similar or greater mortality risk, and similar cardiovascular disease prevalence. Analysis of only those patients with clinical normal spirometry values (n = 544) showed these associations persisted for DLCO. Conclusion Low DLCO, KCO, and VA measurements are associated with cardiovascular disease prevalence. As risk factors of all-cause mortality, they are more sensitive than spirometry even among patients with no diagnosed respiratory disease.

Australian First Nations children are at very high risk of early, recurrent, and persistent bacterial otitis media and respiratory tract infection. With the PREVIX randomised controlled trials, we aimed to evaluate the immunogenicity of novel pneumococcal conjugate vaccine (PCV) schedules.PREVIX_BOOST was a parallel, open-label, outcome-assessor-blinded, randomised controlled trial. Aboriginal children living in remote communities of the Northern Territory of Australia were eligible if they had previously completed the three-arm PREVIX_COMBO randomised controlled trial of the following vaccine schedules: three doses of a 13-valent PCV (PCV13; PPP) or a ten-valent pneumococcal Haemophilus influenzae protein D conjugate vaccine (PHiD-CV10; SSS) given at 2, 4, and 6 months, or SSS given at 1, 2, and 4 months followed by PCV13 at 6 months (SSSP). At age 12 months, eligible children were randomly assigned by a computer-generated random sequence (1:1, stratified by primary group allocation) to receive either a PCV13 booster or a PHiD-CV10 booster. Analyses used intention-to-treat principles. Co-primary outcomes were immunogenicity against protein D and serotypes 3, 6A, and 19A. Immunogenicity measures were geometric mean concentrations (GMC) and proportion of children with IgG concentrations of 0·35 μg/mL or higher (threshold for invasive pneumococcal disease), and GMCs and proportion of children with antibody levels of 100 EU/mL or higher against protein D. Standardised assessments of otitis media, hearing impairment, nasopharyngeal carriage, and developmental outcomes are reported. These trials are registered with ClinicalTrials.gov (NCT01735084 and NCT01174849).Between April 10, 2013, and Sept 4, 2018, 261 children were randomly allocated to receive a PCV13 booster (n=131) or PHiD-CV10 booster (n=130). Adequate serum samples for pneumococcal serology were obtained from 127 (95%) children in the PCV13 booster group and 126 (97%) in the PHiD-CV10 booster group; for protein D, adequate samples were obtained from 126 (96%) children in the PCV13 booster group and 123 (95%) in the PHiD-CV10 booster group. The proportions of children with IgG concentrations above standard thresholds in PCV13 booster versus PHiD-CV10 booster groups were the following: 71 (56%) of 126 versus 81 (66%) of 123 against protein D (difference 10%, 95% CI -2 to 22), 85 (67%) of 127 versus 59 (47%) of 126 against serotype 3 (-20%, -32 to -8), 119 (94%) of 127 versus 91 (72%) of 126 against serotype 6A (-22%, -31 to -13), and 116 (91%) of 127 versus 108 (86%) of 126 against serotype 19A (-5%, -13 to 3). Infant PCV13 priming mitigated differences between PCV13 and PHiD-CV10 boosters. In both groups, we observed a high prevalence of otitis media (about 90%), hearing impairment (about 75%), nasopharyngeal carriage of pneumococcus (about 66%), and non-typeable H influenzae (about 57%). Of 66 serious adverse events, none were vaccine related.Low antibody concentrations 6 months post-booster might indicate increased risk of pneumococcal infection. The preferred booster was PCV13 if priming did not have PCV13, otherwise either PCV13 or PHiD-CV10 boosters provided similar immunogenicity. Mixed schedules offer flexibility to regional priorities. Non-PCV13 serotypes and non-typeable H influenzae continue to cause substantial disease and disability in Australian First Nation's children.National Health and Medical Research Council (NHMRC).

A prospective, multicentre observational cohort study of carbapenem-resistant Klebsiella spp. (CRK) bloodstream infections was conducted in Turkey from June 2018 to June 2019. One hundred eighty-seven patients were recruited. Single OXA-48-like carbapenemases predominated (75%), followed by OXA-48-like/NDM coproducers (16%). OXA-232 constituted 31% of all OXA-48-like carbapenemases and was mainly carried on ST2096. Thirty-day mortality was 44% overall and 51% for ST2096. In the multivariate cox regression analysis, SOFA score and immunosuppression were significant predictors of 30-day mortality and ST2096 had a non-significant effect. All OXA-48-like producers remained susceptible to ceftazidime-avibactam.

Melioidosis is an infection caused by the bacterium Burkholderia pseudomallei. The most common presentation is bacteremia occurring in 38–73% of all patients, and the mortality rate ranges from 9% to 42%. Although there is abundant data representing risk factors for infection and patient outcomes, there is limited information regarding laboratory investigations associated with bacteremia and mortality. We assessed a range of baseline and diagnostic investigations and their association with patient outcomes in a retrospective cohort study in Townsville, Australia. 124 patients’ medical and laboratory records were reviewed between January 1, 1997 and December 31, 2020. Twenty-seven patients died and 87 patients were bacteremic. The presence of lymphopenia (< 1.5 × 109 cells/L) was the highest risk for bacteremia (relative risk [RR] 2.2; 95% CI: 1.3–3.7, P < 0.001). Factors associated with mortality included lymphopenia, (RR: 1.4; 95% CI: 1.2–1.6, P = 0.004); uremia (RR: 1.7; 95% CI: 1.1–2.5, P = 0.03); and an elevated international normalized ratio (RR: 1.5; 95% CI: 1.2–2.0, P = 0.006). Median incubation to positive blood culture result was 28 hours with 15/82 (18%) positive in ≤ 24 hours. For serological testing during admission only 53/121 (44%) were indirect hemagglutination assay positive, 67/120 (56%) enzyme immunoassay IgG positive, and 23/89 (26%) IgM positive. Simple baseline investigations at time of presentation may be used to stratify patients at high risk for both bacteremia and mortality. This information can be used as a decision aid for early intensive management.

Reducing the volume of blood sampled from neonatal or paediatric patients is important to facilitate research in a group that is under-represented in clinical studies. Not all patients have a cannula available for blood sampling, meaning there are real advantages in obtaining a blood microsample by skin prick. In this study, the results obtained from both capillary microsamples (CMS) and a microfluidic (MF)-CMS by skin prick are compared to conventional plasma sampled from an arterial catheter in a clinical bridging study. Six critically ill patients receiving meropenem were included with the incurred sample reanalysis test meeting the acceptance criteria for both CMS (n = 24 samples) and MF-CMS (n = 20 samples). Bland-Altman plots comparing MF-CMS to conventional arterial blood sampling revealed a difference of - 12.7 ± 22.1% (mean ± standard deviation (SD), and comparing CMS to conventional arterial blood sampling a difference of - 3.4 ± 17.0%. At - 12.7%, the bias between MF-CMS and conventional sampling is greater than the bias found with CMS, although within the limit of acceptability for analytical accuracy (that being ± 15%). Samples collected by skin prick and using CMS produced meropenem concentrations that were comparable to those obtained from conventional arterial catheter sampling. CMS samples were found to be stable when stored in the capillary tube for 24 h at 5 °C or for 4 h at room temperature.

Objectives: Understand the long-term mortality, risk of readmission for sepsis and cause of death following a gram-negative bloodstream infection (GN-BSI). Methods: This was a propensity-matched study using data linkage of Queensland hospital data, Australia. GN-BSIs were collected from 2005 to 2010 and matched 1:1 to hospital admissions without BSI for age, gender, year of culture collection, frequency of admissions in the prior year and Charlson-Deyo Comorbidity score and each comorbidity within the Charlson-Deyo score. Readmissions for sepsis, mortality and causes of death were evaluated. Results: Cases of GN-BSI were propensity-matched 1:1 to culture-negative hospital admissions (n = 14016). Readmissions for sepsis were higher in the GN-BSI cohort from 91 to 365 days (P

Background Increasing rates of antibiotic resistance in Gram-negative organisms due to the presence of extended-spectrum beta-lactamases (ESBL), hyperproduction of AmpC enzymes, carbapenemases and other mechanisms of resistance are identified in common hospital- and healthcare-associated pathogens including Enterobacteriaceae, Pseudomonas aeruginosa and Acinetobacter baumannii. Cefiderocol is a novel siderophore cephalosporin antibiotic with a catechol moiety on the 3-position side chain. Cefiderocol has been shown to be potent in vitro against a broad range of Gram-negative organisms, including carbapenem-resistant Enterobacteriaceae (CRE) and multi-drug-resistant (MDR) P. aeruginosa and A. baumannii. Recent clinical data has shown cefiderocol to be effective in the setting of complicated urinary tract infections and nosocomial pneumonia, but it has not yet been studied as treatment of bloodstream infection. Methods This study will use a multicentre, open-label non-inferiority trial design comparing cefiderocol and standard of care antibiotics. Eligible participants will be adult inpatients who are diagnosed with a bloodstream infection with a Gram-negative organism on the basis of a positive blood culture result where the acquisition meets the definition for healthcare-associated or hospital-acquired. It will compare cefiderocol with the current standard of care (SOC) antibiotic regimen according to the patient’s treating clinician. Eligible participants will be randomised 1:1 to cefiderocol or SOC and receive 5–14 days of antibiotic therapy. Trial recruitment will occur in at least 20 sites in ten countries (Australia, Malaysia, Singapore, Thailand, Turkey and Greece). The sample size has been derived from an estimated 14 day, all-cause mortality rate of 10% in the control group, and a non-inferiority margin of 10% difference in the two groups. A minimum of 284 patients are required in total to achieve 80% power with a two-sided alpha level of 0.05. Data describing demographic information, risk factors, concomitant antibiotics, illness scores, microbiology, multidrug-resistant organism screening, discharge and mortality will be collected. Discussion With increasing antimicrobial resistance, there is a need for the development of new antibiotics with broad activity against Gram-negative pathogens such as cefiderocol. By selecting a population at risk for multi-drug-resistant pathogens and commencing study treatment early in the clinical illness (within 48 h of index blood culture) the trial hopes to provide guidance to clinicians of the efficacy of this novel agent. Trial registration The GAME CHANGER trial is registered under the US National Institute of Health ClinicalTrials.gov register, reference number NCT03869437. Registered on March 11, 2019.

