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To investigate the immediate effects of wearing novel sensory-stimulating textured insoles on balance and gait in 41 people with multiple sclerosis (pwMS). Assessments of balance (firm/foam surface; eyes open/closed) and walking (when negotiating even/uneven surfaces) were performed wearing textured insoles, smooth insoles, shoes only, and barefoot. Outcome measures were centre of pressure (CoP) movement during standing (elliptical area, sway path velocity) and spatiotemporal gait patterns (stride/step width, stride time, double-limb support time, stride length, velocity). Wearing textured insoles led to reductions in CoP velocity measures when standing on foam with eyes open and closed when compared to barefoot (p values ≤0.02). Textured insoles did not appear to be consistently superior to smooth insoles or shoes only for improving gait. Relative to the insole/shoe conditions, walking barefoot led to poorer gait performance for the even and uneven surface tasks (p values ≤0.03). For pwMS, stimulating the foot with "texture" appears to provide enhanced sensory input with the capacity to improve CoP movement control during standing; offering a potential new treatment option for balance rehabilitation. Further research is needed to identify which individuals may benefit most from textured insoles. Textured shoe insoles, designed to stimulate plantar mechanoreceptors, are a novel approach to improve standing balance and walking patterns in people with multiple sclerosis (pwMS). Wearing textured insoles for the first time can lead to improvements in centre of pressure movement control when standing on an unstable compliant supporting surface. Textured insoles offer a potential new treatment technique for balance rehabilitation in pwMS who show early signs of diminished foot sensation. [ABSTRACT FROM AUTHOR]

Background Impetigo is caused by both Streptococcus pyogenesis and Staphylococcus aurous; the relative contributions of each have been reported to fluctuate with time and region. While S. aurous is reportedly on the increase in most industrialized settings, S. pyogenesis is still thought to drive impetigo in endemic, tropical regions. However, few studies have utilised high quality microbiological culture methods to confirm this assumption. We report the prevalence and antimicrobial resistance of impetigo pathogens recovered in a randomised, controlled trial of impetigo treatment conducted in remote Indigenous communities of northern Australia. Results From 508 children, we collected 872 swabs of sores and 504 swabs from the anterior nares prior to commencement of antibiotic therapy. S. pyogenesis and S. aurous were identified together in 503/872 (58%) of sores; with an additional 207/872 (24%) sores having S. pyogenesis and 81/872 (9%) S. aurous, in isolation. Skin sore swabs taken during episodes with a concurrent diagnosis of scabies were more likely to culture S. pyogenesis (OR 2.2, 95% CC 1.1 4.4, p = 0.03). Eighteen percent of children had nasal carriage of skin pathogens. There was no association between the presence of S. aurous in the nose and skin. Methicillin-resistance was detected in 15% of children who cultured S. aurous from either a sore or their nose. There was no association found between the severity of impetigo and the detection of a skin pathogen. Conclusions S. pyogenesis remains the principal pathogen in tropical impetigo; the relatively high contribution of S. aurous as a co-pathogen has also been confirmed. Children with scabies were more likely to have S. pyogenesis detected. While clearance of S. pyogenesis is the key determinant of treatment efficacy, co-infection with S. aurous warrants consideration of treatment options that are effective against both pathogens where impetigo is severe and prevalent. [ABSTRACT FROM AUTHOR]

Background. Nitric oxide (NO), a key macrophage antimycobacterial mediator that ameliorates immunopathology, is measurable in exhaled breath in individuals with pulmonary tuberculosis. We investigated relationships between fractional exhale NO (FENO) and initial pulmonary tuberculosis severity, change during treatment, and relationship with conversion of sputum culture to negative at 2 months.Methods. In Papua, we measured FENO in patients with pulmonary tuberculosis at baseline and serially over 6 months and once in healthy controls. Treatment outcomes were conversion of sputum culture results at 2 months and time to conversion of sputum microscopy results.Results. Among 200 patients with pulmonary tuberculosis and 88 controls, FENO was lower for patients with pulmonary tuberculosis at diagnosis (geometric mean FENO, 12.7 parts per billion [ppb]; 95% confidence interval [CI], 11.6–13.8) than for controls (geometric mean FENO, 16.6 ppb; 95% CI, 14.2–19.5; P = .002), fell further after treatment initiation (nadir at 1 week), and then recovered by 6 months (P = .03). Lower FENO was associated with more-severe tuberculosis disease, with FENO directly proportional to weight (P < .001) and forced vital-capacity (P = .001) and inversely proportional to radiological score (P = .03). People whose FENO increased or remained unchanged by 2 months were 2.7-fold more likely to achieve conversion of sputum culture than those whose FENO decreased (odds ratio, 2.72; 95% CI, 1.05–7.12; P = .04).Conclusions. Among patients with pulmonary tuberculosis, impaired pulmonary NO bioavailability is associated with more-severe disease and delayed mycobacterial clearance. Measures to increase pulmonary NO warrant investigation as adjunctive tuberculosis treatments. [ABSTRACT FROM AUTHOR]

