Past, present, and future of Phase 3 vaccine trial design: rethinking statistics for the 21st century.

Vaccines are crucial for protecting health globally; however, their widespread use relies on rigorous clinical development programmes. This includes Phase 3 randomized controlled trials (RCTs) to confirm their safety, immunogenicity, and efficacy. Traditionally, such trials used fixed designs with predetermined assumptions, lacking the flexibility to change during the trial or stop early due to overwhelming evidence of either efficacy or futility.

Immunogenicity, reactogenicity, and IgE-mediated immune responses of a mixed whole-cell and acellular pertussis vaccine schedule in Australian infants: A randomised, double-blind, noninferiority trial.

Background: In many countries, infant vaccination with acellular pertussis (aP) vaccines has replaced use of more reactogenic whole-cell pertussis (wP) vaccines. Based on immunological and epidemiological evidence, we hypothesised that substituting the first aP dose in the routine vaccination schedule with wP vaccine might protect against IgE-mediated food allergy. We aimed to compare reactogenicity, immunogenicity, and IgE-mediated responses of a mixed wP/aP primary schedule versus the standard aP-only schedule.

Symptom-based staging for logopenic variant primary progressive aphasia.

Background And Purpose: Logopenic variant primary progressive aphasia (lvPPA) is a major variant presentation of Alzheimer's disease (AD) that signals the importance of communication dysfunction across AD phenotypes. A clinical staging system is lacking for the evolution of AD-associated communication difficulties that could guide diagnosis and care planning. Our aim was to create a symptom-based staging scheme for lvPPA, identifying functional milestones relevant to the broader AD spectrum.

Grief and loss in people living with dementia: a review and metasynthesis of qualitative studies.

Objectives: This review seeks to synthesise qualitative studies that focus on the experience of grief and loss in people living with dementia.

Methods: Included studies were quality appraised, synthesised and analysed using inductive thematic analysis.

Results: 19 studies were selected for inclusion in the final review and metasynthesis, including 486 participants (115 participants living with dementia, 152 family carers, 219 professionals).

Early transcriptional responses to human enteric fever challenge.

Enteric fever, caused by oral infection with typhoidal serovars, presents as a non-specific febrile illness preceded by an incubation period of 5 days or more. The enteric fever human challenge model provides a unique opportunity to investigate the innate immune response during this incubation period, and how this response is altered by vaccination with the Vi polysaccharide or conjugate vaccine. We find that on the same day as ingestion of typhoidal , there is already evidence of an immune response, with 199 genes upregulated in the peripheral blood transcriptome 12 hours post-challenge (false discovery rate <0.

Symptom-led staging for semantic and non-fluent/agrammatic variants of primary progressive aphasia.

Introduction: Here we set out to create a symptom-led staging system for the canonical semantic and non-fluent/agrammatic variants of primary progressive aphasia (PPA), which present unique diagnostic and management challenges not well captured by functional scales developed for Alzheimer's disease and other dementias.

Methods: An international PPA caregiver cohort was surveyed on symptom development under six provisional clinical stages and feedback was analyzed using a mixed-methods sequential explanatory design.

Results: Both PPA syndromes were characterized by initial communication dysfunction and non-verbal behavioral changes, with increasing syndromic convergence and functional dependency at later stages.

Exploring the views of infection consultants in England on a novel delinked funding model for antimicrobials: the SMASH study.

Objectives: A novel 'subscription-type' funding model was launched in England in July 2022 for ceftazidime/avibactam and cefiderocol. We explored the views of infection consultants on important aspects of the delinked antimicrobial funding model.

Methods: An online survey was sent to all infection consultants in NHS acute hospitals in England.

A mixed methods evaluation of a program exploring predeath grief and loss for carers of people with rarer dementias.

Objectives: Predeath grief conceptualizes complex feelings of loss experienced for someone who is still living and is linked to poor emotional well-being. The Road Less Travelled program aimed to help carers of people with rarer dementias identify and process predeath grief. This study evaluated the feasibility, acceptability, and preliminary effectiveness of this program.

'The oxygen of shared experience': exploring social support processes within peer support groups for carers of people with non-memory-led and inherited dementias.

Objectives: To explore support processes and behaviours taking place during online peer support groups for family carers of people living with rare, non-memory-led and inherited dementias (PLWRD).

Methods: Twenty-five family carers of PLWRD participated in a series of ongoing online peer support groups on the theme of 'Independence and Identity'. Transcripts from 16 sessions were analysed using qualitative directed content analysis with a coding framework informed by Cutrona & Suhr's (2004) Social Support Behaviour Code (SSBC).

Symptom-led staging for primary progressive aphasia.

