Daily Respiratory Research Analysis

BACKGROUND: In non-experimental studies, early-life exposure to paracetamol is associated with an increased risk of eczema and wheeze. We aimed to compare paracetamol with ibuprofen, as required for fever or pain in the first year of life, for the risk of eczema and bronchiolitis at age 1 year. METHODS: PIPPA Tamariki is a multicentre, open-label, two-arm, parallel-group, superiority, randomised controlled trial done at three sites in Auckland and Wellington in New Zealand. Infants younger than 8 weeks and born in New Zealand were randomly assigned (1:1) to paracetamol alone (15 mg/kg every 6 h at age <1 months and every 4 h at age ≥1 months) or ibuprofen alone (5 mg/kg every 6 h at age <3 months and 10 mg/kg every 6 h at age ≥3 months), received orally as required for fever or pain, until age 1 year. Dosing was based on the New Zealand Formulary for Children. Research staff used REDCap for randomisation, which was stratified by recruitment site, maternal asthma status, and multiple birth. Key outcomes were eczema as defined by the UK Diagnostic Criteria or eczema hospitalisation in the first year of life, and hospitalisation for bronchiolitis as defined by at least one hospitalisation for bronchiolitis, viral-induced wheeze, or asthma in the first year of life. Analysis was according to the intention-to-treat principle. This trial is registered with the Australian New Zealand Clinical Trials Registry, ACTRN12618000303246 (active, not recruiting). FINDINGS: Between April 18, 2018, and July 28, 2023, 3923 infants were enrolled. 15 participants withdrew, leaving 3908 infants (1985 were randomly assigned to the paracetamol group, and 1923 to the ibuprofen group) in the intention-to-treat population. Of these participants, 1914 (49·0%) were female and 1994 (51·0%) were male; 609 (15·6%) were Māori, 607 (15·5%) were Pacific, 926 (23·7%) were Asian, and 1754 (44·9%) were New Zealand European or other. Eczema occurred in 322 (16·2%) of 1985 participants in the paracetamol group and 296 (15·4%) of 1923 participants in the ibuprofen group (absolute risk difference 0·8% [95% CI -1·5 to 3·1]; p=0·48; adjusted odds ratio [OR] 1·10 [95% CI 0·92 to 1·32]; p=0·29). Bronchiolitis occurred in 98 (4·9%) participants in the paracetamol group and 82 (4·3%) participants in the ibuprofen group (absolute risk difference 0·7% [95% CI -0·6 to 2·0]; p=0·32; adjusted OR 1·23 [95% CI 0·82 to 1·71]; p=0·21). 19 serious adverse events were reported in 17 participants (eight [0·4%] of 1985 in the paracetamol group and nine [0·5%] of 1923 in the ibuprofen group; adjusted OR 0·47 [95% CI 0·14-1·56; p=0·21]); none were attributed to trial medication. INTERPRETATION: There was no evidence of an important difference between paracetamol and ibuprofen in the risk of eczema or bronchiolitis at age 1 year. FUNDING: Health Research Council of New Zealand, Cure Kids New Zealand, University of Auckland.