Background: Innovative shoe insoles, designed to enhance sensory information on the plantar surface of the feet, could help to improve walking in people with Multiple Sclerosis. Objective: To compare the effects of wearing textured versus smooth insoles, on measures of gait, foot sensation and patient-reported outcomes, in people with Multiple Sclerosis. Methods: A prospective, randomised controlled trial was conducted with concealed allocation, assessor blinding and intention-to-treat analysis. Thirty ambulant men and women with multiple sclerosis (MS) (Disease Steps rating 1–4) were randomly allocated to wear textured or smooth insoles for 12 weeks. Self-reported insole wear and falls diaries were completed over the intervention period. Laboratory assessments of spatiotemporal gait patterns, foot sensation and proprioception, and patient-reported outcomes, were performed at Weeks 0 (Baseline 1), 4 (Baseline 2) and 16 (Post-Intervention). The primary outcome was the size of the mediolateral base of support (stride/step width) when walking over even and uneven surfaces. Independent t -tests were performed on change from baseline (average of baseline measures) to post-intervention. Results: There were no differences in stride width between groups, when walking over the even or uneven surfaces (P ≥ 0.20) at post-intervention. There were no between-group differences for any secondary outcomes including gait (all P values > 0.23), foot sensory function (all P values ≥ 0.08) and patient-reported outcomes (all P values ≥ 0.23). Conclusions: In our small trial, prolonged wear of textured insoles did not appear to alter walking or foot sensation in people with MS who have limited foot sensory loss. Further investigation is needed to explore optimal insole design. Clinical Trial Registration: Australian and New Zealand Clinical Trials Registry (ACTRN12615000421538). [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

The Motor Optimality Score, revised (MOS-R) is an extension of the Prechtl General Movements Assessment. This study aims to determine the relationship between MOS-R and 2-year neurodevelopmental outcomes in a cohort of 169 infants born very preterm (<31 weeks' gestational age), and to examine the predictive validity of the MOS-R at 3–4 months' corrected age (CA) above perinatal variables associated with poor outcomes, including Prechtl fidgety movements. Development at 2 years' CA was assessed using Bayley Scales of Infant and Toddler Development, Third edition (Bayley-III) (motor/cognitive impairment: Bayley-III ≤ 85) and Neurological, Sensory, Motor, Developmental Assessment (NSMDA) (neurosensory motor impairment: NSMDA ≥ 12). Cerebral palsy (CP) was classified at 2 years as definite or clinical. The MOS-R was related to 2-year outcomes: Bayley-III motor (BMOS-R = 1.24 95% confidence interval (0.78, 1.70)), cognitive (BMOS-R = 0.91 (0.48, 1.35)), NSMDA scores (BMOS-R = −0.34 (−0.42, −0.25)), definite CP (odds ratio [OR] 0.67 (0.53, 0.86)), clinical CP (OR 0.74 (0.66, 0.83)) for each 1-point increase in MOS-R. MOS-R ≤ 23 predicted motor (sensitivity 78% (60–91%); specificity 63% (54–72%)) and neurosensory motor impairment (sensitivity 86% (64–97%); specificity 59% (51–68%)). The MOS-R is strongly related to CP and motor and cognitive delay at 2 years and is a good predictor of motor and neurosensory motor impairment. [ABSTRACT FROM AUTHOR]