ObjectiveChildren with tracheomalacia can develop chronic lower airway infection and neutrophilic inflammation. It is plausible children with tracheomalacia are at increased risk of developing bronchiectasis. We hypothesised that compared with controls, tracheomalacia in children is associated with bronchiectasis.DesignSingle-centre, case–control study.Setting and patients45 children with chest high-resolution CT (c-HRCT) confirmed bronchiectasis (cases) and enrolled in the Australian Bronchiectasis Registry were selected randomly from Queensland, and 90 unmatched children without chronic respiratory symptoms or radiographic evidence of bronchiectasis (disease controls). Cases and controls had flexible bronchoscopy performed for clinical reasons within 4 weeks of their c-HRCT.InterventionsThe bronchoscopy videos were reviewed in a blinded manner for: (a) any tracheomalacia (any shape deformity of the trachea at end-expiration) and (b) tracheomalacia defined by the European Respiratory Society (ERS) statement (>50% expiratory reduction in the cross-sectional luminal area).Main outcome measures and resultsCases were younger (median age=2.6 years, IQR 1.5–4.1) than controls (7.8 years, IQR 3.4–12.8), but well-balanced for sex (56% and 52% male, respectively). Using multivariable analysis (adjusted for age), the presence of any tracheomalacia was significantly associated with bronchiectasis (adjusted OR (ORadj)=13.2, 95% CI 3.2 to 55), while that for ERS-defined tracheomalacia further increased this risk (ORadj=24.4, 95% CI 3.4 to infinity).ConclusionBronchoscopic-defined tracheomalacia is associated with childhood bronchiectasis. While causality cannot be inferred, children with tracheomalacia should be monitored for chronic (>4 weeks) wet cough, the most common symptom of bronchiectasis, which if present should be treated and then investigated if the cough persists or is recurrent.

Background: Spirometry values of First Nations Australian children are lower than White children. One explanation relates to differences in the sitting-height/standing-height ratio (Cormic Index), as this accounts for up to half the observed differences in spirometry values between White children and other ethnicities. We investigated whether the Cormic Index of First Nations children differs from White children and if this explains the lower spirometry values of First Nations children. Methods: First Nations children (n = 619) aged 8–16 years were recruited from nine Queensland communities. Their spirometry and Cormic Index data were compared to that of White children (n = 907) aged 8–16 years from the NHANES III dataset. Results: FEV and FVC of First Nations children was 8% lower for children aged 8–11.9 years and 9%–10% lower for children aged 12–16 years. The Cormic Index was statistically lower in the First Nations 8–11.9 years group (median = 0.515, interquartile range [IQR]: 0.506–0.525) compared with White children (0.519, IQR: 0.511–0.527), and this difference was greater in the 12–16 years group (0.505, IQR: 0.492–0.516; 0.520, IQR: 0.510–0.529). Adjusting for age, sex, and standing height, lower Cormic Index of First Nations children accounts for 14% (95% confidence interval [CI]: 7%–21%) of FEV and 15% (95% CI: 8%–21%) of FVC differences in the younger group, and 26% (95% CI: 16%–37%) of FEV and 31% (95% CI: 19%–42%) of FVC differences in the older group. Conclusion: Ethnic differences in Cormic Index partly account for why healthy First Nations Australian children have lower spirometry values than White children. As childhood spirometry values impact adult health, other contributing factors require attention.

Background Melioidosis in an infection caused by Burkholderia pseudomallei, an organism endemic to tropical and subtropical regions. Methods This study describes the epidemiology of melioidosis in Townsville, QLD, Australia, as well as clinical features, risk factors associated with the disease, the burden of infection on the Aboriginal and Torres Strait Islander (ATSI) community and patient outcomes over time. Results From 1997 to 2020, 128 patients were admitted to Townsville University Hospital. The total annual incidence of infection was 3.2 cases per 100 000 compared with 15.3 per 100 000 in the ATSI population. The majority of cases (n=82 [64%]) were male. Alcohol excess (55%) and diabetes mellitus (48%) were the most common risk factors. Bacteraemia occurred in 87 (70%) patients and pneumonia was the most common focus of infection in 84 (69%). The case fatality rate was 23%, with no difference for the ATSI population (6/32 [19%]). The presence of malignancy was the risk factor most associated with mortality (relative risk 2.7 [95% confidence interval 1.4–5.1], p=0.005). Conclusions The ATSI community was overrepresented in this study, however, there was no significant difference in adverse outcomes. The case fatality rate was higher than in other regions in Australia. This discrepancy may relate in part to the different risk groups seen in these settings coupled with potential organism variability.

Objectives: In children with asthma exacerbations, we evaluated the relationship between Canadian Acute Respiratory Illness and Flu Scale (CARIFS) scores and (a) Asthma Diary Scale (ADS) scores for 14 days; (b) Pediatric Asthma Caregiver's Quality of Life (QoL) Questionnaire (PACQLQ) scores on days 1, 7 and 14; (c) viral detection. We hypothesized that in children with acute asthma, CARIFS scores correlate with ADS and PACQLQ scores over time and that viruses have little impact on CARIFS scores.Methods: In children aged 2-16 years who presented with acute asthma to the Emergency Departments of 2 hospitals, we documented the clinical history, examination, asthma severity at baseline and on presentation. Eighteen respiratory pathogens were determined by PCR on nasopharyngeal aspirate (NPA) collected on recruitment. The parent(s) recorded their child's daily CARIFS and ADS and weekly PACQLQ for 14 days. We used Spearman's correlation to relate the scores of 108 children.Results: CARIFS scores correlated well with ADS scores throughout 14 days (rs ranged 0.30-0.67). CARIFS and PACQLQ scores correlated -0.28, -0.14 and -0.44 on days 1, 7 and 14 respectively. There was no significant difference in CARIFS scores between children whose NPAs were PCR virus-positive or -negative over 14 days.Conclusions: CARIFS and ADS scores correlated well as a disease severity measure during the recovery period in children with acute asthma and this was not influenced by the virus state. The ADS may be used as an alternative in selected situations. The CARIFS reflects different aspects to acute asthma severity and QoL.

To assess European Association of Urology (EAU) risk groups for biochemical recurrence (BCR) of prostate cancer relative to prostate-specific membrane antigen-positron emission tomography (PSMA-PET) status and oncological outcomes.A retrospective analysis of a study that incorporated PSMA-PET for men with BCR after radical prostatectomy (RP) was undertaken. EAU risk groups were considered relative to clinical variables, PSMA-PET findings, and deployment of salvage radiotherapy (SRT). The primary oncological outcome was event-free survival (EFS) and this was analysed relative to clinical and imaging variables. An 'event' occurred if prostate-specific antigen (PSA) level rose0.2 ng/mL above nadir or additional therapies were introduced.A total of 137 patients were included, most of whom had EAU high-risk disease (76%) and/or low PSA levels (80%0.5 ng/mL) at the time of PSMA-PET. EAU risk group was not associated with regional nodal/distant metastasis on PSMA-PET. Regional nodal/distant metastasis on PSMA PET (compared to negative/local recurrence: hazard ratio [HR] 2.2; P = 0.002) and SRT use (vs no SRT: HR 0.44; P = 0.004) were associated with EFS. EAU high-risk status was not significantly associated with worse EFS (HR 1.7, P = 0.12) compared to EAU low-risk status. Among patients who received SRT, both regional/distant metastasis on PSMA-PET (HR 3.1; P 0.001) and EAU high-risk status (HR 2.9; P = 0.04) were independently associated with worse EFS, which was driven by patients in the EAU high-risk group with regional/distant metastases (38%; HR 3.1, P = 0.001).In patients with post-RP BCR, PSMA-PET findings and receipt of SRT predicted EFS. In patients receiving SRT, PSMA status combined with EAU risk grouping was most predictive of EFS. These findings suggest that the EAU risk groups could be improved with the addition of PSMA-PET.

Patient satisfaction is a critical component of quality of care assessment in the pursuit of universal health coverage to end the tuberculosis epidemic and other diseases. This study aimed to review the level of satisfaction of tuberculosis patients and related factors. Articles were accessed from Web of Science, EMBASE, PubMed and Google Scholar. Twenty-six papers fulfilled the eligibility criteria from 13 countries. The percentage of satisfied tuberculosis patients ranged from 53.5% to 97.0% in the five African countries, 67.8 to 97.2% in India, South-East Asia, 82.0% in Pakistan, East-Mediterranean and 92.9% in Armenia, the European region. Accessibility, healthcare cost, treatment duration and taking supervised-directly observed treatment were healthcare service-related determinants. Technical competency, interpersonal relationships, confidentiality, time spent with healthcare providers, time spent waiting for care and counselling and health education were health worker-related determinants. Patient-related variables that determine satisfaction were gender, age, ethnicity, place of residence, marital status, educational status, income and health status. Developing and/or approaching an internationally-agreed tool to measure tuberculosis patient satisfaction in healthcare settings will improve the availability of high-quality and comparable data to verify actual variation across and within a country. A multidimensional approach considering clients, health workers and healthcare settings is required to holistically address satisfaction issues of tuberculosis patients to gradually realise universal health coverage.

