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Author(s): Amanda Jane Leach 1,*, Nicole Wilson 1, Beth Arrowsmith 1,2, Jemima Beissbarth 1, Kim Mulholland 3,4,5, Mathuram Santosham 6,7, Paul John Torzillo 8,9, Peter McIntyre 10,11, Heidi Smith-Vaughan 1, [...], Background In Australian remote communities, First Nations children with otitis media (OM)-related hearing loss are disproportionately at risk of developmental delay and poor school performance, compared to those with normal hearing. Our objective was to compare OM-related hearing loss in children randomised to one of 2 pneumococcal conjugate vaccine (PCV) formulations. Methods and findings In 2 sequential parallel, open-label, randomised controlled trials (the PREVIX trials), eligible infants were first allocated 1:1:1 at age 28 to 38 days to standard or mixed PCV schedules, then at age 12 months to PCV13 (13-valent pneumococcal conjugate vaccine, +P) or PHiD-CV10 (10-valent pneumococcal Haemophilus influenzae protein D conjugate vaccine, +S) (1:1). Here, we report prevalence and level of hearing loss outcomes in the +P and +S groups at 6-monthly scheduled assessments from age 12 to 36 months. From March 2013 to September 2018, 261 infants were enrolled and 461 hearing assessments were performed. Prevalence of hearing loss was 78% (25/32) in the +P group and 71% (20/28) in the +S group at baseline, declining to 52% (28/54) in the +P groups and 56% (33/59) in the +S group at age 36 months. At primary endpoint age 18 months, prevalence of moderate (disabling) hearing loss was 21% (9/42) in the +P group and 41% (20/49) in the +S group (difference -19%; (95% confidence interval (CI) [-38, -1], p = 0.07) and prevalence of no hearing loss was 36% (15/42) in the +P group and 16% (8/49) in the +S group (difference 19%; (95% CI [2, 37], p = 0.05). At subsequent time points, prevalence of moderate hearing loss remained lower in the +P group: differences -3%; (95% CI [-23, 18], p = 1.00 at age 24 months), -12%; (95% CI [-30, 6], p = 0.29 at age 30 months), and -9%; (95% CI [-23, 5], p = 0.25 at age 36 months). A major limitation was the small sample size, hence low power to reach statistical significance, thereby reducing confidence in the effect size. Conclusions In this study, we observed a high prevalence and persistence of moderate (disabling) hearing loss throughout early childhood. We found a lower prevalence of moderate hearing loss and correspondingly higher prevalence of no hearing loss in the +P group, which may have substantial benefits for high-risk children, their families, and society, but warrant further investigation. Trial registration ClinicalTrials.gov NCT01735084 and NCT01174849

Author(s): Andrew J. Collaro [sup.1] [sup.2], Anne B. Chang [sup.1] [sup.2] [sup.3] [sup.4], Julie M. Marchant [sup.1] [sup.2], Mark D. Chatfield [sup.3] [sup.6], Annette Dent [sup.4] [sup.5] [sup.7], Kwun M. [...], Purpose Low diffusing capacity of the lung for carbon monoxide (D.sub.LCO) 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 (K.sub.CO) and alveolar volume (V.sub.A) are unknown. This cohort study: (i) evaluated whether D.sub.LCO, K.sub.CO, and V.sub.A 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 D.sub.LCO, K.sub.CO, and V.sub.A values below the lower limit of normal (< - 1.64 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, D.sub.LCO, K.sub.CO, and V.sub.A 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 D.sub.LCO. Conclusion Low D.sub.LCO, K.sub.CO, and V.sub.A 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.

Purpose: To determine whether short-term wear of textured insoles alters balance, gait, foot sensation, physical activity, or patient-reported outcomes, in people with diabetic neuropathy. Materials and Methods: 53 adults with diabetic neuropathy were randomised to wear textured or smooth insoles for 4-weeks. At baseline and post-intervention, balance (foam/firm surface; eyes open/closed) and walking were assessed whilst barefoot, wearing shoes only, and two insoles (textured/smooth). The primary outcome was center of pressure (CoP) total sway velocity. Secondary outcomes included other CoP measures, spatiotemporal gait measures, foot sensation, physical activity, and patient-reported outcomes (foot health, falls efficacy). Results: Wearing textured insoles led to improvements in CoP measures when standing on foam with eyes open, relative to smooth insoles (p ≤ 0.04). The intervention group demonstrated a 5% reduction in total sway velocity, indicative of greater balance. The intervention group also showed a 9-point improvement in self-perceived vigour (p = 0.03). Adjustments for multiple comparisons were not applied. Conclusions: This study provides weak statistical evidence in favour of textured insoles. Wearing textured insoles may alter measures of balance, suggestive of greater stability, in people with diabetic neuropathy. Plantar stimulation, through textured insoles, may have the capacity to modulate the perception of foot pain, leading to improved well-being. IMPLICATIONS FOR REHABILITATION: Short-term wear of textured insoles can lead to improvements in centre of pressure sway measures when standing on a compliant supporting surface. Wearing textured insoles may have the capacity to help relieve foot pain leading to enhanced self-perceived vitality in people with diabetic peripheral neuropathy. [ABSTRACT FROM AUTHOR]

