Integrating omics techniques and culture-independent systems may improve the detection of persistent candidemia: data from an observational study.

INTRODUCTION: Blood cultures have low sensitivity for candidemia. Sensitivity can be improved by the culture-independent system T2 Magnetic Resonance (T2). SeptiCyte RAPID is a host response assay quantifying the risk of infection-related inflammation through a scoring system (SeptiScore). We investigate the performance of SeptiScore in detecting persistent candidemia as defined by conventional cultures and T2. METHODS: This is a prospective multicentre observational study on patients with candidemia. Blood cultures and blood samples for assessment by T2 and SeptiCyte were collected for 4 consecutive days after the index culture. The performance of SeptiScore was explored to predict persistent candidemia as defined by (1) positive follow-up blood culture (2) either positive follow-up blood culture or T2 sample. RESULTS: 10 patients were enrolled including 34 blood collections assessed with the 3 methods. Overall, 4/34 (12%) follow-up blood cultures and 6/34 (18%) T2 samples were positive. A mixed model showed significantly higher SeptiScores associated with persistent candidemia when this was defined as either a positive follow-up blood culture or T2 sample (0.82, 95%CI 0.06 to 1.58) but not when this was defined as a positive follow-up blood culture only (-0.57, 95%CI -1.28 to 0.14). ROC curve for detection of persistent candidemia by SeptiScore at day 1 follow-up showed an AUC of 0.85 (95%CI 0.52-1.00) when candidemia was defined by positive follow-up blood culture, and an AUC of 1.00 (95%CI 1.00-1.00) when candidemia was defined according to both methods. CONCLUSION: Integrating transcriptome profiling with culture-independent systems and conventional cultures may increase our ability to diagnose persistent candidemia.

Benchmarking for healthy food stores: protocol for a randomised controlled trial with remote Aboriginal and Torres Strait Islander communities in Australia to enhance adoption of health-enabling store policy and practice.

BACKGROUND: Aboriginal and Torres Strait Islander communities in remote Australia have initiated bold policies for health-enabling stores. Benchmarking, a data-driven and facilitated 'audit and feedback' with action planning process, provides a potential strategy to strengthen and scale health-enabling best-practice adoption by remote community store directors/owners. We aim to co-design a benchmarking model with five partner organisations and test its effectiveness with Aboriginal and Torres Strait Islander community stores in remote Australia. METHODS: Study design is a pragmatic randomised controlled trial with consenting eligible stores (located in very remote Northern Territory (NT) of Australia, primary grocery store for an Aboriginal community, and serviced by a Nutrition Practitioner with a study partner organisation). The Benchmarking model is informed by research evidence, purpose-built best-practice audit and feedback tools, and co-designed with partner organisation and community representatives. The intervention comprises two full benchmarking cycles (one per year, 2022/23 and 2023/24) of assessment, feedback, action planning and action implementation. Assessment of stores includes i adoption status of 21 evidence-and industry-informed health-enabling policies for remote stores, ii implementation of health-enabling best-practice using a purpose-built Store Scout App, iii price of a standardised healthy diet using the Aboriginal and Torres Strait Islander Healthy Diets ASAP protocol; and, iv healthiness of food purchasing using sales data indicators. Partner organisations feedback reports and co-design action plans with stores. Control stores receive assessments and continue with usual retail practice. All stores provide weekly electronic sales data to assess the primary outcome, change in free sugars (g) to energy (MJ) from all food and drinks purchased, baseline (July-December 2021) vs July-December 2023. DISCUSSION: We hypothesise that the benchmarking intervention can improve the adoption of health-enabling store policy and practice and reduce sales of unhealthy foods and drinks in remote community stores of Australia. This innovative research with remote Aboriginal and Torres Strait Islander communities can inform effective implementation strategies for healthy food retail more broadly. TRIAL REGISTRATION: ACTRN12622000596707, Protocol version 1.

Can capillary microsampling facilitate a clinical pharmacokinetics study of cefazolin in critically ill children?