To examine the relationship between self-care and bimanual performance in children aged 8 to 12 years with cerebral palsy (CP).This was a cross-sectional study of 74 children with CP (unilateral n=30, bilateral n=44; 48 males, 26 females; median age 9y 8mo [25th, 75th centiles 9y 1mo, 10y 8mo], Manual Abilities Classification System level I=30, II=28, III=16). Self-care was measured using the Pediatric Evaluation of Disability Inventory-Computer Adaptive Test (PEDI-CAT), and bimanual performance using the Assisting Hand Assessment (AHA) and Both Hands Assessment (BoHA). Measures of cognition, behavioural regulation, inattention, and gross motor function were included. Analyses used a directed acyclic graph to select variables for linear regression modelling.Higher AHA and BoHA scores were associated with higher PEDI-CAT scores. An increase of 1 AHA unit was associated with an increase of 0.12 PEDI-CAT scores, and a 1 BoHA unit increase was associated with an increase of 0.17 PEDI-CAT scores. The BoHA accounted for 57% of variance in PEDI-CAT scores for children with bilateral CP, while BoHA and cognition accounted for 68% of variance. The AHA accounted for 40% of variance in PEDI-CAT scores for unilateral CP with no effect of cognition on self-care.Self-care was strongly and positively associated with bimanual performance. Associations between self-care and bimanual performance differed for those with unilateral and bilateral CP.There is a strong positive relationship between self-care and bimanual performance for unilateral and bilateral cerebral palsy (CP). Both Hands Assessment (BoHA) scores have a stronger association with self-care than Assisting Hand Assessment scores. BoHA scores also account for more variation in self-care. There is a strong positive relationship between self-care and cognition overall. The effect of cognition on self-care performance differed for bilateral and unilateral CP.

Objectives In hospitalized and nonhospitalized children with asthma exacerbations, we evaluated the determinants of (a) prolonged cough on day-14 and (b) asthma quality of life (QoL) questionnaires for parents (PACQLQ) on day-21. We hypothesized that children with more severe acute asthma are more likely to have prolonged cough and/or poorer PACQLQ during the recovery phase.Design Prospective cohort study performed during 2009-2011.Methodology Two hundred and forty-four children aged 2-16 years presenting with acute asthma to the Emergency Departments of two hospitals were recruited. Clinical history, examination, baseline asthma severity, and acute asthma severity on presentation were documented. Validated daily cough diaries and weekly PACQLQ were recorded for 14 and 21 days, respectively.Results 34.4% and 32.2% of children who returned the daytime and nighttime cough diaries respectively had a prolonged cough. Those on regular inhaled corticosteroids (ICS) were significantly more likely to have a daytime or nighttime cough score of >= 1 on day-14 (odds ratio [ORadjusted] = 4.70, 95% confidence interval [CI] 1.65, 13.35, p = .004 and ORadjusted = 2.65, 95% CI 1.05, 6.69, p = .040, respectively). PACQLQ on day-21 was significantly poorer in younger children (mean difference [MD] = -0.04 per year, 95% CI -0.08, -0.01, p = .016), those on ICS (MD = -0.31, 95% CI -0.52, -0.09, p = .005), leukotriene antagonists (MD = -0.42, 95% CI -0.83, -0.02, p = .040) and in those who had an unplanned visit for asthma on day-21 (MD = -1.20, 95% CI -1.61, -0.78, p = .0001).Conclusions Post an acute asthma exacerbation, children on regular ICS were more likely to have prolonged cough and poorer QoL. While this may be reflective of asthma severity or control, its association deserves further evaluation.

Neonatal group B streptococcal sepsis remains a leading cause of neonatal sepsis globally and is characterized by unique epidemiologic features. Extracorporeal membrane oxygenation has been recommended for neonatal septic shock refractory to conventional management, but data on extracorporeal membrane oxygenation in group B streptococcal sepsis are scarce. We aimed to assess outcomes of extracorporeal membrane oxygenation in neonates with group B streptococcal sepsis.Retrospective study of the international registry of the Extracorporeal Life Support Organization.Extracorporeal membrane oxygenation centers contributing to Extracorporeal Life Support Organization registry.Patients less than or equal to 30 days treated with extracorporeal membrane oxygenation and a diagnostic code of group B streptococcal sepsis between January 1, 2007, and December 31, 2016.None.In-hospital mortality was the primary outcome. Univariable and multivariable logistic regression models to predict mortality were established. One hundred ninety-two runs in 191 neonates were identified meeting eligibility criteria, of which 55 of 191 (29%) died. One hundred thirty-seven (71%) were treated with venoarterial extracorporeal membrane oxygenation. One hundred sixty-nine runs (88%) occurred during the first week of life for early-onset sepsis and 23 (12%) after 7 days of life. The in-hospital mortality for extracorporeal membrane oxygenation used after 7 days of life was significantly higher compared with early-onset sepsis (65% vs 24%; p0.01). In addition, lower weight, lower pH, lower bicarbonate, and surfactant administration precannulation were significantly associated with mortality (p0.05). Adjusted analyses confirmed that age greater than 7 days, lower weight, and lower pH were associated with higher mortality (p0.05). One hundred fifty-one of 192 runs (79%) experienced a major complication. The number of major complications during extracorporeal membrane oxygenation was associated significantly with mortality (p0.001; adjusted odds ratio, 1.27 [1.08-1.49; p = 0.004]).This large registry-based study indicates that treatment with extracorporeal membrane oxygenation for neonatal group B streptococcal sepsis is associated with survival in the majority of patients. Future quality improvement interventions should aim to reduce the burden of major extracorporeal membrane oxygenation-associated complications which affected four out of five neonatal group B streptococcal sepsis extracorporeal membrane oxygenation patients.

Evolutionary theories of senescence, such as the ‘disposable soma’ theory, propose that natural selection trades late survival for early fecundity. ‘Frailty’, a multidimensional measure of health status, may help to better define the long-term consequences of reproduction. We examined the relationship between parity and later life frailty (as measured by the Frailty Index) in a sample of 3,534 adults aged 65 years and older who participated in the English Longitudinal Study of Ageing. We found that the most parous adults were the most frail and that the parity-frailty relationship was similar for both sexes. Whilst this study provided some evidence for a ‘parity-frailty trade-off’, there was little support for our hypothesis that the physiological costs of childbearing influence later life frailty. Rather, behavioural and social factors associated with rearing many children may have contributed to the development of frailty in both sexes.

Aim To investigate self-care developmental trajectories in children with cerebral palsy (CP) across all functional ability levels, according to Manual Ability Classification System (MACS) levels. Method This was a prospective longitudinal population-based study of 71 children aged from 2 years 6 months to 12 years, with CP (47 [66%] males, 24 [34%] females). Pediatric Evaluation of Disability Inventory (PEDI) measures were taken at 2 years 6 months, 3, 4, and 5 years, and the PEDI - Computer Adaptive Test (PEDI-CAT) between 8 and 12 years. At 8 to 12 years, children were classified in MACS levels I (21; 30%), II (22; 31%), III (16; 23%), IV (6; 8%), and V (6; 8%). Longitudinal analysis of the PEDI Functional Skills Scale self-care and PEDI-CAT daily activities domains used the published linking equation, and multilevel mixed-effects regression modelling with interaction between age and MACS. Results Between 5 and 12 years of age, children classified in MACS levels I to III continued to show progress in self-care development (PEDI-CAT scaled scores estimated change per year: I, 0.72; II, 0.49; III, 0.48). Children classified in MACS level IV showed an upward non-significant trend between 5 and 8 to 12 years (estimated change 0.42; 95% confidence interval [CI] -0.04 to 0.88). Children in MACS level V showed a decline in self-care (estimated change: -0.65; 95% CI -1.16 to -0.14). Interpretation Self-care development attained by 8 to 12 years of age was related to the severity of manual ability impairment. Application of the linking equation from PEDI to PEDI-CAT is somewhat uncertain at the extreme lower end of the scale. Our study supports recommendations for items to be added to the PEDI-CAT to address floor effect.

Purpose Malignant polyps present a treatment dilemma for clinicians and patients. This meta-analysis sought to identify the factors that predicted the management strategy for patients diagnosed with a malignant polyp. Methods A literature search was performed following the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) and the Cochrane Collaboration prognostic studies guidelines. Reports from 1985 onwards were included, data on patient and pathological factors were extracted and random effects meta-analysis models were used. Results Fifteen studies were included. Seven studies evaluated lymphovascular invasion (LVI). The odds of surgery were significantly higher in malignant polyps with LVI (OR 2.20, 95% CI 1.36–3.55). Ten studies revealed the odds of surgery were significantly higher with positive polypectomy margins (OR 8.09, 95% CI 4.88–13.40). Tumour differentiation was compared in eight studies. There were significantly lower odds of surgery in malignant polyps with well/moderate differentiation compared with poor differentiation (OR 0.31, 95% CI 0.21–0.46). There were non-significant trends favouring surgical resection in younger patients, males and Haggitt 4/Kikuchi Sm3 lesions. There was considerable heterogeneity in the meta-analyses for the variables age, gender, polyp morphology and Haggitt/Kikuchi level (I2 > 75%). Conclusion This meta-analysis has demonstrated that LVI, positive polypectomy resection margins, and poor tumour differentiation significantly predict malignant polypectomy patients who underwent subsequent surgery. Age and gender were important factors predicting management, but not consistently across studies, whilst polyp morphology and Haggitt/Kikuchi levels did not significantly predict the management strategy. Further research may assist in understanding the management preferences.

