We examine the plausibility of Liu et al’s findings that COVID-19 (covid) vaccinations in 2022 protected older Australians from death from any cause, cerebrovascular disease, ischaemic heart disease, dementia, respiratory disease, and cancer. Such findings of protection from all-cause death need to be scrutinised given the Australian Bureau of Statistics’ (ABS) report of 13% excess mortality in 2022 in people aged 65-plus, a heavily vaccinated group. We examine the compatibility of a weighted average of Liu et al.’s all-cause mortality vaccine effectiveness data in the context of the ABS data on excess mortality. We find that the study results imply that, if there had been no vaccination of Australians in 2022, the excess mortality would have been 121%. Two independent lines of evidence (one based on OECD data, the other on Australian historical data) show 121% excess mortality to be implausible. We conclude that the effects on all-cause mortality attributed by the authors to the vaccine are more likely due to the study methodology. This raises concerns about the study findings on the effectiveness of the vaccines against covid itself. We suggest that the study should not be used to make recommendations for elderly Australians.

BACKGROUND:Self-expanding valves appear to have superior hemodynamics compared with balloon-expandable valves for valve-in-valve transcatheter aortic valve replacement (ViV-TAVR). OBJECTIVES:This study aimed to compare echocardiographic and clinical outcome data between supra-annular self-expanding valves (SASEVs) and intra-annular self-expanding valves (IASEVs), which in the past has remained limited, raising the need for further evaluation. METHODS:We analyzed ViV-TAVR procedures in the ACOR (Australian Cardiovascular Outcomes Registry). Patients receiving SASEV or IASEV were included. Baseline clinical and echocardiographic characteristics and postprocedure and 12-month outcomes were assessed. Echocardiographic parameters included gradients and left ventricular ejection fraction. Clinical outcomes included major adverse cardiac and cerebrovascular events, defined according to Valve Academic Research Consortium criteria. RESULTS:A total of 683 patients underwent ViV-TAVR: 566 (82.9%) with SASEV and 117 (17.1%) with IASEV. Baseline demographics were similar, although IASEV had higher rates of heart failure and a higher rate of baseline bioprosthetic valve regurgitation. Postprocedure echocardiographic findings were similar in both groups, with comparable mean gradients (14.9 mm Hg vs 13.3 mm Hg; P = 0.070), peak atrioventricular velocities (2.5 m/s vs 2.4 m/s; P = 0.073) and Dimensionless Performance Index (SASEV 0.4 vs IASEV 0.5; P < 0.001). At 12 months, although not statistically significant, there was a numerical trend toward higher major adverse cardiac and cerebrovascular events (11.9% vs 7.1%; P = 0.129) and stroke rates (5.4% vs 1.7%; P = 0.058) in the IASEV group. No significant differences were observed in mortality or bleeding. Findings were consistent after propensity score adjustment and multivariable logistic regression. CONCLUSIONS:Both SASEV and IASEV provide favorable and similar hemodynamic and clinical outcomes following ViV-TAVR.

OBJECTIVE:Rectal disease activity in ulcerative colitis is associated with a high symptom burden. The British Society of Gastroenterology (BSG) provides evidence-based recommendations for the management of ulcerative proctitis, which are relevant to patients with rectal disease activity; however, real-world adherence and outcomes remains unclear. This study aimed to evaluate adherence to BSG guideline-recommended management and its relationship with treatment timing and clinical outcomes. METHODS:We conducted a retrospective observational cohort study at a single tertiary center (2022-2024). Adults with endoscopically confirmed rectal disease activity in ulcerative colitis were included. Guideline adherence was assessed using predefined criteria derived from the BSG algorithm. Clinical, biochemical, endoscopic, and histological remission were evaluated at 12 months. RESULTS:Of 119 patients, 63 (52.9%) received guideline-adherent management. Adherence was significantly higher when treatment decisions were made at endoscopy compared with deferral to clinic (73 vs. 22%, RR: 0.30, 95% CI: 0.16-0.51; P < 0.001). At 12 months, clinical remission was achieved in 97/119 (81.5%), biochemical remission in 80/96 (83.3%), endoscopic remission in 36/68 (52.9%), and histological remission in 30/68 (44.1%). Guideline-adherent management showed numerically higher clinical remission rates, though not statistically significant. Deferral of treatment decisions was associated with a lower rate of clinical remission (72 vs. 86%), although not statistically significant (P = 0.06). CONCLUSION:Guideline adherence is suboptimal in real-world practice. Endoscopy-led decision-making were strongly associated with guideline adherence and represents a modifiable system-level factor in care delivery. High overall remission rates suggest that guideline adherence alone may be an incomplete surrogate for care quality.