Aim: Pharmacokinetic studies in children are limited, in part due to challenges in blood sampling. We compare the use of capillary microsampling and conventional sampling techniques in pediatric patients to show results that can be used in the pharmacokinetic analysis of Cefazolin. Patients & Methods: Paired blood samples (n = 48) were collected from 12 patients (median age/weight 49 months/18 kg). Results: The United States Federal Drug Administration incurred sample reanalysis acceptance criteria was used and identified 79% of paired samples achieved a difference of less than 20% in magnitude with a capillary microsampling bias of -10% (SD 20%). With exclusion of PK outliers, this rose to 88%. Conclusion: Capillary microsampling is reliable, meets acceptance criteria and can be used in pharmacokinetic studies.ACTRN: 12618001469202.

What is this article about? This study assesses a novel method of blood sample collection (capillary microsampling) for the analysis of a common antibiotic, cefazolin. In this study, we compare the results from samples collected using this method to blood tests taken in the traditional way.Capillary microsampling collects a very small volume of blood (about a drop of blood or 0.05 ml) taken from a skin prick and collected in a capillary tube. Traditional blood sampling collects a larger volume of blood (typically from 1 to 3 ml) taken from an artery or a vein. In this study, the patients (10 male and 2 female) had a mean age of 49 months and a mean weight of 18 kg. The amount of cefazolin in the blood samples were analyzed using the same methodology and results compared with assess the variability and reliability of the capillary microsampling method.What were the results? The results showed that difference of the two sample types is within the accepted criteria of the United States Federal Drug Administration and the European Medicines Agency, meaning the results are reliable.What do the results of the study mean? Blood samples for cefazolin can be small and easily obtained from a skin prick as a capillary microsample and can give reliable results. This greatly aids the ability to study the metabolism of cefazolin in children, particularly those that are not able to give a large amount of blood.

The Genomic Epidemiology of Clinical Burkholderia pseudomallei Isolates in North Queensland, Australia.

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.

Sensitivity and specificity of the Neonatal Visual Assessment to predict motor and cognitive outcomes in infants born very preterm.

BACKGROUND: Very preterm infants are at increased risk of neurodevelopmental impairments. The Neonatal Visual Assessment (NVA) assesses visual function and outcomes and has been used to assess early neurodevelopmental outcomes. This study aimed to compare NVA results of very preterm and term-born infants and to calculate the sensitivity and specificity of the NVA at term equivalent age (TEA) and three months corrected age (CA) to predict motor and cognitive outcomes at 12 months CA in very preterm infants. METHODS: This prospective observational cohort study recruited infants born before 31 weeks gestation and a healthy term-born control group. The NVA was assessed at TEA and three months CA, and neurodevelopmental outcomes (Bayley Scales of Infant and Toddler Development, Third Edition; Neurosensory Motor Developmental Assessment; Alberta Infant Motor Scale) were performed at 12 months CA. The sensitivity and specificity of the NVA to predict outcomes were calculated based on a previously published optimality score. RESULTS: 248 preterm (54 % male) and 46 term-born infants (48 % male) were analysed. The mean NVA scores of preterm and term-born infants were significantly different at TEA (preterm 3.1±2.1; term-born 1.2±1.7, p < 0.001). The NVA had moderate sensitivity (59-78 %) and low specificity (25-27 %) at TEA, and low sensitivity (21-28 %) and high specificity (86-87 %) at three months CA for the prediction of preterm infants' outcomes at 12 months CA. CONCLUSION: The NVA at TEA and three months CA was not a strong predictor of motor and cognitive impairments in this contemporary cohort of very preterm infants.

Hearing loss in Australian First Nations children at 6-monthly assessments from age 12 to 36 months: Secondary outcomes from randomised controlled trials of novel pneumococcal conjugate vaccine schedules.

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.

Characterization of gram-negative bloodstream infections in hospitalised Australian children and their clinical outcomes.