Author(s): Andrew J. Collaro [sup.1] [sup.2], Anne B. Chang [sup.1] [sup.2] [sup.3] [sup.4], Julie M. Marchant [sup.1] [sup.2], Mark D. Chatfield [sup.3] [sup.5], Annette Dent [sup.4] [sup.6], Tamara Blake [sup.1] [...], Purpose 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. Methods 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. Results In the combined cohort, the forced expiratory volume in 1 s (FEV.sub.1) was clinically abnormal for 54% of First Nations patients (51% of non-First Nations patients), forced vital capacity (FVC) for 46% (36%), FEV.sub.1/FVC% for 30% (36%), and gas diffusing capacity (D.sub.LCO) for 44% (37%). A respiratory diagnosis was assigned by a respiratory physician in 78% of First Nations (76% non-First Nations) patients. Smoking, household smoke exposure, underweight BMI, and respiratory disease were associated with reduced lung function. In the 40% of patients (709/1765) followed up, FEV.sub.1 and FVC significantly improved (mean change: zFEV.sub.1 = 0.15 [95% CI 0.10-0.20]; zFVC = 0.25 [0.20, 0.31]), and FEV.sub.1/FVC% significantly reduced (mean = - 0.10 [95%CI - 0.07 to - 0.03]), with no significant change in D.sub.LCO. Patients with COPD had lower FEV.sub.1 improvement, whilst underweight and obese patients had lower FVC improvement. Conclusion Regional-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 Gram-negative bloodstream infections (GNBSIs) more commonly occur in children with comorbidities and are increasingly associated with antimicrobial resistance. There are few large studies of GNBSIs in children that relate the clinical presentation, pathogen characteristics, and outcomes. Methods A 3-year prospective study of GNBSIs in children aged <18 years was conducted in 5 Australian children's hospitals between 2019 and 2021. The clinical characteristics, disease severity, and outcomes were recorded. Causative pathogens underwent antibiotic susceptibility testing and whole genome sequencing. Results There were 931 GNBSI episodes involving 818 children. Median age was 3 years (interquartile range, 0.6–8.5). A total of 576/931 episodes (62%) were community onset, though 661/931 (71%) occurred in children with comorbidities and a central venous catheter was present in 558/931 (60%). Central venous catheter (145/931) and urinary tract (149/931) were the most common sources (16% each). One hundred of 931 (11%) children required intensive care unit admission and a further 11% (105/931) developed GNBSIs in intensive care unit. A total of 659/927 (71%) isolates were Enterobacterales, of which 22% (138/630) were third-generation cephalosporin resistant (3GCR). Extended spectrum beta-lactamase genes were confirmed in 65/138 (47%) 3GCR Enterobacterales. Most common extended spectrum beta-lactamase genes were bla CTX-M-15 (34/94, 36%) and bla SHV-12 (10/94, 11%). There were 48 deaths overall and 30-day in-hospital mortality was 3% (32/931). Infections with 3GCR Enterobacterales were independently associated with higher mortality (adjusted odds ratio, 3.2; 95% confidence interval, 1.6–6.4). Conclusions GNBSIs in children are frequently healthcare associated and affect children younger than age 5 years. Infections with 3GCR Enterobacterales were associated with worse outcomes. These findings will inform optimal management guidelines and help prioritize future antimicrobial clinical trials. [ABSTRACT FROM AUTHOR]

Background Evidence about the clinical impact of rapid diagnostic tests (RDTs) for the diagnosis of bloodstream infections is limited, and whether RDT are superior to conventional blood cultures (B Cs) embedded within antimicrobial stewardship programs (ASPs) is unknown. Methods We performed network meta-analyses using results from studies of patients with bloodstream infection with the aim of comparing the clinical impact of RDT (applied on positive BC broth or whole blood) to conventional BC, both assessed with and without ASP with respect to mortality, length of stay (LOS), and time to optimal therapy. Results Eighty-eight papers were selected, including 25 682 patient encounters. There was an appreciable amount of statistical heterogeneity within each meta-analysis. The network meta-analyses showed a significant reduction in mortality associated with the use of RDT + ASP versus BC alone (odds ratio [OR], 0.72; 95% confidence interval [CI],.59–.87) and with the use of RDT + ASP versus BC + ASP (OR, 0.78; 95% CI,.63–.96). No benefit in survival was found associated with the use of RDT alone nor with BC + ASP compared to BC alone. A reduction in LOS was associated with RDT + ASP versus BC alone (OR, 0.91; 95% CI,.84–.98) whereas no difference in LOS was shown between any other groups. A reduced time to optimal therapy was shown when RDT + ASP was compared to BC alone (−29 hours; 95% CI, −35 to −23), BC + ASP (−18 hours; 95% CI, −27 to −10), and to RDT alone (−12 hours; 95% CI, −20 to −3). Conclusions The use of RDT + ASP may lead to a survival benefit even when introduced in settings already adopting effective ASP in association with conventional BC. [ABSTRACT FROM AUTHOR]