Background Premature infants are at high risk for acute kidney injury (AKI) and current diagnostic criteria are flawed. The objective of this study was to determine the diagnostic accuracy of urine and serum biomarkers not currently used in routine clinical practice to predict AKI in premature infants. Method A systematic review was performed that followed the Preferred Reporting Items for Systematic Reviews and Meta-Analyses of Diagnostic Test Accuracy Studies (PRISMA-DTA). Data were extracted on the diagnostic accuracy of AKI biomarkers using serum creatinine or urine output as the reference standard. Quality and validity were assessed using modified Standards for Reporting Diagnostic Accuracy (STARD) criteria. Results We identified 1024 articles, with 15 studies (791 infants) eligible for inclusion. Twenty-seven biomarkers were identified including serum cystatin C and urinary neutrophil gelatinase-associated lipocalin (uNGAL), osteopontin, kidney injury molecule-1, epidermal growth factor, and protein S100-P. However, many were only reported by one study each. A meta-analysis could only be conducted on uNGAL (288 infants from 6 studies) using a hierarchical, random-effects logistic-regression model. uNGAL had a summary sensitivity of 77% (95% CI 58–89%), specificity of 76% (95% CI 57–88%) and AUC-SROC of 0.83 (95% CI 0.80–0.86) for the diagnosis of AKI. By utilising uNGAL, the post-test probability of AKI increased to 52% (95% CI 37–66%) with a positive test and decreased to 9% (95% CI 5–16%) with a negative test if the pre-test probability was 25%. Conclusion uNGAL shows promise as a diagnostically accurate biomarker for AKI in premature infants. Graphical abstract

BACKGROUND: Adjuvant aromatase inhibitors (AI) improve survival compared to tamoxifen in postmenopausal women with hormone receptor‐positive stage I to III breast cancer. In approximately half of these women, AI are associated with aromatase inhibitor‐induced musculoskeletal symptoms (AIMSS), often described as symmetrical pain and soreness in the joints, musculoskeletal pain and joint stiffness. AIMSS may have significant and prolonged impact on women's quality of life. AIMSS reduces adherence to AI therapy in up to a half of women, potentially compromising breast cancer outcomes. Differing systemic therapies have been investigated for the prevention and treatment of AIMSS, but the effectiveness of these therapies remains unclear. OBJECTIVES: To assess the effects of systemic therapies on the prevention or management of AIMSS in women with stage I to III hormone receptor‐positive breast cancer. SEARCH METHODS: We searched CENTRAL, MEDLINE, Embase, WHO International Clinical Trials Registry Platform (ICTRP) and Clinicaltrials.gov registries to September 2020 and the Cochrane Breast Cancer Group (CBCG) Specialised Register to March 2021. SELECTION CRITERIA: We included all randomised controlled trials that compared systemic therapies to a comparator arm. Systemic therapy interventions included all pharmacological therapies, dietary supplements, and complementary and alternative medicines (CAM). All comparator arms were allowed including placebo or standard of care (or both) with analgesia alone. Published and non‐peer‐reviewed studies were eligible. DATA COLLECTION AND ANALYSIS: Two review authors independently screened studies, extracted data, and assessed risk of bias and certainty of the evidence using the GRADE approach. Outcomes assessed were pain, stiffness, grip strength, safety data, discontinuation of AI, health‐related quality of life (HRQoL), breast cancer‐specific quality of life (BCS‐QoL), incidence of AIMSS, breast cancer‐specific survival (BCSS) and overall survival (OS). For continuous outcomes, we used vote‐counting by reporting how many studies reported a clinically significant benefit within the confidence intervals (CI) of the mean difference (MD) between treatment arms, as determined by the minimal clinically importance difference (MCID) for that outcome scale. For dichotomous outcomes, we reported outcomes as a risk ratio (RR) with 95% CI. MAIN RESULTS: We included 17 studies with 2034 randomised participants. Four studies assessed systemic therapies for the prevention of AIMSS and 13 studies investigated treatment of AIMSS. Due to the variation in systemic therapy studies, including pharmacological, and CAM, or unavailable data, meta‐analysis was limited, and only two trials were combined for meta‐analysis. The certainty of evidence for all outcomes was either low or very low certainty. Prevention studies The evidence is very uncertain about the effect of systemic therapies on pain (from baseline to the end of the intervention; 2 studies, 183 women). The two studies, investigating vitamin D and omega‐3 fatty acids, showed a treatment effect with 95% CIs that did not include an MCID for pain. Systemic therapies may have little to no effect on grip strength (RR 1.08, 95% CI 0.37 to 3.17; 1 study, 137 women) or on women continuing to take their AI (RR 0.16, 95% 0.01 to 2.99; 1 study, 147 women). The evidence suggests little to no effect on HRQoL and BCS‐QoL from baseline to the end of intervention (the same single study; 44 women, both quality of life outcomes showed a treatment effect with 95% CIs that did include an MCID). The evidence is very uncertain for outcomes assessing incidence of AIMSS (RR 0.82, 95% CI 0.63 to 1.06; 2 studies, 240 women) and the safety of systemic therapies (4 studies, 344 women; very low‐certainty evidence). One study had a US Food and Drug Administration alert issued for the intervention (cyclo‐oxygenase‐2 inhibitor) during the study, but there were no serious adverse events in this or any study. There were no data on stiffness, BCSS or OS. Treatment studies The evidence is very uncertain about the effect of systemic therapies on pain from baseline to the end of intervention in the treatment of AIMSS (10 studies, 1099 women). Four studies showed an MCID in pain scores which fell within the 95% CI of the measured effect (vitamin D, bionic tiger bone, Yi Shen Jian Gu granules, calcitonin). Six studies showed a treatment effect with 95% CI that did not include an MCID (vitamin D, testosterone, omega‐3 fatty acids, duloxetine, emu oil, cat's claw). The evidence was very uncertain for the outcomes of change in stiffness (4 studies, 295 women), HRQoL (3 studies, 208 women) and BCS‐QoL (2 studies, 147 women) from baseline to the end of intervention. The evidence suggests systemic therapies may have little to no effect on grip strength (1 study, 107 women). The evidence is very uncertain about the safety of systemic therapies (10 studies, 1250 women). There were no grade four/five adverse events reported in any of the studies. The study of duloxetine reported more all‐grade adverse events in this treatment group than comparator group. There were no data on the incidence of AIMSS, the number of women continuing to take AI, BCCS or OS from the treatment studies. AUTHORS' CONCLUSIONS: AIMSS are chronic and complex symptoms with a significant impact on women with early breast cancer taking AI. To date, evidence for safe and effective systemic therapies for prevention or treatment of AIMSS has been minimal. Although this review identified 17 studies with 2034 randomised participants, the review was challenging due to the heterogeneous systemic therapy interventions and study methodologies, and the unavailability of certain trial data. Meta‐analysis was thus limited and findings of the review were inconclusive. Further research is recommended into systemic therapy for AIMSS, including high‐quality adequately powered RCT, comprehensive descriptions of the intervention/placebo, and robust definitions of the condition and the outcomes being studied.

In their article, Nylen and Grooten (2021) examined the stability over time of the Gross Motor Function Classification System (GMFCS) (Palisano et al., 1997) in children with cerebral palsy. They f...

To test the efficacy of a group social skills intervention on social functioning in adolescents with a brain injury.Thirty-six adolescents (mean age 14y, SD 1y 8mo, age range 12y 1mo-16y 3mo; 17 females) with acquired brain injury (ABI; ≥12mo postintervention; n=19) or cerebral palsy (n=17) were randomly allocated to the Program for the Education in Enrichment of Relational Skills (PEERS) or usual care. The primary outcome was the Social Skills Improvement System-Rating Scales (SSIS-RS). Secondary outcomes were scores derived from the Test of Adolescent Social Skills Knowledge-Revised (TASSK-R), Social Responsiveness Scale, Second Edition, and Quality of Socialization Questionnaire. Between-group differences postintervention and at the 26-week retention time point were compared using linear mixed modelling for continuous outcomes and Poisson regression for count data.There were no between-group differences on the primary outcome (SSIS-RS). Regarding the secondary outcomes, the PEERS-exposed group achieved significantly greater improvements on the TASSK-R (mean difference [MD]=6.8, 95% confidence interval [CI]=4.8-8.8, p0.001), which were maintained at the 26-week retention time point (MD=8.1, 95% CI=6.0-10.2, p0.001). PEERS was also associated with a significant increase in parent-reported invited get-togethers at 26 weeks (incidence rate ratio=4.0, 95% CI=1.0-16.0, p=0.05).Adolescents with brain injury who completed the PEERS learned and retained social knowledge and increased social participation.

AIM To describe development of gross motor capacity and mobility performance in children with cerebral palsy. METHOD This longitudinal cohort study measured gross motor capacity with the Gross Motor Function Measure and mobility performance with the Pediatric Evaluation of Disability Inventory (PEDI) between 18 months and 5 years, and the PEDI - Computer Adaptive Test (PEDI-CAT) between 8 years and 12 years. Longitudinal analyses used mixed-effects regression modelling with interaction between age and Gross Motor Function Classification System (GMFCS). Stability of GMFCS levels over time was measured using agreement. RESULTS Two hundred and twenty-two children provided 871 observations (median 4 observations, range 1-7). Children classified in GMFCS level I improved in both capacity and performance until 8 to 12 years. Children classified in GMFCS levels II and III continued to develop mobility performance after gross motor capacity had plateaued at 5 years. Children classified in GMFCS level IV plateaued at 5 years in capacity and performance. Children classified in GMFCS level V showed no changes in capacity or performance between 18 months and 8 to 12 years. Stability of GMFCS levels was 73%. INTERPRETATION Change in mobility performance over time somewhat reflected gross motor capacity trajectories. Continued improvement in mobility performance after plateau of gross motor capacity for children classified in GMFCS levels II and III suggests importance of other personal or environmental factors.

Group social skills interventions (GSSIs) are offered to youth with Autism Spectrum Disorder (ASD) to improve social functioning. This systematic review focused on the adolescent population, including a wider range of disabilities.To evaluate effectiveness of GSSIs at improving social functioning in adolescents with congenital, acquired or developmental disabilities.Databases, trial registries and dissertations were systematically searched and a meta-analysis of randomized controlled trials conducted. Study screening, risk-of-bias assessment and Grading of Recommendations Assessment, Development and Evaluation were completed.Sixteen studies (n = 1119), 15 with adolescents with ASD and one with brain tumor survivors, revealed GSSIs reduced social impairment on the Social Responsiveness Scale (mean difference (MD) 9.68, 95% CI 5.63-13.73; P 0.001), increased social skills on the Social Skill Improvement System Rating Scales (SMD 0.38, 95% CI 0.10-0.65; P = 0.007), and improved adolescent social knowledge on the Test of Adolescent Social Skills (MD 7.43 points, 95% CI 5.36-9.50; P 0.001).There is moderate certainty evidence that GSSIs improve social responsiveness, social skills and knowledge, and low certainty of evidence to improve social participation for adolescents with ASD. High quality randomized studies are required to inform clinical practice with adolescents with other disabilities.Current evidence for group social skills interventions (GSSIs) is for adolescents with autism (ASD). GSSIs likely improve social knowledge and reduce impairments in adolescents with ASD, however the effect of GSSIs on social participation is not well understood. Only one randomized trial investigated GSSIs in another population of adolescents, highlighting the need for more high-quality studies including adolescents with other disabilities.