BACKGROUND: Gram-negative bloodstream infections (GNBSI) more commonly occur in children with comorbidities and are increasingly associated with antimicrobial resistance. There are few large studies of GNBSI in children that relate the clinical presentation, pathogen characteristics and outcomes. METHODS: A 3-year prospective study of GNBSI in children aged <18 years was conducted in five Australian children's hospitals between 2019-2021. 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 (IQR 0.6-8.5). 576/931 episodes (62%) were community onset though 661/931 (71%) occurred in children with comorbidities and a central venous catheter (CVC) was present in 558/931 (60%). CVC (145/931) and urinary tract (149/931) were the most common sources (16% each). 100/931 (11%) children required Intensive Care Unit (ICU) admission and a further 11% (105/931) developed GNBSI in ICU. 659/927 (71%) isolates were Enterobacterales of which 22% (138/630) were third generation cephalosporin resistant (3GCR). Extended spectrum beta-lactamase genes (ESBL) were confirmed in 65/138 (47%) 3GCR-Enterobacterales. Most common ESBL genes were blaCTX-M-15 (34/94, 36%) and blaSHV-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 OR 3.2, 95%CI 1.6-6.4). CONCLUSION: GNBSI in children are frequently healthcare-associated and affect children under 5 years. Infections with 3GCR Enterobacterales were associated with worse outcomes. These findings will inform optimal management guidelines and help prioritise future antimicrobial clinical trials.

Patient outcome quality indicators for older persons in acute care: original development data using interRAI AC-CGA.

BACKGROUND: A range of strategies are available that can improve the outcomes of older persons particularly in relation to basic activities of daily living during and after an acute care (AC) episode. This paper outlines the original development of outcome-oriented quality indicators (QIs) in relation to common geriatric syndromes and function for the care of the frail aged hospitalized in acute general medical wards. METHODS: Design QIs were developed using evidence from literature, expert opinion, field study data and a formal voting process. A systematic literature review of literature identified existing QIs (there were no outcome QIs) and evidence of interventions that improve older persons' outcomes in AC. Preliminary indicators were developed by two expert panels following consideration of the evidence. After analysis of the data from field testing (indicator prevalence, variability across sites), panel meetings refined the QIs prior to a formal voting process. SETTING: Data was collected in nine Australian general medical wards. PARTICIPANTS: Patients aged 70 years and over, consented within 24 h of admission to the AC ward. MEASUREMENTS: The interRAI Acute Care - Comprehensive Geriatric Assessment (interRAI AC-CGA) was administered at admission and discharge; a daily risk assessment in hospital; 28-day phone follow-up and chart audit. RESULTS: Ten outcome QIs were established which focused on common geriatric syndromes and function for the care of the frail aged hospitalized in acute general medical wards. CONCLUSION: Ten outcome QIs were developed. These QIs can be used to identify areas where specific action will lead to improvements in the quality of care delivered to older persons in hospital.

The effects of wearing textured versus smooth shoe insoles for 4-weeks in people with diabetic peripheral neuropathy: a randomised controlled trial.

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 REHABILITATIONShort-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.

Erdosteine in children and adults with bronchiectasis (BETTER trial): study protocol for a multicentre, double-blind, randomised controlled trial.