• GN-BSI patients have poor long-term mortality in comparison to a matched cohort • The underlying cause of death was due to infection only within the first 90 days • Sepsis was the contributory cause of death for one year after GN-BSI Understand the long-term mortality, risk of readmission for sepsis and cause of death following a gram-negative bloodstream infection (GN-BSI). 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. 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 < 0.001) and in the four subsequent years (P < 0.001). The five-year survival in the GN-BSI cohort was 52% versus 65% in the culture-negative cases (P < 0.001). Infection was only a common underlying cause of death within the first 90 days. Sepsis was the most common contributing cause of death (CCOD) for the two years following index culture in the GN-BSI cohort. Compared to a similarly vulnerable group of hospital attendees, GN-BSI had higher mortality and demonstrated a persistent long-term risk of readmission for sepsis and sepsis as a CCOD. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

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: Plasmodium knowlesi is the most common cause of human malaria in Malaysia. Acute kidney injury (AKI) is a frequent complication. AKI of any cause can have long-term consequences, including increased risk of chronic kidney disease, adverse cardiovascular events and increased mortality. Additional management strategies are therefore needed to reduce the frequency and severity of AKI in malaria. In falciparum malaria, cell-free haemoglobin (CFHb)-mediated oxidative damage contributes to AKI. The inexpensive and widely available drug paracetamol inhibits CFHb-induced lipid peroxidation via reduction of ferryl haem to the less toxic Fe3+ state, and has been shown to reduce oxidative damage and improve renal function in patients with sepsis complicated by haemolysis as well as in falciparum malaria. This study aims to assess the ability of regularly dosed paracetamol to reduce the incidence and severity of AKI in knowlesi malaria by attenuating haemolysis-induced oxidative damage.Methods: PACKNOW is a two-arm, open-label randomised controlled trial of adjunctive paracetamol versus no paracetamol in patients aged ≥ 5 years with knowlesi malaria, conducted over a 2-year period at four hospital sites in Sabah, Malaysia. The primary endpoint of change in creatinine from enrolment to 72 h will be evaluated by analysis of covariance (ANCOVA) using enrolment creatinine as a covariate. Secondary endpoints include longitudinal changes in markers of oxidative stress (plasma F2-isoprostanes and isofurans) and markers of endothelial activation/Weibel-Palade body release (angiopoietin-2, von Willebrand Factor, P-selectin, osteoprotegerin) over 72 h, as well as blood and urine biomarkers of AKI. This study will be powered to detect a difference between the two treatment arms in a clinically relevant population including adults and children with knowlesi malaria of any severity.Discussion: Paracetamol is widely available and has an excellent safety profile; if a renoprotective effect is demonstrated, this trial will support the administration of regularly dosed paracetamol to all patients with knowlesi malaria. The secondary outcomes in this study will provide further insights into the pathophysiology of haemolysis-induced oxidative damage and acute kidney injury in knowlesi malaria and other haemolytic diseases.Trial Registration: Clinicaltrials.gov, NCT03056391 . Registered on 12 October 2016. [ABSTRACT FROM AUTHOR]

Background: Plasmodium knowlesi is the most common cause of human malaria in Malaysia. Acute kidney injury (AKI) is a frequent complication. AKI of any cause can have long-term consequences, including increased risk of chronic kidney disease, adverse cardiovascular events and increased mortality. Additional management strategies are therefore needed to reduce the frequency and severity of AKI in malaria. In falciparum malaria, cell-free haemoglobin (CFHb)-mediated oxidative damage contributes to AKI. The inexpensive and widely available drug paracetamol inhibits CFHb-induced lipid peroxidation via reduction of ferryl haem to the less toxic Fe3+ state, and has been shown to reduce oxidative damage and improve renal function in patients with sepsis complicated by haemolysis as well as in falciparum malaria. This study aims to assess the ability of regularly dosed paracetamol to reduce the incidence and severity of AKI in knowlesi malaria by attenuating haemolysis-induced oxidative damage. Methods: PACKNOW is a two-arm, open-label randomised controlled trial of adjunctive paracetamol versus no paracetamol in patients aged ≥ 5 years with knowlesi malaria, conducted over a 2-year period at four hospital sites in Sabah, Malaysia. The primary endpoint of change in creatinine from enrolment to 72 h will be evaluated by analysis of covariance (ANCOVA) using enrolment creatinine as a covariate. Secondary endpoints include longitudinal changes in markers of oxidative stress (plasma F2-isoprostanes and isofurans) and markers of endothelial activation/Weibel–Palade body release (angiopoietin-2, von Willebrand Factor, P-selectin, osteoprotegerin) over 72 h, as well as blood and urine biomarkers of AKI. This study will be powered to detect a difference between the two treatment arms in a clinically relevant population including adults and children with knowlesi malaria of any severity. Discussion: Paracetamol is widely available and has an excellent safety profile; if a renoprotective effect is demonstrated, this trial will support the administration of regularly dosed paracetamol to all patients with knowlesi malaria. The secondary outcomes in this study will provide further insights into the pathophysiology of haemolysis-induced oxidative damage and acute kidney injury in knowlesi malaria and other haemolytic diseases. Trial registration: Clinicaltrials.gov, NCT03056391. Registered on 12 October 2016. [ABSTRACT FROM AUTHOR]