Homelessness among adults receiving care in Australian public mental health services is common and clinically important. This study characterised homelessness across community and hospital settings among all publicly case managed adults in the Gold Coast region (Queensland, Australia) between January 2021 and December 2022, distinguishing primary homelessness (rough sleeping/public space), secondary homelessness (temporary or informal arrangements), and a hospital specific category, referred homelessness (loss of stable housing during admission).This retrospective longitudinal observational study linked 15,135 routinely collected service contacts for 2047 adults across community care, acute inpatient care, and extended treatment settings. Homelessness type was analysed separately at key service timepoints (community, admission, discharge) using multinomial generalised structural equation models with an individual-level random effect to account for repeated observations. Models produced adjusted, setting specific estimates for demographic, diagnostic, functional, and life-skills covariates.Overall, 33.22% of individuals experienced homelessness during the study period. Among those admitted to hospital, 41.75% had at least one admission while homeless, and 61.11% of those with a homeless admission also experienced a discharge to homelessness. In community care, homelessness was associated with substance use, violence related indicators, functional deficits, interpersonal difficulties, and self-care limitations. In hospital settings, homelessness at admission was strongly associated with homelessness at discharge, and discharge homelessness was associated with aggression, substance use, and occupational/activity impairment.These findings provide a whole of service adjusted description of homelessness across community and inpatient mental health care in a high-risk case managed cohort. Across settings, homelessness aligned more consistently with behavioural, functional, and system factors than with diagnosis alone, supporting service responses that integrate housing, substance use, functional support, and discharge planning.

BACKGROUND:Despite extensive efforts to lower low-density lipoprotein cholesterol (LDL-C), cardiovascular disease remains highly prevalent. Remnant cholesterol (RC) has been proposed as a potentially more relevant therapeutic target. OBJECTIVE:To evaluate the association between RC reduction and cardiovascular outcomes in randomized controlled trials (RCTs) of cholesterol- and triglyceride-lowering therapies, assessing whether RC independently influences cardiovascular risk. METHODS:Cochrane Central and Embase were searched for RCTs with ≥1000 participants and ≥2 years' planned duration that assessed cholesterol- or triglyceride-lowering therapies vs placebo, usual care, or other lipid-lowering drugs in adults. Two reviewers independently extracted data and evaluated methodological quality. Meta-analysis and meta-regression were performed. RESULTS:Forty-three RCTs met the inclusion criteria; most had some risk of bias, and evidence certainty was moderate. Meta-analysis showed absolute risk reductions of 0.4% (95% CI 0.1%-0.6%) for all-cause mortality, 1.3% (95% CI 1.1%-1.6%) for myocardial infarction, and 0.4% (95% CI 0.2%-0.6%) for stroke in treatment vs control groups. Meta-regression demonstrated no association between RC reduction and any clinical outcome, whereas LDL-C and non-high-density lipoprotein cholesterol reductions were associated with risk reduction. CONCLUSION:RC reduction was not associated with cardiovascular benefit. This contrasts with observational and Mendelian randomization (MR) studies, likely reflecting methodological differences; MR estimates lifelong genetically mediated exposure and may not reliably predict the effects of short-term pharmacological lipid lowering.