INTRODUCTION: Bronchiectasis is a worldwide chronic lung disorder where exacerbations are common. It affects people of all ages, but especially Indigenous populations in high-income nations. Despite being a major contributor to chronic lung disease, there are no licensed therapies for bronchiectasis and there remain relatively few randomised controlled trials (RCTs) conducted in children and adults. Our RCT will address some of these unmet needs by evaluating whether the novel mucoactive agent, erdosteine, has a therapeutic role in children and adults with bronchiectasis.Our primary aim is to determine in children and adults aged 2-49 years with bronchiectasis whether regular erdosteine over a 12-month period reduces acute respiratory exacerbations compared with placebo. Our primary hypothesis is that people with bronchiectasis who regularly use erdosteine will have fewer exacerbations than those receiving placebo.Our secondary aims are to determine the effect of the trial medications on quality of life (QoL) and other clinical outcomes (exacerbation duration, time-to-next exacerbation, hospitalisations, lung function, adverse events). We will also assess the cost-effectiveness of the intervention. METHODS AND ANALYSIS: We are undertaking an international multicentre, double-blind, placebo-RCT to evaluate whether 12 months of erdosteine is beneficial for children and adults with bronchiectasis. We will recruit 194 children and adults with bronchiectasis to a parallel, superiority RCT at eight sites across Australia, Malaysia and Philippines. Our primary endpoint is the rate of exacerbations over 12 months. Our main secondary outcomes are QoL, exacerbation duration, time-to-next exacerbation, hospitalisations and lung function. ETHICS AND DISSEMINATION: The Human Research Ethics Committees (HREC) of Children's Health Queensland (for all Australian sites), University of Malaya Medical Centre (Malaysia) and St. Luke's Medical Centre (Philippines) approved the study. We will publish the results and share the outcomes with the academic and medical community, funding and relevant patient organisations. TRIAL REGISTRATION NUMBER: ACTRN12621000315819.

Which reference equation should we use for interpreting spirometry values for First Nations Australians? A cross-sectional study.

OBJECTIVES: To evaluate the suitability of the Global Lung Function Initiative (GLI)-2012 other/mixed and GLI-2022 global reference equations for evaluating the respiratory capacity of First Nations Australians. DESIGN, SETTING: Cross-sectional study; analysis of spirometry data collected by three prospective studies in Queensland, the Northern Territory, and Western Australia between March 2015 and December 2022. PARTICIPANTS: Opportunistically recruited First Nations participants in the Indigenous Respiratory Reference Values study (Queensland, Northern Territory; age, 3-25 years; 18 March 2015 - 24 November 2017), the Healthy Indigenous Lung Function Testing in Adults study (Queensland, Northern Territory; 18 years or older; 14 August 2019 - 15 December 2022) and the Many Healthy Lungs study (Western Australia; five years or older; 10 October 2018 - 7 November 2021). MAIN OUTCOME MEASURES: Goodness of fit to spirometry data for each GLI reference equation, based on mean Z-score and its standard deviation, and proportions of participants with respiratory parameter values within 1.64 Z-scores of the mean value. RESULTS: Acceptable and repeatable forced expiratory volume in the first second (FEV1) values were available for 2700 First Nations participants in the three trials; 1467 were classified as healthy and included in our analysis (1062 children, 405 adults). Their median age was 12 years (interquartile range, 9-19 years; range, 3-91 years), 768 (52%) were female, and 1013 were tested in rural or remote areas (69%). Acceptable and repeatable forced vital capacity (FVC) values were available for 1294 of the healthy participants (88%). The GLI-2012 other/mixed and GLI-2022 global equations provided good fits to the spirometry data; the race-neutral GLI-2022 global equation better accounted for the influence of ageing on FEV1 and FVC, and of height on FVC. Using the GLI-2012 other/mixed reference equation and after adjusting for age, sex, and height, mean FEV1 (estimated difference, -0.34; 95% confidence interval [CI], -0.46 to -0.22) and FVC Z-scores (estimated difference, -0.45; 95% CI, -0.59 to -0.32) were lower for rural or remote than for urban participants, but their mean FEV1/FVC Z-score was higher (estimated difference, 0.14; 95% CI, 0.03-0.25). CONCLUSION: The normal spirometry values of healthy First Nations Australians may be substantially higher than previously reported. Until more spirometry data are available for people in urban areas, the race-neutral GLI-2022 global or the GLI-2012 other/mixed reference equations can be used when assessing the respiratory function of First Nations Australians.

Rapid Diagnostic Tests and Antimicrobial Stewardship Programs for the Management of Bloodstream Infection: What Is Their Relative Contribution to Improving Clinical Outcomes? A Systematic Review and Network Meta-analysis.