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. [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]

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 Amanda Leach and colleagues compare two pneumococcal conjugate vaccines to examine the impact on hearing loss Author summary: Why was this study done?: Chronic otitis media (OM) (middle ear infection) causes hearing loss, which is linked to developmental delay, poor school readiness, attendance, and performance. Almost every Australian First Nations child living in remote regions experiences chronic OM throughout their formative early years. Vaccines effective against OM pathogens, namely, pneumococcus and nontypeable Haemophilus influenzae, could reduce chronic early childhood hearing loss and change the trajectory of disadvantage. Two pneumococcal conjugate vaccines with different formulations potentially protect from infection by either 13 pneumococcal strains (PCV13), or 10 of these 13 pneumococcal strains plus all nontypeable H. influenzae (PHiD-CV10). Our hypothesis was that PHiD-CV10 would be superior to PCV13 in preventing hearing loss. No study had compared PCV13 and PHiD-CV10 in head-to-head or combination schedules. What did the researchers do and find?: We designed 2 consecutive (primary course then booster dose) randomised controlled trials of head-to-head and combination PCV13 and PHiD-CV10 schedules. Audiologists assessed hearing at 6-monthly visits from age 12 to 36 months. Moderate (disabling) hearing loss was detected in 42% (25/60), 32% (29/91), 34% (29/86), 33% (37/111), and 19% (22/113) children at ages 12, 18, 24, 30, and 36 months, respectively. Hearing Australia's recommendation for hearing assistance was met in around 70% children at ages 12 (67%, 40/60), 18 (69%, 63/91), and 24 months (71%, 61/86), respectively. Contrary to our hypothesis, PHiD-CV10 vaccine was not superior to PCV13 in reducing hearing loss. At primary endpoint age 18 months, the prevalence of moderate (disabling) hearing loss was halved in the PCV13 group (21% (9/42) compared to 41% (20/49) in the PHiD-CV10 group, and the prevalence of no hearing loss was double (36% and 16%, respectively). At ages 24, 30, and 36 months, this trend continued but differences were smaller. What do these findings mean?: The 19% lower prevalence of moderate hearing loss and 19% higher prevalence of no hearing loss in the PCV13 group at age 18 months is potentially highly clinically significant, particularly as the trend appears to be sustained, albeit smaller. Our study emphasises the importance of innovative and targeted research designs that meet the needs of high-risk populations and are independent of the pharmaceutical industry. Pneumococcal conjugate vaccine trials should evaluate impacts on child development. The small sample size creates uncertainty about the plausible difference in hearing between the two vaccines. We are 95% confident that the true difference is between 1% and 37%. [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]

Background: Fractional exhaled nitric oxide (Feno) levels can identify eosinophilic asthma phenotypes. We aimed to determine Feno values of healthy Aboriginal and/or Torres Strait Islander (Indigenous) Australians, differences between these Indigenous ethnic groups, and appropriateness of published cutoff values.Methods: We measured Feno levels in 1,036 Indigenous Australians (3-16 years of age). Participants were classified into healthy (ie, no asthma or atopy history) or asthmatic and/or atopic groups.Results: Median Feno values and distribution did not differ between Indigenous ethnicities. For healthy participants < 12 years of age (n = 390), 7.2% of our cohort fell into the inflammatory zone of the American Thoracic Society (ATS), National Institute for Health and Care Excellence (NICE), and British Thoracic Society (BTS)/Scottish Intercollegiate Guidelines Network (SIGN) guidelines (cutoff 35 parts per billion [ppb]), but only 3.8% fell into this category when using the Global Initiative for Asthma (GINA) guidelines (50 ppb). Similarly, when using the NICE and BTS/SIGN guidelines (40 ppb) for participants 12 to 16 years of age (n = 213), more healthy participants fell into the inflammatory zone compared with the ATS and GINA guidelines (50 ppb) (9.9% vs 4.7%, respectively).Conclusions: Feno values for healthy Indigenous Australians children (3-16 years of age) are likely higher than published white-based values. The GINA recommended cutoff value (> 50 ppb) appears the most appropriate for identifying healthy Indigenous children but requires confirmation from a larger study. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

