Antenatal corticosteroids (ACS), most commonly administered as betamethasone or dexamethasone, remain a cornerstone of care for women at risk of preterm birth. However, the standard 24-mg regimen introduced more than five decades ago has not undergone formal dose-finding evaluation. Emerging concerns regarding possible dose-related adverse effects, particularly among late preterm infants subsequently born at term, have renewed interest in optimizing corticosteroid exposure. Experimental data across species, supported by human pharmacokinetic analyses, indicate that fetal lung maturation is driven by sustained low corticosteroid concentrations rather than high peak levels. This commentary summarizes key experimental, pharmacokinetic, and modelling evidence that informed the selection of the lower-dose betamethasone phosphate regimen evaluated in the WHO ACTION-III trial and explains the scientific rationale for this dosing strategy. Pharmacokinetic modeling indicates that 2 mg betamethasone phosphate administered intramuscularly every 12 h for four doses achieves fetal concentrations within the 1 to 4 ng/mL range identified in experimental studies, while avoiding the supratherapeutic peaks observed with conventional regimens. The ACTION-III trial will evaluate whether this lower dose ACS regimen, chosen on the basis of carefully developed models and clinical studies, maintains clinical efficacy while potentially reducing unnecessary systemic corticosteroid exposure in women at risk of late preterm birth.Trial registration: ISRCTN11434567, registered on 7 June 2021. https://www.isrctn.com/ISRCTN11434567?q=ACTION-III&filters=&sort=&offset=1&totalResults=1&page=1&pageSize=10 .

This article provides an overview of the main study designs for hyperbaric oxygen therapy (HBOT) clinical research. Based on study objectives, study types and use cases across different phases and settings are described, including before-and-after studies to detect early signals and feasibility, randomized controlled trials, including pragmatic RCTs, to confirm causality, multicenter stratified or adaptive designs to optimize protocols, and real-world studies to evaluate real-world effectiveness, safety, adherence, and health economic outcomes. To improve comparability and reproducibility, the following key elements are also proposed: the use of a pre-specified, pooled set of intervention parameters in each study (pressure, session duration, frequency, and overall course), the establishment of consistent and feasible inclusion and exclusion criteria, and the creation of a multilevel outcomes framework focusing on objective clinical endpoints and patient-reported outcomes, including specific safety and adherence monitoring. To overcome common challenges in HBOT research-protocol heterogeneity, blinding difficulties, interindividual variability in responses, and limitations in evidence synthesis-the article recommends standardized multicenter templates, stratified randomization, a predesigned statistical analysis plan, and mechanisms for data registration and sharing to enable cross-study pooling and long-term follow-up. Finally, a stepwise research pathway is proposed that begins with signal detection and confirmatory studies, progresses through parameter optimization and practice expansion, and ultimately leads to the creation of standardized clinical pathways and generalizable results. The goal is to provide a concise, practical methodological reference for proposal writing, funding applications, and implementation planning, thereby supporting more rigorous HBOT research in neurorehabilitation, tissue repair, chronic disease management, and healthy aging, particularly where current evidence remains exploratory or heterogeneous. This article is not intended as a systematic review of HBOT efficacy; instead, it is positioned as a narrative methodological review that uses current evidence limitations to inform trial design, feasibility assessment, interpretation, and transparent reporting.