Treatment options for multidrug-resistant (MDR) gram-negative infection are growing. However, postregistration, pragmatic, and clinician-led clinical trials in this field are few, recruit small sample sizes, and experience deficiencies in design and operations. MDR gram-negative therapeutic trials are often inefficient, only evaluating a single antibiotic or strategy at a time. Novel clinical trial designs offer potential solutions by attempting to obtain clinically meaningful conclusions at the end or during a trial, for many treatment strategies, simultaneously. An integrated, consensus approach to MDR gram-negative infection trial design is crucial.

Antecedents of the high rates of chronic kidney disease in Australian Indigenous peoples may originate early in life. Fourteen percent of Australian Indigenous infants are born preterm (under 37 weeks gestation) and, therefore, at risk. Here, our observational cohort study sought to determine the impact of preterm birth on renal function in Australian Indigenous and non-Indigenous infants. Renal function was assessed between 4-29 days postnatally in 60 Indigenous and 42 non-Indigenous infants born at 24-36 weeks gestation. Indigenous ethnicity was associated with impaired renal function, with significantly higher serum creatinine (geometric mean ratio (GMR) 1.15 [1.06, 1.25]), fractional excretion of sodium (GMR 1.21 [1.04, 1.39]), and urine albumin (GMR 1.57 [1.05, 2.34]), β-2 microglobulin (GMR 1.82 [1.11, 2.98]) and cystatin C (GMR 3.27 [1.54, 6.95]) when controlling for gestational/postnatal age, sex and birth weight Z-score. Renal injury, as indicated by high urine neutrophil gelatinase-associated lipocalin levels, was associated with maternal smoking and postnatal antibiotic exposure. Indigenous infants appeared to be most susceptible to the adverse impact of antibiotics. These findings show that preterm Australian Indigenous infants are highly vulnerable to renal dysfunction. Preterm birth may contribute to their increased risk of chronic kidney disease. Thus, we recommended that renal function should be closely monitored life-long in Indigenous children born preterm.

Introduction Depression is a leading cause of human disability. Telemedicine-based interventions using text messaging are currently being trialled for the management of community-based clients with clinical depression. However, little is known about the effectiveness of such methods. Methods We searched the databases PubMed, Embase, Informit, Cochrane Central Register of Controlled Trials, PsycINFO and Scopus for randomised controlled trials (RCTs) published between January 2000 and April 2019. Studies comparing text messaging interventions to a comparator group for patients with depression were included in the review. Articles were assessed for quality using the Joanna Briggs Institute critical appraisal checklist for RCTs. Results Nine RCTs (945 patients: 764 adults and 181 adolescents) were included in the systematic review. Five studies used text messaging as the only intervention, whilst the remaining combined text messaging with other treatment modalities such as behavioural activation or cognitive behavioural therapy. A meta-analysis was conducted on seven selected RCTs (845 patients: 664 adults and 181 adolescents). The standardised mean reduction in depression due to text messaging interventions was 0.23 (95% confidence interval: –0.02 to 0.48). There was evidence of heterogeneity in treatment effect between studies. Discussion There is marginal evidence supporting text messaging interventions as an effective treatment modality for people living with clinical depression. However, further research is needed to determine how best to utilise text-message interventions alongside other conventional forms of health services delivery.

Summary Background Bronchiectasis guidelines recommend antibiotics for the treatment of acute respiratory exacerbations, but randomised placebo-controlled trials in children are lacking. We hypothesised that oral amoxicillin–clavulanate and azithromycin would each be superior to placebo in achieving symptom resolution of non-severe exacerbations in children by day 14 of treatment. Methods In this multicentre, three-arm, parallel, double-dummy, double-blind, randomised placebo-controlled trial at four paediatric centres in Australia and New Zealand, we enrolled children aged 1–18 years with CT-confirmed bronchiectasis unrelated to cystic fibrosis, who were under the care of a respiratory physician and who had had at least two respiratory exacerbations in the 18 months before study entry. Participants were allocated (1:1:1) at exacerbation onset to receive oral suspensions of amoxicillin–clavulanate (45 mg/kg per day) plus placebo azithromycin, azithromycin (5 mg/kg per day) plus placebo amoxicillin–clavulanate, or both placebos for 14 days. An independent statistician prepared a computer-generated, permuted-block (size 2–8) randomisation sequence, stratified by centre, age, and cause. Participants, caregivers, study coordinators, and investigators were masked to treatment assignment until data analysis was completed. The primary outcome was the proportion of children with exacerbation resolution by day 14 in the intention-to-treat population. Treatment groups were compared using generalised linear models. Statistical significance was set at p

The objective of the study was to review the technical and peri-operative outcomes using the da Vinci Xi (dVXi) and da Vinci Si (dVSi) models with suprapubic port placement (SPPP) or traditional port placements (TPP) during a robotic right hemicolectomy (RRHC). A retrospective review was undertaken of prospectively maintained databases of RRHC performed by two senior colorectal surgeons in the USA and Australia. Data were prospectively collected for patient demographics, intra-operative technical outcomes and peri-operative clinical outcomes. A cohort of 138 patients underwent RRHC between 2013 and 2017: 134 (97%) had intra-corporeal anastomoses (ICA), 50% for polyp disease and 38% for cancer. 16 (12%) patients had post-operative complications, 11 (8%) of whom had only one complication. There were five (4%) anaemias requiring transfusion; five (4%) anastomotic bleeds; one (1%) leucocytosis/sepsis; two (1%) paralytic ileus; and two (1%) delayed readmissions. There were no conversions to open operations, anastomotic leaks, 30-day readmissions, or 30-day mortalities. With dVSi compared to dVXi, median (IQR) total operation time (TOT) reduced by 16% [134 (118–169) min versus 113 (90–132), p

Background Chronic suppurative otitis media (CSOM) is a significant health issue affecting Aboriginal Australians. Long-term hearing loss can cause communication problems, educational disadvantage, and social isolation. Current standard treatment for CSOM in our region is twice daily dry mopping of the pus from the ear canal followed by instillation of ciprofloxacin antibiotic ear drops for up to 16 weeks, or until the discharge resolves for a period of 3 days. The treatment is long, laborious and fails to resolve ear discharge in 70% of cases in remote communities. Bacterial pathogens also persist. Povidone-iodine ear wash is the preferred method of clearing ear discharge in Western Australia. However, evidence of its effectiveness is lacking. In systematic reviews, topical antibiotics (ciprofloxacin) have been shown to be more effective than oral antibiotics or topical antiseptics. Currently, it is unclear whether there are any benefits of combining these treatments. Methods This protocol describes a 2 × 2 factorial randomised controlled trial of two different interventions (povidone-iodine ear wash and oral cotrimoxazole), given as adjunctive therapy to standard treatment for CSOM. 280 children, between 2 months and 17 years of age, Indigenous or non-Indigenous, living in participating Northern Territory (NT) communities are randomised to standard treatment (dry mopping and ciprofloxacin drops) plus one of two topical treatments (dilute povidone-iodine ear wash or no wash) and one of two oral medication treatments (16 weeks of cotrimoxazole or placebo). Discussion Current treatment of CSOM in our region shows that eradication of bacterial pathogens from the middle ear space and dry ears is often not achieved. This trial will evaluate the efficacy of adjunctive treatments of antiseptic ear washes and oral antibiotics. Clinical, microbiological and hearing outcomes will be reported. Trial registration This trial (ACTRN12614000234617) was registered with ANZCTR on 05 April 2014.

Burkholderia pseudomallei is a tier 1 select agent that is associated with laboratory-acquired melioidosis, with international guidelines recommending isolate handling within a class II biosafety cabinet (BSC) in a biosafety level 3 (BSL3) facility. In low-resource settings, this may not be practical; therefore, we aimed to assess the risk of laboratory-acquired melioidosis during routine work. Prior exposure to the organism was determined with a questionnaire and concomitant serology. Of 30 laboratory scientists handling B. pseudomallei on 1,267 occasions outside a biosafety cabinet, no infections were documented and all participants remained seronegative. Additionally, we performed controlled environmental air sampling during 78 laboratory handling events, including plate opening, oxidase testing, and McFarland suspension creation. None of the experiments demonstrated aerosolization of the organism. This study suggests the risk of laboratory-acquired melioidosis is low. However, individual laboratories will need to undertake a risk assessment, including melioidosis endemicity, availability of resources for containment, the nature of routine handling to be undertaken, and the presence of predisposing risk factors for infection in the staff concerned. Additionally, laboratories should take region-specific guidelines into consideration. Further research is required to better inform on the overall risk of infection in the microbiology laboratory.

Objective: Ascertain predictors of inactivated influenza vaccine (IIV) uptake in pregnancy in mother–infant pairs from six Australian sites over four consecutive influenza seasons (2012–2015). Methods: Prospective observational cohort study calculating proportions of unvaccinated and vaccinated pregnancies. Multivariable logistic regression calculating adjusted odds ratios (aOR) and 95% confidence intervals (95%CI) to determine demographic, pregnancy and birth characteristics as predictors of IIV uptake in pregnancy. Results: Uptake of IIV was 36% (n=3,651/9,878) with only 3–4% during the first trimester. Validation of IIV receipt was obtained for 77% of vaccinated participants. Predictors of IIV uptake in pregnancy were: healthcare provider recommendation to have IIV during pregnancy (aOR 7.04 [95%CI 5.83‐8.50]): GP (aOR 4.12 [95%CI 3.43‐4.98]), obstetrician (aOR 4.41 [95%CI 3.45‐5.64]), midwife (aOR 1.88 [95%CI 1.51‐2.36]); previous IIV within 12 months of their current pregnancy (aOR 2.87 [95%CI 2.36‐3.50]); and pertussis vaccination during the current pregnancy (aOR 4.88 [95%CI 4.08‐5.83]). Conclusions and implications for public health: Healthcare provider discussions with pregnant women about the risks associated with influenza infection during pregnancy and early infancy and evidence about the safety and effectiveness of IIV are required. Recommending and offering IIV in pregnancy needs to be included in these discussions to improve uptake.