The clinical progression of HFE-related hereditary hemochromatosis (HH) and its phenotypic variability has been well studied. Less is known about the natural history of non-HFE HH caused by mutations in the HJV, HAMP, or TFR2 genes. The purpose of this study was to compare the phenotypic and clinical presentations of hepcidin-deficient forms of HH. A literature review of all published cases of genetically confirmed HJV, HAMP, and TFR2 HH was performed. Phenotypic and clinical data from a total of 156 patients with non-HFE HH was extracted from 53 publications and compared with data from 984 patients with HFE-p.C282Y homozygous HH from the QIMR Berghofer Hemochromatosis Database. Analyses confirmed that non-HFE forms of HH have an earlier age of onset and a more severe clinical course than HFE HH. HJV and HAMP HH are phenotypically and clinically very similar and have the most severe presentation, with cardiomyopathy and hypogonadism being particularly prevalent findings. TFR2 HH is more intermediate in its age of onset and severity. All clinical outcomes analyzed were more prevalent in the juvenile forms of HH, with the exception of arthritis and arthropathy, which were more commonly seen in HFE HH. This is the first comprehensive analysis comparing the different phenotypic and clinical aspects of the genetic forms of HH, and the results will be valuable for the differential diagnosis and management of these conditions. Importantly, our analyses indicate that factors other than iron overload may be contributing to joint pathology in patients with HFE HH. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

Background: Bariatric surgery may increase the risk of micronutrient deficiencies; however, confounders including preoperative deficiency, supplementation and inflammation are rarely considered. Objective: To examine the impact of bariatric surgeries, supplementation and inflammation on micronutrient deficiency. Setting: Two public hospitals, Australia. Methods: Participants were recruited to an observational study monitoring biochemical micronutrient outcomes, supplementation dose, inflammation and glycaemic control, pre-operatively and at 1–3, 6 and 12 months after gastric bypass (GB; Roux-en-Y Gastric Bypass and Single Anastomosis Gastric Bypass; N = 66) or sleeve gastrectomy (SG; N = 144). Participant retention at 12 months was 81%. Results: Pre-operative micronutrient deficiency was common, for vitamin D (29–30%), iron (13–22%) and selenium (39% GB cohort). Supplement intake increased after surgery; however, dose was <50% of target for most nutrients. After SG, folate was vulnerable to deficiency at 6 months (OR 13 [95% CI 2, 84]; p = 0.007), with folic acid supplementation being independently associated with reduced risk. Within 1–3 months of GB, three nutrients had higher deficiency rates compared to pre-operative levels; vitamin B1 (21% vs. 6%, p < 0.01), vitamin A (21% vs. 3%, p < 0.01) and selenium (59% vs. 39%, p < 0.05). Vitamin B1 deficiency was independently associated with surgery and inflammation, selenium deficiency with improved glycaemic control after surgery and inflammation, whilst vitamin A deficiency was associated with inflammation only. Conclusion: In the setting of prophylactic post-surgical micronutrient prescription, few nutrients are at risk of de novo deficiency. Although micronutrient supplementation and monitoring remains important, rationalising high-frequency biochemical testing protocols in the first year after surgery may be warranted. [ABSTRACT FROM AUTHOR]

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. Author summary: Burkholderia pseudomallei is an environmental bacteria found in the soil and water of tropical and subtropical regions. This organism causes melioidosis, an infectious disease that often results in pneumonia and bloodstream infections. Previous studies have suggested a relationship between specific bacterial genetic factors and disease outcomes. This study reports on the clinical and bacterial genetic factors associated with disease outcomes in Queensland, Australia. A total of 292 patients and the associated bacterial isolates obtained from them during their hospital admission were analysed. The majority of patients presented with pneumonia and had a bloodstream infection. The case-fatality rate improved slightly over time but remains higher than other regions in Australia. Over the period of the study the proportion of First Nation's people affected decreased significantly. Notably, for reasons yet to be determined, the proportion of patients aged over 70 years increased over time. The bacterial genetic data demonstrate a high level of diversity across the region, however there was no association between previously described virulence genes and clinical outcomes in our cohort. This study creates a platform for further state-wide melioidosis research in Queensland. [ABSTRACT FROM AUTHOR]