Background:The estimated effectiveness of SMS (short message service) reminders for improving childhood vaccine coverage and timeliness has varied in previous studies. The observed heterogeneity in effectiveness may be explained in part by variation in reminder content or timing of the reminder relative to the vaccine schedule date. We sought to evaluate the effectiveness of a range of SMS reminders of varied content and timing for improving on-time childhood vaccination. Methods:AuTOMATIC was a multi-centre Bayesian adaptive factorial randomised trial comparing four alternative SMS message framings at three alternative message timings versus a no reminder control strategy. Participants were parents of children registered with one of 20 primary care clinics Australia-wide and randomly assigned to one of 12 SMS reminder arms or to control. Reminders varied by framing of content (neutral, positive, risk-based or social benefit) and timing (14 days prior to the due date, on the due date, or 7 days afterwards). The primary endpoint was on-time vaccination, i.e. within 28 days of its scheduled date. Allocation probabilities were updated and stopping rules implemented over the trial according to pre-specified rules based on the posterior probability of effectiveness of each arm evaluated at interim analyses. Trial procedures were largely digitally automated. This trial was registered on Australian New Zealand Clinical Trials Registry (ACTRN12618000789268). Findings:Between January 14, 2021 and February 26, 2024, 9993 parents were randomised and all were included in the primary analysis; between 380 and 1110 were assigned to each of the 12 SMS reminder arms and 637 to control. The adjusted odds ratio (aOR) of on-time vaccination for each of the 12 SMS arms compared to control ranged from 1.02 [95% CrI 0.76-1.34] to 1.53 [1.22, 1.92] with a pooled effect aOR of 1.29 [1.06, 1.55]. This pooled effect corresponded to a standardised difference of 6% [2%, 11%] in the proportion of on-time vaccinations. Interpretation:On average, SMS reminders were associated with a modest increase in on-time vaccination compared to no reminder. There was evidence that neutral SMS reminders were less effective than persuasive reminders, but we were unable to identify a single best combination of reminder content framing and timing. Funding:Ramaciotti Foundations, Royal Australasian College of Physicians, and the Western Australia Department of Health.

AIM:The aim of this Phase I trial was to assess the safety, compliance, and potential efficacy of iLidcombe, a standalone internet version of the Lidcombe Program for young children who stutter. METHOD:We used a prospective single-group design involving 6 months of access to iLidcombe. Assessments occurred pretreatment and after 6 months of access. Participants were 20 parents of young children who stuttered. RESULTS:There was evidence of stuttering severity reduction after using iLidcombe for 6 months. Compliance with the program was favorable, and there was no suggestion of any psychologically adverse impact on children. CONCLUSION:The results of this Phase I trial provide a roadmap for further Phases II-IV clinical trial development.

Background: Catheter-related thrombosis (CRT) is a complication of central venous access devices (CVADs). Evidence is variable regarding the significance of the side of catheter insertion. The role of the patient's hand dominance in predisposition to CRT remains uncertain. Objectives: In a prospective randomized controlled trial, adult cancer patients were randomly allocated to either dominant or nondominant side CVAD insertion. The primary endpoint of this trial examined the incidence of catheter-associated bloodstream infection. Here, we report the secondary endpoint of the incidence of CRT. Methods: Six hundred forty CVADs were randomized to the dominant (n = 322) or nondominant (n = 318) side of insertion. Only symptomatic patients underwent ultrasound imaging to evaluate for CRT. Results: The median patient age was 58 years, 60% of patients had hematologic malignancies and 40% had solid tumors. CVADs used were peripherally-inserted central catheter line (67%), tunneled CVAD (23%), or nontunneled CVAD (10%). The CRT incidence rate was 0.65 versus 0.82 per 1000 line days in the dominant versus nondominant group (hazard ratio [HR], 1.2; 95% CI, 0.58-2.48; P = .63). There was no significant difference in CRT incidence rate between left- and right-sided insertions (HR, 0.63; 95% CI, 0.30-1.32; P = .22). The CRT incidence rate was lower in right-handed versus left-handed line inserters (HR, 0.29; 95% CI, 0.12-0.71; P = .007). Conclusion: The rate of CRT was not associated with whether CVAD insertion was on the patient's dominant or nondominant side or the side of insertion. The role of inserter hand dominance requires further investigation.