In the inpatient setting, antibiotics are generally administered via bedside pumps with multiple daily dosing. Utilisation of a continuous antibiotic infusion (CAI) instead might have patient and nursing satisfaction, workflow efficiencies and infection control benefits. We aimed to study the utilisation of CAI in the inpatient setting for routine antibiotic administration. Patients receiving a peripherally inserted central venous catheter (PICC) for antibiotic administration were screened for the study. The patients were randomised to either (1) standard pump and intermittent antibiotic administration (IAA) or (2) CAI via an ambulatory pump. An accelerometer placed on the ankle was used to assess patient activity. Nursing and patient satisfaction surveys were also carried out. Forty patients met the study criteria for enrolment with 21 patients being enrolled in the CAI arm of the study. One hundred and five days of accelerometer recordings were available for analysis. The geometric mean activity was 45 min/day in the standard arm and 64 min/day in the CAI arm. This represented a 42% (95% CI: −14 to 133%, p = 0.16) difference in activity between the two groups. Nursing staff reported that they spent less time throughout their shift attending the antibiotic line or pump in patients who were in the CAI arm of the study (p < 0.001). In addition, patients in this arm of the study were more likely to recommend this method of administration of antibiotics to a family member (p =0.0001). The MOBILISE study showed nursing and patient satisfaction when CAI were utilised in the inpatient setting. A statistically non-significant difference in mobility was seen. The trial was registered (28/03/2018) with the Australia New Zealand Clinical Trials Registry (ACTRN12618000452291).

Northern Territory (NT)-based clinical service data suggest substantial lung function impairment amongst First Nations adults as young as 18-40 years. Our objectives were to describe the burden of disease and lung function of adults living in regional-remote Queensland, identify determinants of lung function, and evaluate the impact of a specialist respiratory outreach service on lung function.Retrospective 8-year cohort study (February 2012-March 2020) of 1113 First Nations Australian adults (and 648 non-First Nations adults) referred to respiratory outreach clinics in regional-remote Queensland.In the combined cohort, the forced expiratory volume in 1 s (FEVRegional-remote First Nations adult Queenslanders have higher lung function than previously reported, with no lung function decline observed at follow-up visit, including for those with respiratory disease.

Background Aboriginal children living in Australian remote communities are at high risk of early and persistent otitis media, hearing loss, and social disadvantage. Streptococcus pneumoniae and non-typeable Haemophilus influenzae (NTHi) are the primary pathogens. We compared otitis media outcomes in infants randomised to either a combination of Synflorix™ (PHiD-CV10, with protein D of NTHi) and Prevenar13™ (PCV13, with 3, 6A, and 19A), with recommended schedules for each vaccine alone. We previously reported superior broader overall immunogenicity of the combination schedule at 7 months, and early superiority of PHiD-CV10 compared to PCV13 at 4 months. Methods In an open-label superiority trial, we randomised (1:1:1) Aboriginal infants at 28 to 38 days of age, to either Prevenar13™ (P) at 2–4-6 months (_PPP), Synflorix™ (S) at 2–4-6 months (_SSS), or Synflorix™ at 1–2-4 months plus Prevenar13™ at 6 months (SSSP). Ears were assessed using tympanometry at 1 and 2 months, combined with otoscopy at 4, 6, and 7 months. A worst ear diagnosis was made for each child visit according to a severity hierarchy of normal, otitis media with effusion (OME), acute otitis media without perforation (AOMwoP), AOM with perforation (AOMwiP), and chronic suppurative otitis media (CSOM). Results Between September 2011 and September 2017, 425 infants were allocated to _PPP(143), _SSS(141) or SSSP(141). Ear assessments were successful in 96% scheduled visits. At 7 months prevalence of any OM was 91, 86, and 90% in the _PPP, _SSS, and SSSP groups, respectively. There were no significant differences in prevalence of any form of otitis media between vaccine groups at any age. Combined group prevalence of any OM was 43, 57, 82, 87, and 89% at 1, 2, 4, 6, and 7 months of age, respectively. Of 388 infants with ear assessments at 4, 6 and 7 months, 277 (71.4%) had OM that met criteria for specialist referral; rAOM, pOME, or CSOM. Conclusions Despite superior broader overall immunogenicity of the combination schedule at 7 months, and early superiority of PHiD-CV10 compared to PCV13 at 4 months, there were no significant differences in prevalence of otitis media nor healthy ears throughout the first months of life. Trial registration ACTRN12610000544077 registered 06/07/2010 and ClinicalTrials.govNCT01174849 registered 04/08/2010.

IntroductionYoung children with bilateral cerebral palsy (BCP) often experience difficulties with gross motor function, manual ability and posture, impacting developing independence in daily life activities, participation and quality of life. Hand Arm Bimanual Intensive Training Including Lower Extremity (HABIT-ILE) is a novel intensive motor intervention integrating upper and lower extremity training that has been developed and tested in older school-aged children with unilateral and BCP. This study aims to compare an adapted preschool version of HABIT-ILE to usual care in a randomised controlled trial.Methods and analysis60 children with BCP aged 2–5 years, Gross Motor Function Classification System (GMFCS) II–IV will be recruited. Children will be stratified by GMFCS and randomised using concealed allocation to either receive Preschool HABIT-ILE or usual care. Preschool HABIT-ILE will be delivered in groups of four to six children, for 3 hours/day for 10 days (total 30 hours). Children receiving Preschool HABIT-ILE be provided a written home programme with the aim of achieving an additional 10 hours of home practice (total dose 40 hours). Outcomes will be assessed at baseline, immediately following intervention and then retention of effects will be tested at 26 weeks. The primary outcome will be the Peabody Developmental Motors Scales–Second Edition to evaluate gross and fine motor skills. Secondary outcomes will be gross motor function (Gross Motor Function Measure-66), bimanual hand performance (Both Hands Assessment), self-care and mobility (Pediatric Evaluation of Disability Inventory-Computer Adapted Test), goal attainment (Canadian Occupational Performance Measure), global performance of daily activities (ACTIVLIM-CP), cognition and adaptive function (Behavior Rating Inventory of Executive Function—Preschool Version), habitual physical activity (ActiGraph GT3X+) and quality of life (Infant Toddler Quality of Life Questionnaire and Child Health Utility Index-9). Analyses will follow standard principles for RCTs using two-group comparisons on all participants on an intention-to-treat basis. Comparisons between groups for primary and secondary outcomes will be conducted using regression models.Ethics and disseminationEthics approval has been granted by the Medical Research Ethics Committee Children’s Health Queensland Hospital and Health Service Human Research Ethics Committee (HREC/19/QCHQ/59444) and The University of Queensland (2020000336/HREC/19/QCHQ/59444).Trial registration numberACTRN126200000719.

Background Antimicrobial susceptibility testing (AST) is the standard of care for treating bacterial infections. In randomized clinical trials of new antimicrobials, AST might not be performed or reported in real time. Objectives To determine local, real-time laboratory AST performance, its usage in the trial flow, quality control (QC) of the local testing, central AST performance and the effect of using AST categorization on the trials' primary outcomes. Data sources We systematically searched PubMed, Embase, PsychINFO and Web of Science. Eligibility criteria We included registered randomized controlled trials published in journals between January 2015 and December 2019. Participants and interventions We included trials comparing different antibiotics for the treatment of infections caused predominantly by Gram-negative bacteria. Methods Primary outcomes for different trial populations were extracted and differences between trial arms were compared for patients with infections caused by susceptible versus non-susceptible bacteria. Results are described narratively. Results Of 32 randomized trials, 25 trials reported that local AST was performed, 1312 reported the local laboratory AST methods, no trial reported QC, but post-hoc referral for AST at a reference laboratory was common. Patients' outcomes were superior when patients with infections due to susceptible and non-susceptible pathogens were compared post hoc (median difference 14%, interquartile range 8%–24%) in trials allowing this comparison (seven antimicrobials), except for colistin, where 14-day mortality was 9% higher when patients were treated with colistin for colistin-susceptible versus colistin-resistant carbapenem-resistant Acinetobacter baumannii. When excluding patients with pathogens that were non-susceptible to either antimicrobial in the trials, the difference in the primary outcome between the trial arms was reduced in five out of six trials. Conclusions Trials should perform AST to guide patient inclusion or exclusion from the study and consider the impact of the central laboratory susceptibility results on the study outcomes when using post-hoc reference testing.

Introduction This study aims to assess the association of piperacillin/tazobactam and meropenem minimum inhibitory concentration (MIC) and beta-lactam resistance genes with mortality in the MERINO trial. Methods Blood culture isolates from enrolled patients were tested by broth microdilution and whole genome sequencing at a central laboratory. Multivariate logistic regression was performed to account for confounders. Absolute risk increase for 30-day mortality between treatment groups was calculated for the primary analysis (PA) and the microbiologic assessable (MA) populations. Results In total, 320 isolates from 379 enrolled patients were available with susceptibility to piperacillin/tazobactam 94% and meropenem 100%. The piperacillin/tazobactam nonsusceptible breakpoint (MIC >16 mg/L) best predicted 30-day mortality after accounting for confounders (odds ratio 14.9, 95% confidence interval [CI] 2.8–87.2). The absolute risk increase for 30-day mortality for patients treated with piperacillin/tazobactam compared with meropenem was 9% (95% CI 3%–15%) and 8% (95% CI 2%–15%) for the original PA population and the post hoc MA populations, which reduced to 5% (95% CI −1% to 10%) after excluding strains with piperacillin/tazobactam MIC values >16 mg/L. Isolates coharboring extended spectrum β-lactamase (ESBL) and OXA-1 genes were associated with elevated piperacillin/tazobactam MICs and the highest risk increase in 30-day mortality of 14% (95% CI 2%–28%). Conclusions After excluding nonsusceptible strains, the 30-day mortality difference from the MERINO trial was less pronounced for piperacillin/tazobactam. Poor reliability in susceptibility testing performance for piperacillin/tazobactam and the high prevalence of OXA coharboring ESBLs suggests that meropenem remains the preferred choice for definitive treatment of ceftriaxone nonsusceptible Escherichia coli and Klebsiella.