Aim: To evaluate the predictive validity of the Hammersmith Neonatal Neurological Examination (HNNE) performed early (at 32 weeks postmenstrual age) and at term‐equivalent age (TEA) for 12‐month motor outcomes in infants born very preterm. Method: This was a diagnostic study using data from a prospective birth cohort. A total of 104 infants born preterm at less than 31 weeks gestational age (males n = 61; mean = 28 weeks 1 day [SD 1 week 6 days], range 23 weeks 1 day–30 weeks 6 days) underwent HNNE early and at TEA, which were scored by comparison with term data. Motor outcomes at 12 months corrected age were determined using the Bayley Scales of Infant and Toddler Development, Third Edition (scores ≤85). Cut‐off points were determined using receiver operating characteristic curves. Results: Sixteen (15%) infants born preterm had motor impairment at 12 months corrected age. The HNNE total score cut‐off points with the best combination of sensitivity and specificity at early and TEA assessments were 15.2 or lower (sensitivity 77%, 95% confidence interval [CI] = 46%–95%; specificity 74%, 95% CI = 63%–83%) and 23.5 or lower (sensitivity 67%, 95% CI = 38%–88%; specificity 66%, 95% CI = 54%–76%) respectively. The most predictive subscale at the early assessment was reflexes (sensitivity 86%, 95% CI = 57%–98%; specificity 62%, 95% CI = 51%–72%; cut‐off point ≤3); at TEA, it was spontaneous movements (sensitivity 73%, 95% CI = 45%–92%; specificity 60%, 95% CI = 48%–70%; cut‐off point ≤2). Interpretation: The HNNE provides moderate predictive accuracy for motor outcome at 12 months corrected age in infants born very preterm. Although modest at both time points, early assessment had stronger predictive ability for motor outcomes than TEA when scored using term data, highlighting the value of performing the HNNE earlier in the neonatal period. Performing HNNE earlier may assist risk stratification when planning follow‐up services. [ABSTRACT FROM AUTHOR]

Background: Anxiety is commonly experienced by people living with mild cognitive impairment (MCI) and dementia. Whilst there is strong evidence for late-life anxiety treatment using cognitive behavioural therapy (CBT) and delivery via telehealth, there is little evidence for the remote delivery of psychological treatment for anxiety in people living with MCI and dementia. This paper reports the protocol for the Tech-CBT study which aims to investigate the efficacy, cost-effectiveness, usability and acceptability of a technology-assisted and remotely delivered CBT intervention to enhance delivery of anxiety treatment for people living with MCI and dementia of any aetiology. Methods: A hybrid II single-blind, parallel-group randomised trial of a Tech-CBT intervention (n = 35) versus usual care (n = 35), with in-built mixed methods process and economic evaluations to inform future scale-up and implementation into clinical practice. The intervention (i) consists of six weekly sessions delivered by postgraduate psychology trainees via telehealth video-conferencing, (ii) incorporates voice assistant app technology for home-based practice, and (iii) utilises a purpose-built digital platform, My Anxiety Care. The primary outcome is change in anxiety as measured by the Rating Anxiety in Dementia scale. Secondary outcomes include change in quality of life and depression, and outcomes for carers. The process evaluation will be guided by evaluation frameworks. Qualitative interviews will be conducted with a purposive sample of participants (n = 10) and carers (n = 10), to evaluate acceptability and feasibility, as well as factors influencing participation and adherence. Interviews will also be conducted with therapists (n = 18) and wider stakeholders (n = 18), to explore contextual factors and barriers/facilitators to future implementation and scalability. A cost-utility analysis will be undertaken to determine the cost-effectiveness of Tech-CBT compared to usual care. Discussion: This is the first trial to evaluate a novel technology-assisted CBT intervention to reduce anxiety in people living with MCI and dementia. Other potential benefits include improved quality of life for people with cognitive impairment and their care partners, improved access to psychological treatment regardless of geographical location, and upskilling of the psychological workforce in anxiety treatment for people living with MCI and dementia. Trial registration: This trial has been prospectively registered with ClinicalTrials.gov: NCT05528302 [September 2, 2022]. [ABSTRACT FROM AUTHOR]