Background: The proportional odds (PO) model is the most common analytic method for ordinal outcomes in randomised controlled trials. While parameter estimates obtained under departures from PO can be interpreted as an average odds ratio, they can obscure differing treatment effects across the distribution of the ordinal categories. Extensions to the PO model exist and this work evaluates their performance under deviations to the PO assumption. Methods: We evaluated the bias, coverage and mean square error of four modeling approaches for ordinal outcomes via Monte Carlo simulation. Specifically, independent logistic regression models, the PO model, and constrained and unconstrained partial proportional odds (PPO) models were fit to simulated ordinal outcome data. The simulated data were designed to represent a hypothetical two-arm randomised trial under a range of scenarios. Additionally, we report on a case study; an Australasian COVID-19 Trial that adopted multiple secondary ordinal endpoints. Results: The PO model performed best when the data are generated under PO, as expected, but can result in bias and poor coverage in the presence of non-PO, particularly with increasing effect size and number of categories. The odds ratios (ORs) estimated using the unconstrained PPO and separate logistic regression models in the presence of non-PO had negligible bias and good coverage across most scenarios. The unconstrained PPO model under-performed when there was sparse data within some categories. Conclusions: While the PO model is effective when PO holds, the unconstrained and constrained PPO and logistic regression models provide unbiased and efficient estimates under non-PO conditions.

PURPOSE:The present study aims to report on the psychosocial outcomes of children aged 6-12 years who did or did not respond to the Lidcombe Program. METHOD:Thirty-seven 6- to 12-year-old children participated in a Phase II trial of the Lidcombe Program using video telehealth. Treatment progress was documented using stuttering severity ratings and three psychosocial outcome measures (Overall Assessment of the Speaker's Experience of Stuttering-School-Age Children, Communication Attitude Test, and Spence Children's Anxiety Scale). We examine the results of these psychosocial outcomes in relation to children who did and did not respond to the program. RESULTS:Significant improvements were observed across all psychosocial measures, irrespective of responsiveness group. Individual trajectories highlighted heterogeneity, but group data revealed statistically significant reductions in measures of stuttering impact, negative communication attitudes, and anxiety symptoms from pretreatment to 12 months posttreatment, with no evidence of differential effects between responsiveness groups. CONCLUSIONS:Findings suggest that the Lidcombe Program may provide psychosocial benefits beyond stuttering reduction to some children, potentially through the therapeutic alliance fostered between clinicians, children, and families. The Lidcombe Program appears to be psychologically safe and may confer psychosocial advantages for school-age children who stutter, regardless of whether their stuttering partially reduced, stopped, or persisted. Future research should explore longer term maintenance of these psychosocial gains and conduct a randomized controlled trial to evaluate the effect of the Lidcombe Program relative to a control group.

Background: Ordinal outcomes combine multiple distinct ordered patient states into a single endpoint and are commonly analysed using proportional odds (PO) models in clinical trials. When using a Bayesian approach, it is not obvious what the influence of a 'non-informative' prior is in the analysis of a fixed design or on early stopping decisions in adaptive designs. Methods: This study compares different non-informative prior specifications for the Bayesian PO model in the context of both a two-arm trial with a fixed design and an adaptive design with an early stopping rule. We conducted an extensive simulation study, varying the effect size, sample size, number of categories and distribution of the control arm probabilities. Results: Our findings indicate that the choice of prior specification can introduce bias in the estimation of the treatment effect, particularly when control arm probabilities are right-skewed. The R-square prior specification resulted in the smallest bias and increased the likelihood of appropriately stopping early when there was a treatment effect. However, this specification exhibited larger biases when control arm probabilities were U-shaped when there was an early stopping rule. Dirichlet priors with concentration parameters close to zero resulted in the smallest bias when probabilities were right-skewed in the control arm, but were more likely to inappropriately stop early for superiority when there was no treatment effect and an early stopping rule. Conclusions: The specification of non-informative priors in Bayesian adaptive trials with ordinal outcomes has implications for treatment effect estimation and early stopping decisions. We recommend the careful selection of priors that consider the possible distribution of control arm probabilities and that sensitivity analyses to the prior be conducted.