Background: Burkholderia pseudomallei, the causative agent of melioidosis, is highly genetically recombinant, resulting in significant genomic diversity. Multiple virulence factors have been associated with specific disease presentations. To date, there are limited data relating to genomic diversity and virulence factors associated with melioidosis cases in North Queensland, Australia. Aim: To describe the genetic diversity of B. pseudomallei and identify virulence factors associated with clinical risk factors and patient outcomes. Methods: Whole genome sequencing of clinical isolates was performed and analysed with clinical data obtained from a retrospective melioidosis cohort study. Results: Fifty-nine distinct sequence types (STs) were identified from the 128 clinical isolates. Six STs comprised 64/128 (50%) isolates. Novel STs accounted for 38/59 (64%) STs, with ST TSV-13 as the most prevalent (n = 7), and were less likely to possess an LPS A genotype or YLF gene cluster (p < 0.001). These isolates were most likely to be found outside the inner city (aOR: 4.0, 95% CI: 1.7–9.0, p = 0.001). ST TSV-13 was associated with increased mortality (aOR: 6.1, 95% CI: 1.2–30.9, p = 0.03). Patients with a history of alcohol excess were less likely to be infected by fhaB3 (aOR 0.2, 95% CI: 0.1–0.7, p = 0.01) or YLF (aOR: 0.4, 95% CI: 0.2–0.9, p = 0.04) positive isolates. Conclusions: There are a significant number of novel sequence types in Townsville, Australia. An emerging novel ST appears to have an association with geographic location and mortality. Ongoing investigation is required to further understand the impact of this ST on the Townsville region. [ABSTRACT FROM AUTHOR]

Background Clinical trials of treatments for serious infections commonly use the primary endpoint of all-cause mortality. However, many trial participants survive their infection and this endpoint may not truly reflect important benefits and risks of therapy. The win ratio uses a hierarchical composite endpoint that can incorporate and prioritize outcome measures by relative clinical importance. Methods The win ratio methodology was applied post hoc to outcomes observed in the MERINO trial, which compared piperacillin-tazobactam with meropenem. We quantified the win ratio with a primary hierarchical composite endpoint, including all-cause mortality, microbiological relapse, and secondary infection. A win ratio of 1 would correspond to no difference between the 2 antibiotics, while a ratio <1 favors meropenem. Further analyses were performed to calculate the win odds and to introduce a continuous outcome variable in order to reduce ties. Results With the hierarchy of all-cause mortality, microbiological relapse, and secondary infection, the win ratio estimate was 0.40 (95% confidence interval [CI],.22–.71]; P =.002), favoring meropenem over piperacillin-tazobactam. However, 73.4% of the pairs were tied due to the small proportion of events. The win odds, a modification of the win ratio accounting for ties, was 0.79 (95% CI,.68–.92). The addition of length of stay to the primary composite greatly minimized the number of ties (4.6%) with a win ratio estimate of 0.77 (95% CI,.60–.99; P =.04). Conclusions The application of the win ratio methodology to the MERINO trial data illustrates its utility and feasibility for use in antimicrobial trials. [ABSTRACT FROM AUTHOR]

A prompt diagnosis of bacteraemia and sepsis is essential. Markers to predict the risk of persistent bacteraemia and metastatic infection are lacking. SeptiCyte RAPID is a host response assay stratifying patients according to the risk of infectious vs sterile inflammation through a scoring system (SeptiScore). In this study we explore the association between SeptiScore and persistent bacteraemia as well as metastatic and persistent infection in the context of a proven bacteraemia episode. This is a prospective multicentre observational 14-month study on patients with proven bacteraemia caused by Staphylococcus aureus or Gram-negative bacilli. Samples for assessment by SeptiCyte were collected with paired blood cultures for 4 consecutive days after the index blood culture. We included 86 patients in the study, 40 with S. aureus and 46 with Gram-negative bacilli bacteraemia. SeptiScores over the follow-up were higher in patients with Gram-negative compared to S. aureus bacteraemia (median 6.4, IQR 5.5–7.4 vs 5.6 IQR 5.1–6.2, p = 0.002). Higher SeptiScores were found to be associated with positive blood cultures at follow-up (AUC = 0.86, 95%CI 0.68–1.00) and with a diagnosis of metastatic infection at day 1 and 2 of follow-up (AUC = 0.79, 95%CI 0.57–1.00 and AUC = 0.82, 95%CI 0.63–1.00 respectively) in the context of Gram-negative bacteraemia while no association between SeptiScore and the outcomes of interest was observed in S. aureus bacteraemia. Mixed models confirmed the association of SeptiScore with positive blood cultures at follow-up (p = 0.04) and metastatic infection (p = 0.03) in the context of Gram-negative bacteraemia but not S. aureus bacteraemia after adjusting for confounders. SeptiScores differ in the follow-up of S. aureus and Gram-negative bacteraemia. In the setting of Gram-negative bacteraemia SeptiScore demonstrated a good negative predictive value for the outcomes of interest and might help rule out the persistence of infection defined as metastatic spread, lack of source control or persistent bacteraemia. [ABSTRACT FROM AUTHOR]