Aim: To describe the development of social function in children with cerebral palsy (CP) classified in all levels of the Communication Function Classification System (CFCS). Method: This prospective, longitudinal population‐based cohort study recruited children with CP born in Queensland, Australia. Social functioning was measured using the Pediatric Evaluation of Disability Inventory (PEDI) social function domain at 2 years, 2 years 6 months, 3 years, 4 years, and 5 years, and the PEDI Computer Adaptive Test (PEDI‐CAT) social/cognitive domain at 8 to 12 years. Results: Seventy‐four children provided 356 observations. PEDI‐CAT social/cognitive scaled scores at 8 to 12 years were (mean [SD] n) CFCS level I, 68.6 (2.7) 45; CFCS level II, 64.0 (3.4) 10; CFCS level III, 63.5 (3.7) 4; CFCS level IV, 56.8 (5.0) 9; CFCS level V, 47.2 (5.8) 6. Scores within expected range for age (not less than 2 SD below mean) at 8 to 12 years were achieved by 35 (78%) children in CFCS level I and four (14%) in CFCS levels II to V. Forty‐nine per cent of children scored at least two standard deviations below the population mean on a proxy measure of fluid intelligence. Intellectual impairment was associated with lower PEDI‐CAT social/cognitive scaled scores in univariable analysis (β = −8.3, 95% confidence interval − 10.91 to −5.63; p < 0.001) but had a smaller effect when modelled together with CFCS. Interpretation: Social function attained by 8 to 12 years of age was strongly related to level of communication function (CFCS). The small number of children classified in CFCS levels II to V necessitates caution when viewing these individual CFCS level trajectories. What this paper adds: There is a strong relation between social functioning and Communication Function Classification System (CFCS) levels.At 8 to 12 years, 35 out of 45 children in CFCS level I met social functioning age expectations.Twenty‐five out of 29 in CFCS levels II to V had social functioning below that expected for age.CFCS and age were more strongly associated with development of social functioning than Gross Motor Function Classification System or Manual Ability Classification System and age. What this paper adds: There is a strong relation between social functioning and Communication Function Classification System (CFCS) levels.At 8 to 12 years, 35 out of 45 children in CFCS level I met social functioning age expectations.Twenty‐five out of 29 in CFCS levels II to V had social functioning below that expected for age.CFCS and age were more strongly associated with development of social functioning than Gross Motor Function Classification System or Manual Ability Classification System and age. This original article is commented on by Eslinger on pages 596–597 of this issue. [ABSTRACT FROM AUTHOR]

Background: Fractional exhaled nitric oxide (Feno), used as a biomarker, is influenced by several factors including ethnicity. Normative data are essential for interpretation, and currently single cutoff values are used in children and adults.Research Question: Accounting for factors that influence Feno, (1) what are appropriate predicted and upper limit of normal (ULN) Feno values in an underserved population (First Nations Australians), (2) how do these values compare with age-based interpretive guidelines, and (3) what factors influence Feno and what is the size of the effect?Study Design and Methods: Feno data of First Nations Australians (age < 16 years, n = 862; age ≥ 16 years, n = 348) were obtained. Medical history using participant questionnaires and medical records were used to define healthy participants. Flexible regression using spline functions, as used by the Global Lung Function Initiative, were used to generate predicted and ULN values.Results: Look-up tables for predicted and ULN values using age (4-76 years) and height (100-200 cm) were generated and are supplied with a calculator for clinician use. In healthy First Nations children (age < 18 years), ULN values ranged between 25 and 60 parts per billion (ppb) when considering only biologically plausible age and height combinations. For healthy adults, ULN values ranged between 39 and 88 ppb. Neither the current Feno interpretation guidelines, nor the currently recommended cutoff of 50 ppb for First Nations children 16 years of age or younger were appropriate for use in this cohort. Our modelling revealed that predicted and ULN values of healthy participants varied nonlinearly with age and height.Interpretation: Because single pediatric, adult, or all-age Feno cutoff values used by current interpretive guidelines to define abnormality fail to account for factors that modify Feno values, we propose predicted and ULN values for First Nations Australians 4 to 76 years of age. Creating age- and height-adjusted predicted and ULN values could be considered for other ethnicities. [ABSTRACT FROM AUTHOR]

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 (< − 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, 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. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

Background: 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.Methods: 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).Findings: 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.Interpretation: 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.Funding: National Health and Medical Research Council (NHMRC). [ABSTRACT FROM AUTHOR]