Clinical trials are an integral component of medical research. Trials require careful design to, for example, maintain the safety of participants and to use resources efficiently. Adaptive clinical trials are often more efficient and ethical than standard or non-adaptive trials because they can require fewer participants, target more promising treatments, and stop early with sufficient evidence of effectiveness or harm. The design of adaptive trials is usually undertaken via simulation, which requires assumptions about the data-generating process to be specified a priori. Unfortunately, if such assumptions are misspecified, then the resulting trial design may not perform as expected, leading to, for example, reduced statistical power or an increased Type I error. Motivated by a clinical trial of a vaccine to protect against gastroenteritis in infants, we propose an approach to design adaptive clinical trials with time-to-event outcomes without needing to explicitly define the data-generating process. To facilitate this, we consider trial design within a general Bayesian framework where inference about the treatment effect is based on the partial likelihood. As a result, inference is robust to the form of the baseline hazard function, and we exploit this property to undertake trial design when the data-generating process is only implicitly defined. The benefits of this approach are demonstrated via an illustrative example and via redesigning our motivating clinical trial.

Background:Progress in reducing morbidity and mortality due to neonatal sepsis has slowed in recent decades and is threatened by the global rise of antimicrobial resistance. The populous Southeast Asian region has a high burden of both neonatal sepsis and antimicrobial resistance (AMR). Despite this, there remains a lack of robust data on the epidemiology of neonatal sepsis and the prevalence of AMR within the region. Methods:We evaluated positive blood cultures and susceptibility profiles responsible for neonatal sepsis across 10 clinical sites in five countries in South and Southeast Asia (Sri Lanka, Indonesia, The Philippines, Malaysia, and Vietnam). Retrospective data on all blood cultures collected from neonates over two years (1st January 2019-31st December 2020) were extracted from laboratory records. Data were also collected on the availability and implementation of infection prevention and control resources, and antimicrobial prescribing practices. Pooled estimates across sites and pathogens were generated, with adjustment for clustering. Findings:Of 14,804 blood cultures collected over the study period, a total of 2131 positive isolates (including 1483 significant pathogens) were identified. Gram-negative bacteria predominated as causative of neonatal sepsis (78·4%; 1163/1483) with Klebsiella spp. (408/1483; 27·5%) and Acinetobacter spp. (261/1483; 17·6%) most frequently isolated overall. Adjusted pooled non-susceptibility for Klebsiella spp. was 86·7% (95% CI 54·0-98·5) for third-generation cephalosporins (ceftriaxone and/or cefotaxime; 3GC) and 17·1% (95% CI 8·1-24·7) for carbapenems; while non-susceptibility for Escherichia coli was 46·4% (95% CI 20·0-72·0) for 3GC and 15·4% (95% CI 2·7-31·0) for carbapenems. Carbapenem non-susceptibility for Acinetobacter spp. was 76·5% (95% CI 59·4-84·5). Gram-positive bacteria accounted for 13·2% (196/1483) of pathogens causative of neonatal sepsis, whilst Candida spp. accounted for 8·3% (123/1483) of culture-positive sepsis episodes. Interpretation:Neonatal sepsis in tertiary hospitals in Southeast Asia is predominantly caused by gram-negative bacteria, with high rates of non-susceptibility to commonly prescribed antibiotics. Funding:This study was supported by an Australian National Health and Medical Research Council (NHMRC) grant. The NHMRC was not involved in the design or conduct of the research.