The primary progressive aphasias (PPA) present complex and diverse challenges of diagnosis, management and prognosis. A clinically-informed, syndromic staging system for PPA would take a substantial step toward meeting these challenges. This study addressed this need using detailed, multi-domain mixed-methods symptom surveys of people with lived experience in a large international PPA cohort.

The AuTOMATIC trial: a study protocol for a multi-arm Bayesian adaptive randomised controlled trial of text messaging to improve childhood immunisation coverage.

Background: While most Australian children are vaccinated, delays in vaccination can put them at risk from preventable infections. Widespread mobile phone ownership in Australia could allow automated short message service (SMS) reminders to be used as a low-cost strategy to effectively 'nudge' parents towards vaccinating their children on time.

Methods: AuTOMATIC is an adaptive randomised trial which aims to both evaluate and optimise the use of SMS reminders for improving the timely vaccination of children at primary care clinics across Australia.

Development and validation of a dynamic 48-hour in-hospital mortality risk stratification for COVID-19 in a UK teaching hospital: a retrospective cohort study.

Objectives: To develop a disease stratification model for COVID-19 that updates according to changes in a patient's condition while in hospital to facilitate patient management and resource allocation.

Design: In this retrospective cohort study, we adopted a landmarking approach to dynamic prediction of all-cause in-hospital mortality over the next 48 hours. We accounted for informative predictor missingness and selected predictors using penalised regression.

A systematic review and psychometric evaluation of resilience measurement scales for people living with dementia and their carers.

Psychometrically sound resilience outcome measures are essential to establish how health and care services or interventions can enhance the resilience of people living with dementia (PLWD) and their carers. This paper systematically reviews the literature to identify studies that administered a resilience measurement scale with PLWD and/or their carers and examines the psychometric properties of these measures. Electronic abstract databases and the internet were searched, and an international network contacted to identify peer-reviewed journal articles.

Mucosal-Associated Invariant T cells exhibit distinct functional signatures associated with protection against typhoid fever.

We have previously demonstrated that Mucosal-Associated Invariant T (MAIT) cells secrete multiple cytokines after exposure to Salmonella enterica serovar Typhi (S. Typhi), the causative agent of typhoid fever in humans. However, whether cytokine secreting MAIT cells can enhance or attenuate the clinical severity of bacterial infections remain debatable.

Piloting a novel cancer care pathway: socioeconomic background as a barrier to access.

Background: The multidisciplinary diagnostic clinic (MDC) model for 'non-specific' symptoms has been piloted in the UK. We aimed to assess the degree to which the MDC pathway was influenced by socioeconomic factors.

Methods: We collected data for all patients referred to the MDC from 01 January 2017 - 28 March 2019.

A controlled human infection model of Streptococcus pyogenes pharyngitis (CHIVAS-M75): an observational, dose-finding study.

Background: Streptococcus pyogenes is a leading cause of infection-related morbidity and mortality. A reinvigorated vaccine development effort calls for new clinically relevant human S pyogenes experimental infection models to support proof of concept evaluation of candidate vaccines. We describe the initial Controlled Human Infection for Vaccination Against S pyogenes (CHIVAS-M75) study, in which we aimed to identify a dose of emm75 S pyogenes that causes acute pharyngitis in at least 60% of volunteers when applied to the pharynx by swab.

Exploiting genomics to mitigate the public health impact of antimicrobial resistance.

Antimicrobial resistance (AMR) is a major global public health threat, which has been largely driven by the excessive use of antimicrobials. Control measures are urgently needed to slow the trajectory of AMR but are hampered by an incomplete understanding of the interplay between pathogens, AMR encoding genes, and mobile genetic elements at a microbial level. These factors, combined with the human, animal, and environmental interactions that underlie AMR dissemination at a population level, make for a highly complex landscape.

Immunogenicity of a Third Scheduled Dose of Rotarix in Australian Indigenous Infants: A Phase IV, Double-blind, Randomized, Placebo-Controlled Clinical Trial.

Background: Rotarix (GlaxoSmithKline) oral rotavirus vaccine is licensed as 2 doses in the first 6 months of life. In settings with high child mortality rates, clinical protection conferred by 2 doses of Rotarix is reduced. We assessed vaccine immune response when an additional dose of Rotarix was given to Australian Aboriginal children 6 to <12 months old.

Transmission of SARS-CoV-2 by children and young people in households and schools: A meta-analysis of population-based and contact-tracing studies.

Background: The role of children and young people (CYP) in transmission of SARS-CoV-2 in household and educational settings remains unclear. We undertook a systematic review and meta-analysis of contact-tracing and population-based studies at low risk of bias.

Methods: We searched 4 electronic databases on 28 July 2021 for contact-tracing studies and population-based studies informative about transmission of SARS-CoV-2 from 0 to 19 year olds in household or educational settings.