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 (BCs) 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.

The effects of vibrating shoe insoles on standing balance, walking, and ankle-foot muscle activity in adults with diabetic peripheral neuropathy.

BACKGROUND: Peripheral neuropathy is one of the most common complications of type 2 diabetes, which can lead to impaired balance and walking. Innovative footwear devices designed to stimulate foot sensory receptors, such as vibrating insoles, could offer a new route to improve motor impairments in people with diabetic peripheral neuropathy (DPN). RESEARCH QUESTION: Does wearing vibrating insoles for the first time alter measures of balance, walking, and ankle-foot muscle activity, in people with DPN? METHODS: A randomised cross-over study was conducted with 18 ambulant men and women with a diagnosis of DPN. Participants performed tests of standing balance (Bertec® force platform) under four conditions (foam/firm surface, eyes open/closed) and level-ground walking (GAITRite® instrumented walkway), whilst wearing vibrating and non-vibrating (control) insoles on two separate occasions (one insole/session). Electromyography (EMG) was used to assess soleus, medial gastrocnemius, tibialis anterior, peroneus longus activity during balance tests. Outcomes included centre of pressure (CoP) sway, EMG amplitude, spatiotemporal gait patterns, and Timed Up and Go test. One sample t-tests were used to explore %differences in outcomes between insole conditions. RESULTS: Wearing vibrating insoles led to a reduction (improvement) in CoP elliptical area, when standing on a foam surface with eyes closed, relative to non-vibrating insoles (P=0.03). Applying perceptible vibrations to the soles of the feet also reduced the EMG amplitude in soleus (P=0.01 and P=0.04) and medial gastrocnemius (P=0.03 and P=0.09) when standing with eyes closed on firm and foam surfaces. SIGNIFICANCE: Our findings of signs of improved balance and altered muscle activity with suprasensory vibrating insoles provides new insights into how these devices can be used to inform innovative rehabilitation approaches in individuals with DPN. This will be strengthened by further research into possible clinical benefits of these devices - given that the effects we detected were small with uncertain clinical meaning.

Win Ratio Analyses of Piperacillin-Tazobactam Versus Meropenem for Ceftriaxone-Nonsusceptible Escherichia coli or Klebsiella pneumoniae Bloodstream Infections: Post Hoc Insights From the MERINO Trial.

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.

Persistence of Detectable Pathogens by Culture-Independent Systems (T2 Magnetic Resonance) in Patients With Bloodstream Infection: Prognostic Role and Possible Clinical Implications.

BACKGROUND: Persistent Staphylococcus aureus bacteremia is associated with metastatic infection and adverse outcomes, whereas gram-negative bacteremia is normally transient and shorter course therapy is increasingly advocated for affected patients. Whether the prolonged detection of pathogen DNA in blood by culture-independent systems could have prognostic value and guide management decisions is unknown. METHODS: We performed a multicenter, prospective, observational study on 102 patients with bloodstream infection (BSI) to compare time to bloodstream clearance according to T2 magnetic resonance and blood cultures over a 4-day follow-up. We also explored the association between duration of detectable pathogens according to T2 magnetic resonance (magnetic resonance-DNAemia [MR-DNAemia]) and clinical outcomes. RESULTS: Time to bloodstream clearance according to T2 magnetic resonance was significantly longer than blood culture clearance (HR, .54; 95% CI, .39-.75) and did not differ according to the causative pathogen (P = .5). Each additional day of MR-DNAemia increased the odds of persistent infection (defined as metastatic infection or delayed source control) both in the overall population (OR, 1.98; 95% CI, 1.45-2.70) and in S. aureus (OR, 1.92; 95% CI, 1.12-3.29) and gram-negative bacteremia (OR, 2.21; 95% CI, 1.35-3.60). MR-DNAemia duration was also associated with no improvement in Sequential Organ Failure Assessment score at day 7 from infection onset (OR, 1.76; 95% CI, 1.21-2.56). CONCLUSIONS: T2 magnetic resonance may help diagnose BSI in patients on antimicrobials with negative blood cultures as well as to identify patients with metastatic infection, source control failure, or adverse short-term outcome. Future studies may inform its usefulness within the setting of antimicrobial stewardship programs.