BACKGROUND: Idiopathic pulmonary fibrosis (IPF) and telomere length are both strongly linked to rare and common genetic variants. Shortened telomere length might itself be causal for IPF. We aimed to evaluate whether rare and common variants compete or cooperate to confer genetic risk of IPF uniformly. METHODS: In this genetic analysis, we used whole-genome sequencing (WGS) data from a discovery case-control cohort sequenced at Columbia University and validated findings using WGS data from Trans-Omics for Precision Medicine (TOPMed) and UK Biobank. In all cohorts, we identified rare damaging variants in disease-associated genes and computed control-normalised non-overlapping polygenic risk scores (PRS) for IPF and telomere length. We assessed the MUC5B rs35705950 single-nucleotide polymorphism (SNP), an IPF common risk variant with a large effect, independently from the polygenic scores. Telomere length in blood leukocytes was measured using a quantitative PCR assay for the discovery cohort and UK Biobank validation cohort. We conducted logistic regression (adjusting for age, sex, and principal components of ancestry) to evaluate the association between IPF risk and the MUC5B SNP, the IPF PRS excluding MUC5B (IPF-PRS-noMUC5B), and the PRS for telomere length in the overall cohort and analysed their effects in patient subgroups for IPF endotypes (carriers and non-carriers of rare variants stratified by telomere length cutoffs). To assess disease prediction, we calculated cross-validated area under the receiver operating receiver operating curve (AUC). We also compared the liability of IPF explained by genetic variables. FINDINGS: The discovery cohort was recruited between April 23, 2003 and June 19, 2019 and included 777 patients with IPF and 2905 controls. We replicated the analyses in the TOPMed (1148 patients with IPF and 5202 controls) and UK Biobank (2739 patients with IPF and 395 331 controls) cohorts. 23-43% of patients with IPF had damaging rare variants or telomeres shorter than the tenth percentile. Analysis of the association of genetic variables with IPF diagnosis yielded odds ratios of 1·63 (95% CI 1·47-1·81) for telomere length PRS and 1·60 (1·44-1·77) for IPF-PRS-noMUC5B in the discovery cohort, with similar effect sizes for the two variables in the replication cohorts (1·47, 1·36-1·59 vs 1·37, 1·25-1·50 in TOPMed; 1·24, 1·19-1·29 vs 1·25, 1·21-1·30 in UK Biobank). The telomere length PRS had the greatest effect on disease risk in patients with IPF not harbouring rare variants and with telomere length shorter than the tenth percentile in the discovery cohort (2·02, 1·76-2·33) and UK Biobank replication cohort (1·70, 1·56-1·85). Accounting for clinical variables and all genetic variables (rare variants, MUC5B SNP, IPF PRS, and telomere length PRS) led to the best disease prediction in the discovery cohort (combined AUC 0·89), TOPMed cohort (0·89), and UK Biobank cohort (0·77). Rare and common variants contributed jointly to the genetic liability of IPF. The telomere length PRS accounted for 13% of the explained genetic liability of IPF in the discovery cohort and 8% and 13% in the TOPMed and UK Biobank cohorts, respectively. INTERPRETATION: Common and rare genetic variation confer context-specific genetic risk in patients with IPF both competitively and cooperatively. In contrast to known IPF common risk variants, the telomere length PRS, which includes more than 180 genetic loci not previously associated with IPF, is associated with increased risk of disease in patients with specific IPF endotypes. Polygenic risk from telomere-associated common variants is a key feature of genetic heterogeneity in IPF. FUNDING: US National Institutes of Health, UK Medical Research Council, and UK National Institute for Health and Care Research.

Deformable image-to-patient registration is essential for surgical navigation and medical imaging, yet real-time computation of spatial transformations across modalities remains a major clinical challenge-often being time-consuming, error-prone, and potentially increasing trauma or radiation exposure. While state-of-the-art methods achieve impressive speed and accuracy on paired medical images, they face notable limitations in cross-modal thoracic applications, where physiological motions such as respiration complicate tumor localization. To address this, we propose a robust, contactless, non-rigid registration framework for dynamic thoracic tumor localization. A highly efficient Recursive Deformable Diffusion Model (RDDM) is trained to reconstruct comprehensive 4DCT sequences from only end-inhalation and end-exhalation scans, capturing respiratory dynamics reflective of the intraoperative state. For real-time patient alignment, we introduce a contactless non-rigid registration algorithm based on GICP, leveraging patient skin surface point clouds captured by stereo RGB-D imaging. By incorporating normal vector and expansion-contraction constraints, the method enhances robustness and avoids local minima. The proposed framework was validated on publicly available datasets and volunteer trials. Quantitative evaluations demonstrated the RDDM's anatomical fidelity across respiratory phases, achieving an PSNR of 34.01 ± 2.78 dB. Moreover, we have preliminarily developed a 4DCT-based registration and surgical navigation module to support tumor localization and high-precision tracking. Experimental results indicate that the proposed framework preliminarily meets clinical requirements and demonstrates potential for integration into downstream surgical systems.