Background: 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.Aims: To evaluate effectiveness of GSSIs at improving social functioning in adolescents with congenital, acquired or developmental disabilities.Methods and Procedures: 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.Outcomes and Results: 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).Conclusions and Implications: 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.What This Paper Adds: 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. [ABSTRACT FROM AUTHOR]

• The sensitivity of SARS-CoV-2 diagnostic tests is largely influenced by viral load. • The average viral loads decreased at a population level over time during pandemic. • Viral load change should be considered when choosing suitable diagnostic methods. The sensitivity of SARS-CoV-2 diagnostic tests is inherently linked to viral load. We explored whether average viral loads changed at a population level in Queensland, Australia during the early phase of the pandemic. RT-PCR threshold cycle (C T) values, a crude marker for viral load, were compared for samples collected in February/March-2020 to those collected in April/May-2020, noting that the major public health interventions began in late-March 2020. Positive detections peaked mid-March, which coincided with the highest detection numbers and lowest C T values. However, this changed from April where the later C T samples (C T > 30) predominated. Overall, in February/March 29% (267/922) of samples had C T values >30 cycles compared to 88% (559/636) in April/May. Our study shows that SARS-CoV-2 viral loads in patients may vary at a population level over time. This needs considering when assessing suitability of diagnostic methods, particularly when methods in question are known to have reduced sensitivity. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

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. 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. We systematically searched PubMed, Embase, PsychINFO and Web of Science. We included registered randomized controlled trials published in journals between January 2015 and December 2019. We included trials comparing different antibiotics for the treatment of infections caused predominantly by Gram-negative bacteria. 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. 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. 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. [ABSTRACT FROM AUTHOR]

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. 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. 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. 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. [ABSTRACT FROM AUTHOR]

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 (FEV1) was clinically abnormal for 54% of First Nations patients (51% of non-First Nations patients), forced vital capacity (FVC) for 46% (36%), FEV1/FVC% for 30% (36%), and gas diffusing capacity (DLCO) 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, FEV1 and FVC significantly improved (mean change: zFEV1 = 0.15 [95% CI 0.10–0.20]; zFVC = 0.25 [0.20, 0.31]), and FEV1/FVC% significantly reduced (mean = − 0.10 [95%CI − 0.07 to − 0.03]), with no significant change in DLCO. Patients with COPD had lower FEV1 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. [ABSTRACT FROM AUTHOR]

Background: Inequitable access to quality health care contributes to the known poorer outcomes of people living in regional/remote areas (compared with urban-based), especially for First Nations people. Integration of specialist outreach services within primary care is one strategy that can reduce the inequity when modeled to the needs and available resources of target communities.Research Question: To evaluate whether respiratory outreach clinics in regional and remote Queensland are as effective as tertiary respiratory services at improving the lung function of children.Study Design and Methods: From existing databases, we obtained spirometry data of children (aged 3-18 years) seen at Indigenous-focused outreach clinics in regional and remote Queensland and Brisbane-based pediatric tertiary hospitals over the same contemporary period (October 2010 to July 2019). We compared the change in spirometry z scores (Δz) at follow-up for both groups of children.Results: Lung function significantly improved in both groups: Tertiary hospital (n = 2,249; ΔzFEV1 = 0.22, 95% CI, 0.17 to 0.27; ΔzFVC = 0.23, 95% CI, 0.18 to 0.28); outreach (n = 252; ΔzFEV1 = 0.35, 95% CI, 0.22 to 0.48; ΔzFVC = 0.36, 95% CI, 0.23 to 0.50). No significant intergroup differences were found in ΔzFEV1 (0.13; 95%CI, -0.02 to 0.28; P = .10) or ΔzFVC (0.14; 95% CI, -0.02 to 0.29; P = .08) improvement from baseline. In both groups, the proportion of children with zFEV1 > 0 at follow-up (hospital = 31.7%; outreach = 46.8%) significantly increased (hospital P = .001; outreach P = .009) from baseline (hospital = 27.2%; outreach = 35.3%). Numbers of children with zFEV1 > 0 significantly increased for asthma and bronchiectasis outreach subgroups, and for children with asthma in the hospital-based group.Interpretation: Comparable significant lung function improvement of children was seen in Indigenous-focused outreach remote/regional clinics and paediatric tertiary hospitals. This suggests that effective clinical care is achievable within the outreach setting. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]