INTRODUCTION:With the increasing accessibility of tools such as ChatGPT, Copilot, DeepSeek, Dall-E, and Gemini, generative artificial intelligence (GenAI) has been poised as a potential, research timesaving tool, especially for synthesising evidence. Our objective was to determine whether GenAI can assist with evidence synthesis by assessing its performance using its accuracy, error rates, and time savings compared to the traditional expert-driven approach. METHODS:To systematically review the evidence, we searched five databases on 17 January 2025, synthesised outcomes reporting on the accuracy, error rates, or time taken, and appraised the risk-of-bias using a modified version of QUADAS-2. RESULTS:We identified 3,071 unique records, 19 of which were included in our review. Most studies had a high or unclear risk-of-bias in Domain 1A: review selection, Domain 2A: GenAI conduct, and Domain 1B: applicability of results. When used for (1) searching GenAI missed 68% to 96% (median = 91%) of studies, (2) screening made incorrect inclusion decisions ranging from 0% to 29% (median = 10%); and incorrect exclusion decisions ranging from 1% to 83% (median = 28%), (3) incorrect data extractions ranging from 4% to 31% (median = 14%), (4) incorrect risk-of-bias assessments ranging from 10% to 56% (median = 27%). CONCLUSION:Our review shows that the current evidence does not support GenAI use in evidence synthesis without human involvement or oversight. However, for most tasks other than searching, GenAI may have a role in assisting humans with evidence synthesis.

Objective: To describe the injury epidemiology of the Australian women's professional football (soccer) league (A-League W) over 7 consecutive seasons. Design: Prospective observational cohort study. Methods: Match-loss injury data was collected from each A-League W club (n = 8-9) for each competition round (n = 12/season) over 7 seasons (2013/14-2019/20). Data was collected by the head physiotherapist in each club based on the governing body regulations and after initial familiarisation with collection methods. Injuries were collected weekly through a standardised protocol for all clubs and were classified by setting, mechanism, severity, the type and location on the body based on club, round and season. Generalised Linear Models were used to estimate the injury incidences (injury/round/season), whilst rate ratios were reported for total injuries and within abovementioned injury classifications for the change between seasons. Results: Injury incidence rate ranged between 0.68 (95 % CI: 0.27-1.74) and 1.17 (95 % CI: 0.59-2.34) injuries/ match/round across the 7 seasons analysed. There was no significant change over time in injuries by occurrence (i.e. match, training or other), mechanism (contact or non-contact), type or region. The most common injuries were joint and ligament injuries (0.24 (95 % CI: 0.05-1.17)-0.85 (95 % CI: 0.38-1.91) injuries/round/season), ankle injuries (0.13 (95 % CI: 0.02-0.95)-0.41 (95 % CI: 0.13-1.32) injuries/round/season) and non-contact mechanisms (0.48 (95 % CI: 0.18-1.27)-1.07 (95 % CI: 0.52-2.2) injuries/round/season). Conclusions: Injury incidence trends did not show a significant change over the seven seasons of the A-League W reported here. Key areas of concern for female players remain injuries to the ankle, thigh and knee. Whilst specific to the Australian environment, these outcomes provide further understanding of the type and rate of injury trends in female footballers. (c) 2024 Sports Medicine Australia. Published by Elsevier Ltd. All rights are reserved, including those for text and data mining, AI training, and similar technologies.