To describe bimanual performance in a sample of Australian children with bilateral cerebral palsy (CP) and, examine the qualitative meaning (or interpretability) of scores on the Both Hands Assessment (BoHA).Children with bilateral CP aged 8-12 years (Bimanual performance was significantly different across MACS levels I-III (The BoHA quantified observations of bimanual performance for children with bilateral CP, differentiated between MACS levels I-III and provided clinically meaningful information. The BoHA may facilitate tailoring of upper limb intervention. Future research is recommended to examine inter-rater and intra-rater reliability and responsiveness of the BoHA, as well as longitudinal studies of bimanual hand skill development in children with bilateral CP.

Background Extended-spectrum beta-lactamase (ESBL) and AmpC-producing Enterobacterales are common causes of bloodstream infection. ESBL-producing bacteria are typically resistant to third-generation cephalosporins and result in a sizeable economic and public health burden. AmpC-producing Enterobacterales may develop third-generation cephalosporin resistance through enzyme hyper-expression. In no observational study has the outcome of treatment of these infections been surpassed by carbapenems. Widespread use of carbapenems may drive the development of carbapenem-resistant Gram-negative bacilli. Methods This study will use a multicentre, parallel group open-label non-inferiority trial design comparing ceftolozane-tazobactam and meropenem in adult patients with bloodstream infection caused by ESBL or AmpC-producing Enterobacterales. Trial recruitment will occur in up to 40 sites in six countries (Australia, Singapore, Italy, Spain, Saudi Arabia and Lebanon). The sample size is determined by a predefined quantity of ceftolozane-tazobactam to be supplied by Merck, Sharpe and Dohme (MSD). We anticipate that a trial with 600 patients contributing to the primary outcome analysis would have 80% power to declare non-inferiority with a 5% non-inferiority margin, assuming a 30-day mortality of 5% in both randomised groups. Once randomised, definitive treatment will be for a minimum of 5 days and a maximum of 14 days with the total duration determined by treating clinicians. Data describing demographic information, risk factors, concomitant antibiotics, illness scores, microbiology, multidrug-resistant organism screening, discharge and mortality will be collected. Discussion Participants will have bloodstream infection due to third-generation cephalosporin non-susceptible E. coli and Klebsiella spp. or Enterobacter spp., Citrobacter freundii, Morganella morganii, Providencia spp. or Serratia marcescens. They will be randomised 1:1 to ceftolozane-tazobactam 3 g versus meropenem 1 g, both every 8 h. Secondary outcomes will be a comparison of 14-day all-cause mortality, clinical and microbiological success at day 5, functional bacteraemia score, microbiological relapse, new bloodstream infection, length of hospital stay, serious adverse events, C. difficile infection, multidrug-resistant organism colonisation. The estimated trial completion date is December 2024. Trial registration The MERINO-3 trial is registered under the US National Institute of Health ClinicalTrials.gov register, reference number: NCT04238390. Registered on 23 January 2020.

This study aimed to identify which MRI and clinical assessments, alone or in combination, from (i) early (32 weeks postmenstrual age, PMA), (ii) term equivalent age (TEA) and (iii) 3 months corrected age (CA) are associated with motor or cognitive outcomes at 2 years CA in infants born31 weeks gestation.Prospective cohort study of 98 infants who underwent early and TEA MRI (n = 59 males; median birth gestational age 28 + 5 weeks). Hammersmith Neonatal Neurological Examination (HNNE), NICU Neonatal Neurobehavioural Scale and General Movements Assessment (GMs) were performed early and at TEA. Premie-Neuro was performed early and GMs, Test of Infant Motor Performance and visual assessment were performed at TEA and 3 months CA. Neurodevelopmental outcomes were determined using Bayley Scales of Infant and Toddler Development 3rd edition.The best combined motor outcome model included 3-month GMs (β = -11.41; 95% CI = -17.34, -5.49), TEA MRI deep grey matter score (β = -6.23; 95% CI = -9.47, -2.99) and early HNNE reflexes (β = 3.51; 95% CI = 0.86, 6.16). Combined cognitive model included 3-month GMs (β = -10.01; 95% CI = -15.90, -4.12) and TEA HNNE score (β = 1.33; 95% CI = 0.57, 2.08).Early neonatal neurological assessment improves associations with motor outcomes when combined with term MRI and 3-month GMs. Term neurological assessment combined with 3-month GMs improves associations with cognitive outcomes.We present associations between 32- and 40-week MRI, comprehensive clinical assessments and later 2-year motor and cognitive outcomes for children born31 weeks gestation. MRI and clinical assessment of motor, neurological and neurobehavioural function earlier than term equivalent age in very preterm infants is safe and becoming more available in clinical settings. Most of these children are discharged from hospital before term age and so completing assessments prior to discharge can assist with follow up. MRI and neurological assessment prior to term equivalent age while the child is still in hospital can provide earlier identification of children at highest risk of adverse outcomes and guide follow-up screening and intervention services.

A randomised controlled trial (RCT) of a mindfulness-based yoga program, MiYoga, for cerebral palsy (CP) demonstrated improved attention in children and decreased mindfulness in parents post-intervention. This paper evaluates the retention of treatment effects at 6-months follow-up.42 children with CP and their parents participated in a RCT with two groups MiYoga (PairedThis study identified possible delayed or sleeper effects in children's executive function and physical function and parent's well-being.Implications for rehabilitation6-month follow-up evidence for retention of effects of MiYoga on children's attention was inconsistent; therefore, booster sessions or continued practice of MiYoga as a lifestyle option are needed to maintain an effect on attention.Because MiYoga can be practised during daily activities, it may provide additional support for children with CP, complementing standard rehabilitation options.By embedding mindfulness in children and parents' daily activities, MiYoga, could provide families with accessible and time-efficient means of learning and practicing mindfulness.

Background The relationship between acute myocardial infarction and infection was recognized in the early 20th century during influenza epidemics. Most recently, a case control study and a self-control design study have identified an association between Staphylococcus aureus infection and acute myocardial infarction. We assessed the association of community-acquired Staphylococcus aureus bloodstream infection (CA-SABSI) and myocardial infarction in the 365 days following blood culture. Methods This was a cohort study assessing the incidence of myocardial infarction 365 days after blood culture for Staphylococcus aureus. Culture-negative patients had blood cultures collected at hospital attendance and were matched to the CA-SABSI participants by sex, 5-year age strata, and year of culture collection. Pathology information was linked to hospital administrative data and index of relative socioeconomic advantage and disadvantage (ISRAD). Results The study included 5157 CA-SABSI cases matched to 10 146 blood culture–negative cases. The mortality rate was significantly higher in the CA-SABSI group (10.9%; 562/5157) than in culture-negative cases (5.1%; 521/10 146) at 365 days (P Conclusions CA-SABSI is associated with an increased short-term risk of myocardial infarction, which is associated with subsequent mortality.

IntroductionStreptococcus pneumoniae and non-typeable Haemophilus influenzae (NTHi) are major otitis media pathogens that densely co-colonise the nasopharynx and infect the middle ear of Australian Aboriginal infants from very early in life. Our co-primary hypotheses are that at 18 months of age infants receiving 10-valent pneumococcal Haemophilus influenzae protein D conjugate vaccine (PHiD-CV10) compared with those receiving 13-valent pneumococcal conjugate vaccine (PCV13) as a booster at 12 months of age will have higher antibody levels to Haemophilus influenzae protein D and that infants receiving PCV13 will have higher antibody levels to PCV13-only serotypes 3, 6A and 19A.Methods and analysesOur randomised controlled trial will enrol 270 Aboriginal children at 12 months of age to a booster dose of either PHiD-CV10 or PCV13. Children who completed the three-dose primary course schedules of PHiD-CV10 at 2, 4, 6 months of age; PCV13 at 2, 4, 6 months of age; or a combination schedule of PHiD-CV10 at 1, 2, 4 months of age plus PCV13 at 6 months of age are eligible. The co-primary assessor-blinded outcomes when the infants are 18 months of age are as follows: (a) IgG geometric mean concentration (GMC) and proportion with IgG ≥100 EU/mL for protein D, and (b) IgG GMC and the proportion with IgG ≥0.35 µg/mL for pneumococcal serotypes 3, 6A and 19A. Secondary immunogenicity comparisons of six primary and booster dose schedules of 10 shared serotypes at 18 months of age, nasopharyngeal carriage, all forms of otitis media, hearing loss and developmental milestones at 18, 24, 30 and 36 months of age will be reported.Ethics and disseminationEthics committees of NT Department of Health, Menzies, WA Department of Health and WA Aboriginal Health approved the study. Results will be presented to communities, at conferences and published in peer-reviewed journals.Trial registration numberNCT01735084.