Host response signature trends in persistent bacteraemia and metastatic infection due to Staphylococcus aureus and Gram-negative bacilli: a prospective multicentre observational study.

BACKGROUND: 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. METHODS: 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. RESULTS: 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. CONCLUSIONS: 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.

Levetiracetam for the treatment of mild cognitive impairment in Parkinson's disease: a double-blind controlled proof-of-concept trial protocol.

BACKGROUND: Mild memory impairment, termed amnestic mild cognitive impairment (aMCI), is associated with rapid progression towards dementia in Parkinson's disease (PD). Studies have shown hyperactivation of hippocampal DG/CA3 subfields during an episodic memory task as a biomarker of aMCI related to Alzheimer's disease. This project investigates the feasibility of a trial to establish the efficacy of a repurposed antiepileptic drug, levetiracetam, in low doses as a putative treatment to target DG/CA3 hyperactivation and improve episodic memory deficits in aMCI in PD. Based on previous work, it is hypothesized that levetiracetam will normalize DG/CA3 overactivation in PD-aMCI participants and improve memory performance. METHODS: Twenty-eight PD-aMCI participants, 28 PD participants without memory impairment (PD-nMI), and 28 healthy controls will be recruited. PD-aMCI participants will undertake a 12-week randomized, placebo-controlled, double-blind cross-over trial with a 14-day treatment of 125 mg levetiracetam or placebo twice daily, separated by a 4-week washout period. After each treatment period, participants will complete an episodic memory task designed to tax hippocampal subregion-specific function during high-resolution functional magnetic resonance imaging (fMRI). PD-nMI and healthy controls will undergo the fMRI protocol only, to compare baseline DG/CA3 subfield activity. RESULTS: Episodic memory task performance and functional activation in the DG/CA3 subfield during the fMRI task will be primary outcome measures. Global cognition, PD severity, and adverse events will be measured as secondary outcomes. Recruitment, eligibility, and study completion rates will be explored as feasibility outcomes. CONCLUSIONS: This study, the first of its kind, will establish hippocampal subregion functional impairment and proof of concept of levetiracetam as an early therapeutic option to reduce dementia risk in PD. TRIAL REGISTRATION: ClinicalTrials.gov, NCT04643327 . Registered on 25 November 2020.

Melioidosis Queensland: An analysis of clinical outcomes and genomic factors.

BACKGROUND: The clinical and genomic epidemiology of melioidosis varies across regions. AIM: To describe the clinical and genetic diversity of B. pseudomallei across Queensland, Australia. METHODS: Whole genome sequencing of clinical isolates stored at the melioidosis reference lab from 1996-2020 was performed and analysed in conjunction with available clinical data. RESULTS: Isolates from 292 patients were analysed. Bacteraemia was present in 71% and pneumonia in 65%. The case-fatality rate was 25%. Novel sequence types (ST) accounted for 51% of all isolates. No association was identified between the variable virulence factors assessed and patient outcome. Over time, the proportion of First Nation's patients declined from 59% to 26%, and the proportion of patients aged >70 years rose from 13% to 38%. CONCLUSION: This study describes a genomically diverse and comparatively distinct collection of B. pseudomallei clinical isolates from across Queensland, Australia. An increasing incidence of melioidosis in elderly patients may be an important factor in the persistently high case-fatality in this region and warrants further investigation and directed intervention.

Bloodstream infections in neutropenic and non-neutropenic patients with haematological malignancies: epidemiological trends and clinical outcomes in Queensland, Australia over the last 20 years.