SummaryBackgroundWhole-cell pertussis (wP) and acellular pertussis (aP) vaccines evoke different immune responses to pertussis vaccine antigens. We compared the effect of a heterologous wP/aP/aP primary series (hereafter mixed wP/aP) versus a homologous aP/aP/aP primary schedule (hereafter aP-only) on antibody responses to co-administered vaccine antigens in infants and toddlers.MethodsWe randomised Australian infants in a 1:1 ratio to receive either a mixed wP/aP schedule (pentavalent diphtheria-tetanus-wP-hepatitis B-Haemophilus influenzaetype b; DTwP-HepB-Hib vaccine at 6 weeks old followed by hexavalent DTaP-inactivated poliovirus vaccine (IPV)-HepB-Hib vaccine at 4 and 6 months old) or to aP-only priming doses of hexavalent DTaP-IPV-HepB-Hib vaccine at the same ages. All infants received 13-valent pneumococcal conjugate vaccine (13vPCV) at 6 weeks, 4 and 12 months of age and DTaP-IPV and Hib vaccine boosters at 18 months. We estimated the ratio (GMR) of IgG geometric mean concentrations (GMCs) in the wP/aP and aP-only groups for the serotypes included in the 13vPCV, for Hib capsular polysaccharide polyribosylribitol phosphate (PRP), and for hepatitis B surface antigen (HBsAg) at 6, 7, 18, and 19 months. We assessed whether the wP/aP schedule is non-inferior to the aP-only schedule for co-administered vaccine antigens (GMR>2/3). Trial registration: ACTRN12617000065392p.ResultsBetween March 2018 and January 2020, 150 infants were randomised (75 per study arm). Responses to all 13vPCV serotypes and Hib-PRP at 6, 7, 18, and 19 months old, as well as HBsAg at 6 and 7 months old were non-inferior (>90% probability). Sera GMCs were higher for each 13vPCV serotype, Hib-PRP, and HBsAg at each timepoint in the wP/aP group than in the aP-only group.InterpretationA mixed wP/aP schedule resulted in non-inferior IgG responses to co-administered vaccine antigens compared to the standard aP-only schedule for pertussis primary immunisation.FundingTelethon New Children’s Hospital Research Fund and National Health and Medical Research Council.Research in contextEvidence before this studyCombination vaccines incorporate antigens that protect against multiple diseases into a single injection. Most low- and middle-income countries (LMICs) currently use wP combination vaccines. Due to the need for periodic boosters to protect older children, adolescents, and adults, these countries may consider moving to the less reactogenic aP combination vaccines that are routinely used in most high-income countries. We searched for evidence about whether a mixed wP/aP primary schedule impacts the immunogenicity of co-administered vaccines. We were particularly interested in evidence for impacts on 13vPCV 2 + 1 schedule and other pneumococcal dose-sparing schedules. We searched PubMed on May 23, 2024, for randomised controlled trials using the following search terms “pneumococcal”, “routine vaccin*”, and “pertussis” combined with Boolean operators, without date or language restrictions. We failed to identify any head-to-head randomised comparisons of the effect of heterologous (mixed) versus homologous pertussis vaccine primary series on co-administered vaccine antigens. Our previous meta-analysis reviewed 15 randomised controlled studies that compared serious adverse events among infants receiving wP versus aP as a first dose before 6 months of age. Few studies reported immune responses to non-DTP co-administered antigens. These findings suggest enhanced Hib responses among recipients of a three-dose primary series of wP compared to those who received three primary aP doses, non-inferior Hib-PRP seroprotection among aP compared to wP vaccinees, and mixed results regarding HBsAg-IgG levels post-wP priming. Both wP and aP groups exhibited weaker Hib-PRP IgG responses when DTP-Hib vaccines were co-administered with meningococcal serogroup C vaccine conjugated to cross-reactive material 197 (CRM197) compared to the meningococcal serogroup C vaccine conjugated to tetanus toxoid (TT).Added value of this studyThis paper is the first reported evidence of a mixed wP/aP schedule resulting in non-inferior IgG responses to co-administered vaccine antigens compared to the standard homologous aP-only schedule for pertussis primary immunisation. In addition, enhanced immune responses were observed to all serotypes included in the 13vPCV and Hib-PRP vaccines in children receiving the mixed wP/aP vaccination strategy versus those vaccinated with a standard aP-only schedule.Implications of all the available evidenceIn settings transitioning from using wP to aP multi-component vaccines, infants receiving a mixed schedule (with wP as the first dose) can be expected have non-inferior, and possibly superior, antibody responses to concomitant vaccine antigens. To better understand the underlying mechanisms of our findings, the assessment of opsonophagocytic activity response rates and serotype-specific memory B cell immune responses to PCV antigens is required. Large population-based studies, particularly in countries where pneumococcal and Hib disease burdens remain high, should be conducted to determine if the observed effects on immune responses translate into differences in protection against disease.