To examine the stability over time of the Manual Ability Classification System (MACS) levels in children with cerebral palsy (CP) aged 18 to 60 months.This was a prospective longitudinal population-based study of 252 Australian children (160 males [63%] 92 females [37%]; mean age [SD] 41.7mo [14], range 17.2mo-69.2mo) with CP. Children were classified at 18 months (n=70), 24 months (n=131), 30 months (n=173), 36 months (n=209), 48 months (n=226), and 60 months (n=221) of age. Stability of the MACS was examined using the proportion of specific positive agreement and transition proportions, which are measures of agreement.There were 1030 unique observations, with each of the 252 participants seen between two and six occasions (median=4). Average specific positive agreement over the study period was 76% for MACS level I, 67% for level II, 50% for level III, 51% for level IV, and 83% for level V. MACS levels I and V have the highest degree of stability, while levels III and IV have the lowest. We show how this may be explained by the proportion of children in each MACS level.Using measures of agreement rather than measures of reliability provides accurate information when measuring stability over time of an ordinal classification system. The relative stability of MACS levels can be explained by the proportion of children in each level.Children classified in Manual Ability Classification System (MACS) levels III and IV change levels at next assessment about 50% of the time. Children should be assessed with the MACS regularly, particularly those in levels III and IV. Stability within ordinal classification level categories can be predicted using a measurement error model. Transition proportions or specific agreement is recommended for reporting stability of ordinal classification systems.Estabilidade do Sistema de Classificação da Habilidade Manual (MACS) em crianças jovens com paralisia cerebral OBJETIVO: Examinar a estabilidade ao longo do tempo dos níveis do Sistema de Classificação da Habilidade Manual (MACS) em crianças com paralisia cerebral (PC) com idade entre 18 e 60 meses. MÉTODO: Este foi um estudo prospectivo de caráter longitudinal, com amostra baseada no estudo da população de 252 crianças Australianas (160 meninos [63%], 92 meninas [37%]; idade média [desvio padrão] de 41,7 meses [14], variação de 17, 2 a 69, 2 meses de idade]) com PC. As crianças foram classificadas aos 18 meses (n = 70), 24 meses (n = 131), 30 meses (n = 173), 36 meses (n = 209), 48 meses (n = 226), e aos 60 meses (n = 221) de idade. A estabilidade do MACS foi examinada utilizando a proporção de concordância positiva específica e proporções de transição, sendo estas as medidas de concordância. RESULTADOS: Foram realizadas um total de 1.030 observações com os 252 participantes, os quais foram avaliados individualmente entre dois e seis momentos (média = 4). A média de concordância específica positiva durante o estudo foi de 76% para MACS nível I, 67% para nível II, 50% para nível III, 51% para nível IV, e 83% para nível V. Os classificados com MACS nível I e V tiveram os maiores graus de estabilidade, enquanto os classificados com os níveis III e IV tiveram os menores graus de estabilidade. Estes resultados podem ser explicados pela proporção de crianças classificadas em cada nível do MACS. INTERPRETAÇÃO: A utilização de medidas de concordância ao invés de medidas de confiabilidade proporciona informações mais precisas quando se mensura estabilidade ao longo do tempo com um sistema de classificação ordinal. A estabilidade relativa dos níveis do MACS pode ser explicada pela proporção de crianças classificadas em cada nível.Estabilidad del Sistema de Clasificación de Habilidad Manual (MACS) en niños pequeños con parálisis cerebral OBJETIVO: Examinar la estabilidad en el tiempo de los niveles del Sistema de Clasificación de Habilidad Manual (MACS) en niños con parálisis cerebral (PC) de 18 a 60 meses. MÉTODO: Este fue un estudio prospectivo longitudinal basado en la población de 252 niños australianos (160 [63%] hombres, 92 mujeres [37%]; edad media [DE] 41.7mo [14], rango 17.2mo-69.2mo]) con PC. Los niños se clasificaron a los 18 meses (n = 70), 24 meses (n = 131), 30 meses (n = 173), 36 meses (n = 209), 48 meses (n = 226) y 60 meses (n = 221) de edad. La estabilidad del MACS se examinó utilizando la proporción de acuerdo positivo específico y las proporciones de transición, que son medidas de acuerdo. RESULTADOS: Con cada uno de los 252 participantes vistos entre dos y seis ocasiones (mediana = 4) hubo 1030 observaciones únicas. La concordancia positiva específica promedio durante el período de estudio fue de 76% para MACS nivel I, 67% para nivel II, 50% para nivel III, 51% para nivel IV y 83% para nivel V. Los niveles I y V de MACS son los más altos de estabilidad, mientras que los niveles III y IV tienen los más bajos. Mostramos cómo esto puede explicarse por la proporción de niños en cada nivel de MACS. INTERPRETACIÓN: El uso de medidas de acuerdo - en lugar de medidas de confiabilidad - proporciona información precisa cuando se mide la estabilidad en el tiempo de un sistema de clasificación ordinal. La estabilidad relativa de los niveles de MACS puede explicarse por la proporción de niños en cada nivel.

IntroductionPrimary ciliary dyskinesia (PCD) is a rare, progressive, inherited ciliopathic disorder, which is incurable and frequently complicated by the development of bronchiectasis. There are few randomised controlled trials (RCTs) involving children and adults with PCD and thus evidence of efficacy for interventions are usually extrapolated from people with cystic fibrosis. Our planned RCT seeks to address some of these unmet needs by employing a currently prescribed (but unapproved for long-term use in PCD) macrolide antibiotic (azithromycin) and a novel mucolytic agent (erdosteine). The primary aim of our RCT is to determine whether regular oral azithromycin and erdosteine over a 12-month period reduces acute respiratory exacerbations among children and adults with PCD. Our primary hypothesis is that: people with PCD who regularly use oral azithromycin and/or erdosteine will have fewer exacerbations than those receiving the corresponding placebo medications. Our secondary aims are to determine the effect of the trial medications on PCD-specific quality-of-life (QoL) and other clinical outcomes (lung function, time-to-next exacerbation, hospitalisations) and nasopharyngeal bacterial carriage and antimicrobial resistance.Methods and analysisWe are currently undertaking a multicentre, double-blind, double-dummy RCT to evaluate whether 12 months of azithromycin and/or erdosteine is beneficial for children and adults with PCD. We plan to recruit 104 children and adults with PCD to a parallel, 2×2 partial factorial superiority RCT at five sites across Australia. Our primary endpoint is the rate of exacerbations over 12 months. Our main secondary outcomes are QoL, lung function and nasopharyngeal carriage by respiratory bacterial pathogens and their associated azithromycin resistance.Ethics and disseminationOur RCT is conducted in accordance with Good Clinical Practice and the Australian legislation and National Health and Medical Research Council guidelines for ethical conduct of Research, including that for First Nations Australians.Trial registration numberACTRN12619000564156.

IntroductionChildren and youth with moderate-severe (Gross Motor Function Classification System (GMFCS) levels II–V) cerebral palsy (CP) participate less frequently in physical activities compared with peers without CP and have elevated risk of cardiorespiratory morbidity and mortality in adulthood. Frame Running (RaceRunning) is a new athletics discipline that is an accessible option for physical activity participation for people with moderate-severe CP. There is no high-quality evidence for the effect of Frame Running on cardiovascular disease in children and young people with CP. The primary aim of this study is to conduct a randomised controlled trial of the effect of 12 weeks of Frame Running training on risk factors for cardiovascular disease.Methods and nalysisSixty-two children and youth with CP (age 8–20 years) in GMFCS levels II–V will be recruited across four sites and randomised to receive either 12 weeks of Frame Running training two times weekly for 60 min, or usual care. Outcomes will be measured at baseline, immediately postintervention (primary endpoint) and 12 weeks later for retention of training effects. The primary outcome is cardiorespiratory fitness as measured by distance covered on Six Minute RaceRunner Test with 1 min heart rate recovery. Other outcomes include blood pressure, objectively measured physical activity, body mass index, waist circumference, percentage body fat, gross motor function capacity, community participation, feasibility, tolerability and safety. Adverse events will be monitored, and participants and their caregivers will be interviewed to discern their experiences of participation in Frame Running.Ethics and disseminationThe Children’s Health Queensland Hospital and Health Service and the University of Queensland Human Research Ethics Committees have approved this study. Results will be disseminated in peer-reviewed journals and scientific conferences; through professional and athletic organisations; and to people with CP and their families.Trial registration numberACTRN12621000317897; Australian New Zealand Clinical Trials Registry number.

Cystic fibrosis (CF)-associated liver disease (CFLD) is a hepatobiliary complication of CF. Current diagnostic modalities rely on non-specific assessments, while liver biopsy is the gold standard to assess severity of fibrosis. MicroRNAs (miRNAs) regulate liver disease pathogenesis and are proposed as diagnostic biomarkers. We investigated the combined use of serum miRNAs and aspartate aminotransferase to platelet ratio (APRI) to diagnose and assess CFLD severity. This was a cross-sectional cohort study of the circulatory miRNA signature of 124 children grouped by clinical, biochemical and imaging assessments as follows: CFLD (n=44), CF patients with no evidence of liver disease (CFnoLD, n=40) and healthy controls (n=40). Serum miRNAs were analysed using miRNA-sequencing. Selected differentially expressed serum miRNA candidates were further validated by qRT-PCR and statistical analysis performed to evaluate utility to predict CFLD and fibrosis severity validated by liver biopsy, alone or in combination with APRI. Serum miR-122-5p, miR-365a-3p and miR-34a-5p levels were elevated in CFLD compared to CFnoLD, while miR-142-3p and let-7g-5p were downregulated in CFLD compared to CFnoLD. Logistic regression analysis combining miR-365a-3p, miR-142-3p and let-7g-5p with APRI showed 21 times greater odds of accurately predicting liver disease in CF with an AUROC=0.91 (sensitivity=83%, specificity=92%; P We identified a distinct circulatory miRNA profile in pediatric CFLD with potential to accurately discriminate liver disease and fibrosis severity in children with CF. This article is protected by copyright. All rights reserved.

Acute lower respiratory infection (ALRI) is a major cause of hospitalization for Indigenous children in remote regions of Australia. The associated microbiology remains unclear. Our aim was to determine whether the microbes present in the nasopharynx before an ALRI were associated with its onset. A retrospective case-control/crossover study among Indigenous children aged up to 2 years. ALRI cases identified by medical note review were eligible where nasopharyngeal swabs were available: (1) 0–21 days before ALRI onset (case); (2) 90–180 days before ALRI onset (same child controls); and (3) from time and age-matched children without ALRI (different child controls). PCR assays determined the presence and/or load of selected respiratory pathogens. Among 104 children (182 recorded ALRI episodes), 120 case-same child control and 170 case-different child control swab pairs were identified. Human adenoviruses (HAdV) were more prevalent in cases compared to same child controls (18 vs 7%; OR = 3.08, 95% CI 1.22–7.76, p = 0.017), but this association was not significant in cases versus different child controls (15 vs 10%; OR = 1.93, 95% CI 0.97–3.87 (p = 0.063). No other microbes were more prevalent in cases compared to controls. Streptococcus pneumoniae (74%), Haemophilus influenzae (75%) and Moraxella catarrhalis (88%) were commonly identified across all swabs. In a pediatric population with a high detection rate of nasopharyngeal microbes, HAdV was the only pathogen detected in the period before illness presentation that was significantly associated with ALRI onset. Detection of other potential ALRI pathogens was similar between cases and controls. Electronic supplementary material The online version of this article (10.1007/s10096-018-3314-7) contains supplementary material, which is available to authorized users.