Knowledge of the epidemiology of bloodstream infection (BSI) in haematology patients is essential to guide patient management. We investigated the epidemiology of BSI in patients with haematological malignancies in Queensland over the last 20 years (2000-2019), including all episodes diagnosed by the state-wide microbiology service. We identified 7749 BSI in 5159 patients, 58% associated with neutropenia. Gram-negatives were the main causative pathogens (58.3%), more frequent in neutropenic than non-neutropenic patients (3308/5309, 62.3% vs 1932/3678, 52.5%, p < 0.001). Amongst 8987 isolates the most common were E. coli (15.4%) and Pseudomonas spp. (14.2%). Pseudomonas spp. (16.6% vs 10.7%, p < 0.001), Klebsiella spp. (11.6% vs 6.8%, p < 0.001), viridans-group streptococci (4.4% vs 1.2%, p < 0.001) and E. faecium (2.4% vs 0.9%, p < 0.001) were more common in neutropenic than non-neutropenic patients, while S. aureus was less common (5.9% vs 15.6%, p < 0.001). Several antimicrobial resistance rates increased over time and had higher prevalence in neutropenic than non-neutropenic patients, including ciprofloxacin-resistant E. coli (94/758, 12.4% vs 42/506, 8.3%, p = 0.021), trimethoprim-sulfamethoxazole-resistant E. coli (366/764, 47.9% vs 191/517, 36.9%, p < 0.001), penicillin-resistant streptococci (51/236, 21.6% vs 28/260, 10.8%, p < 0.001) and vancomycin-resistant enterococci (46/250, 18.4% vs 9/144, 6.3%, p < 0.001). Carbapenem-resistant Pseudomonas spp. (OR 7.32, 95%CI 2.78-19.32) and fungi, including yeasts and moulds (OR 3.33, 95%CI 2.02-5.48) were associated to the highest odds of 30-day case-fatality at a multivariable logistic regression analysis. Neutropenia was associated with survival (OR 0.66, 95%CI 0.55-0.78). Differences were observed in the BSI epidemiology according to neutropenic status, with an overall increase of resistance over time associated to adverse outcome.

A prospective, observational study of frailty, quality of life and dialysis in older people with advanced chronic kidney disease.

BACKGROUND: Frailty is prevalent in older people with chronic kidney disease (CKD) and robust evidence supporting the benefit of dialysis in this setting is lacking. We aimed to measure frailty and quality of life (QOL) longitudinally in older people with advanced CKD and assess the impact of dialysis initiation on frailty, QOL and mortality. METHODS: Outpatients aged ≥65 with an eGFR ≤ 20ml/minute/1.73m2 were enrolled in a prospective observational study and followed up four years later. Frailty status was measured using a Frailty Index (FI), and QOL was evaluated using the EuroQol 5D-5L instrument. Mortality and dialysis status were determined through inspection of electronic records. RESULTS: Ninety-eight participants were enrolled. Between enrolment and follow-up, 36% of participants commenced dialysis and 59% died. Frailty prevalence increased from 47% at baseline to 86% at follow-up (change in median FI = 0.22, p < 0.001). Initiating dialysis was not significantly associated with change in FI. QOL declined from baseline to follow-up (mean EQ-5D-5L visual analogue score of 70 vs 63, p = 0.034), though commencing dialysis was associated with less decline in QOL. Each 0.1 increment in baseline FI was associated with 59% increased mortality hazard (HR = 1.59, 95%CI = 1.20 to 2.12, p = 0.001), and commencing dialysis was associated with 59% reduction in mortality hazard (HR = 0.41, 95%CI = 0.20 to 0.87, p = 0.020) irrespective of baseline FI. CONCLUSIONS: Frailty increased substantially over four years, and higher baseline frailty was associated with greater mortality. Commencing dialysis did not affect the trajectory of FI but positively influenced the trajectory of QOL from baseline to follow-up. Within the limitations of small sample size, our data suggests that frail participants received similar survival benefit from dialysis as non-frail participants.