BACKGROUND:The use of nasal high-flow (NHF) oxygen for apnoeic oxygenation during emergency paediatric intubation is not universally adopted. Although previous studies suggest potential benefits, it remains unclear whether NHF enhances the likelihood of achieving successful first-attempt intubation without oxygen desaturation in children. We aimed to investigate whether the provision of NHF oxygen during paediatric emergency intubation can improve intubation outcomes. METHODS:We conducted a randomised, controlled, open-label trial at ten hospitals in Australia, New Zealand, and Switzerland (four emergency departments, ten paediatric intensive care units, and one non-maternity neonatal intensive care unit were included). Children younger than 16 years undergoing emergency endotracheal intubation were eligible for inclusion. Participants were randomly assigned (1:1) to receive either NHF apnoeic oxygenation or standard care during intubation. The primary outcomes were the occurrence of hypoxaemic events (defined as oxygen saturation [SpO2] ≤90%) and successful intubation on the first attempt without desaturation in the modified intention-to-treat population (all intubations in participants for whom prospective or retrospective consent was given and a primary outcome was recorded). This trial is registered with the Australian New Zealand Clinical Trials Registry (ACTRN12617000147381) and is now completed. FINDINGS:Between May 9, 2017, and Oct 22, 2022, 1069 intubations in 969 children were randomly assigned to the NHF group (535 intubations) or standard care group (534 intubations). The primary analysis comprised 950 intubations in 860 children, with 476 intubations in the NHF group and 474 in the standard care group. In the NHF group, hypoxaemic events occurred in 61 (12·8%) of 476 intubations, compared with 77 (16·2%) of 474 in the standard care group (adjusted odds ratio [aOR] 0·74; 97·5% CI 0·46-1·18; p=0·15). Successful intubation was achieved at the first attempt in 300 (63·0%) of 476 intubations in the NHF group and 280 (59·1%) of 474 intubations in the standard care group (aOR 1·13; 97·5% CI 0·79-1·62; p=0·43). In the per-protocol analysis of 905 intubations, NHF reduced the rate of hypoxaemia (48 [10·8%] of 444) compared with standard care (77 [16·7%] of 461; aOR 0·59; 97·5% CI 0·36-0·97; p=0·017). In this analysis, first-attempt successful intubation was achieved in 284 (64·0%) of 444 intubations in the NHF group versus 268 (58·1%) of 461 intubations in the standard care group (aOR 1·22; 97·5% CI 0·87-1·71; p=0·19). INTERPRETATION:The use of NHF during emergency intubation in children did not result in a reduction in hypoxaemic events or an increase in the frequency of successful intubation on the first attempt. However, in the per-protocol analysis, there were fewer hypoxaemic events but no difference in successful intubation without hypoxaemia on first attempt. Barriers to the application of NHF during emergency intubation and the reasons for abandoning intubation attempts before physiological compromise should be further investigated to inform future research and recommendations for intubation guidelines and clinical practice. FUNDING:Thrasher Research Fund (USA), National Health and Medical Research Council (Australia), and the Emergency Medicine Foundation (Australia).

BACKGROUND:Interventions to reduce antibiotic use focus on general practitioners (GPs) and patient behaviour, not pharmacists, who may inadvertently drive antibiotic expectations by referrals to GPs. No data are available on pharmacist referrals for suspected antibiotic-requiring infections. We conducted a feasibility pilot to provide data for robust sample size calculation and identify areas for further exploration. METHOD:Pharmacists and GPs were recruited independently using convenience sampling. They completed prospective data collection on 20 consecutive minor ailment encounters and consultations respectively. Pharmacists recorded patient gender, age, referral reason, and any comments. GPs recorded patient age, gender, reason for visit, and origin of patient referral including self-referral. All data were analysed descriptively. Generalized estimating equation multivariable logistic regression was used to investigate factors that may be associated with pharmacist referral rates. RESULTS:We recruited 19 pharmacists representing 466 minor ailments encounters, and 19 GPs representing 394 consultations. Pharmacists referred 17% (77/466) of all minor ailments encounters for suspected antibiotic-requiring infections. Comments suggested reasons included upper-respiratory tract, ear nose and throat, and urinary tract infections. Most of suspected antibiotic-requiring infections referrals were to a GP (81%; 62/77). No GP consultations for infection (n = 88) were documented as being referred by a pharmacist; the majority were self-referred (77%; 68/88). DISCUSSION:Our pilot indicated that exploration of pharmacist referral for antibiotics is feasible and warranted. Future studies should quantify referral rates, reasons for referral, and observed differences between pharmacist and GP results. Our results should be used for the basis of a robust sample size calculation.