Starship Hospital

OBJECTIVE:The Fontan operation is the final step in staged palliation for patients with single-ventricle physiology. It has extended their life expectancy and improved their quality of life. However, long-term complications and Fontan failure remain lifelong concerns. We aimed to use machine learning to develop a patient-specific preoperative Fontan failure risk calculator. METHODS:Patient data were obtained from the Australia and New Zealand Fontan Registry (ANZFR). The primary composite end point was Fontan failure, defined as any of death, transplant, Fontan takedown or conversion, protein-losing enteropathy, plastic bronchitis, or New York Heart Association class III/IV. To construct the risk calculator, we first used Cox regression with regularization to predict Fontan failure from 54 preoperative predictors in the ANZFR database. A regularization machine learning tool was used to automate variable selection among many predictors. We then manually added clinically relevant predictors. Six predictors (age, ventricular morphology, primary diagnosis, total anomalous pulmonary venous drainage, Fontan type, and moderate or greater atrioventricular valve regurgitation) were ultimately used in a subsequent multivariable Cox regression (without regularization) to ensure the final risk prediction model was simple and easy to interpret. RESULTS:Data from 1888 patients over 48 years (1975-2023) were available. The ANZFR collects perioperative and follow-up variables about each patient. After excluding patients with Fontan procedures with an atriopulmonary connection (n = 290) and missing predictors or outcome data (n = 125), data from 1473 patients were used to construct the calculator. Median age at Fontan was 4.5 years (interquartile range, 3.7, 5.6 years). Median follow-up was 11.0 years (interquartile range, 5.3, 17.8 years). Freedom from Fontan failure for the overall cohort at 10, 20, and 30 years was 92% (confidence interval [CI], 90%-93%), 83% (CI, 80%-86%), and 72% (CI, 65%-78%), respectively. External validation in an independent cohort demonstrated acceptable model performance. The risk prediction model was then implemented in a Desktop application using the Shiny library in R and used to develop the preoperative Fontan failure calculator on the basis of the 6 predictors. CONCLUSIONS:Machine learning can be applied to "big data" from a binational Fontan Registry to develop a preoperative, patient-specific Fontan failure risk calculator. The model will continue to learn and improve as more data is added. This is a step toward personalized medicine enabling patient-specific pre-operative counselling and realistic expectations.

CONTEXT:We recently reported that zoledronate (zol) given once at baseline or twice (every 5 years) reduced fracture risk over 10 years. OBJECTIVE:We assessed whether the effects of zol differ over time or across important baseline variables, and how they relate to changes in bone mineral density (BMD) over time. METHODS:A 10-year, prospective, randomized, double-blind, placebo-controlled trial, was conducted at a clinical research center from 2012 to 2023. Participants included 1054 postmenopausal women, aged 50 to 60 years, with BMD T-score at the lumbar spine, femoral neck, or total hip between 0 and -2.5. Intervention included either 5-yearly 5-mg zol (zol-zol), 5-mg zol infusion at baseline and placebo at 5 years (zol-placebo), or 5-yearly placebo (placebo-placebo). Main outcome measures included morphometric vertebral fractures, major osteoporotic, and any fractures. RESULTS:Morphometric vertebral fractures were not reduced in the years 0 to 5 following zol but were reduced in years 5 to 10 by 58% (95% CI, 21%-77%) (zol-zol) and 57% (21%-77%) (zol-placebo). For any fracture and major osteoporotic fracture, similar temporal patterns were observed. There were no interactions between treatment effect and baseline variables (including age, body mass index, BMD, falls or fracture history, and estimated fracture risk) or between treatment effect and changes in BMD with zol. CONCLUSION:Fracture reductions with single-dose or 5-yearly zol appear greater during years 5 to 10 than years 0 to 5. The risk reductions are broadly consistent across this cohort and independent of baseline or change in BMD. This suggests that routine BMD monitoring may not be necessary for low-risk women considering the option of less frequent zol for long-term fracture risk reduction.

The International Neonatal Consortium Seizure Working Group of the Critical Path Institute provides an update to the original recommendations for design of clinical trials to treat neonatal seizures based on recent experiences from several trials and developments in the field. Although there aren’t sufficient new data to inform definitions of optimal efficacy endpoints, the Working Group recommended inclusion of alternate measures of seizure burden reduction as secondary or exploratory endpoints, to elucidate clinically meaningful efficacy endpoints for future trials. It was recommended to include additional key covariates, such as timing of seizure onset/cessation, randomization, and ASM administration. There are new recommendations regarding potential for unmasked or single-masked trials, and reporting of concomitant medications and adverse events, and genetic testing. Importantly, specific recommendations were added regarding improved strategies for recruitment and consent, including the use of novel technologies and the involvement of patient advocacy groups. Recommendations regarding trial infrastructure and operational feasibility were included to facilitate trial initiation and conduct, given the many logistical challenges of conducting neonatal seizure treatment trials. Finally, the recommendations consider accommodations for local or national regulations and resources, to ensure that trials are conducted as appropriate to the setting in which the patients are treated.

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.

Abstract Background WNT-activated medulloblastoma (WNT-MB) are uncommon, and report on relevant clinical experience is lacking from Asia. In this study, we report our experience in managing children with WNT-MB at a tertiary referral center in Beijing, China. Methods A retrospective analysis was conducted on 87 patients with WNT-MB managed at the Department of Pediatrics, Beijing Shijitan Hospital, Capital Medical University, from July 2016 to July 2025. Patient demographics, histopathological and molecular, treatment, and survival data were collected. WNT-MB was confirmed by histopathology (classic histology) and molecular profiling (CTNNB1/APC-mutant, and/or subgrouping by methylation array). Results Among the study cohort, male to female ratio was 1.02,and median age was 9.2 years (3.41-16.7); 9 patients (10.3%) had metastasis. Seventy-six patients had gross-total resection, 10 near-total resection, and one subtotal resection. Where sequenced, 82 patients had tumor with CTNNB1 mutation and 1 had APC mutation. Sixty-six tumors were TP53 wild-type and 18 carried pathogenic TP53 variants. Only one of TP53 mutant tumors was metastatic at diagnosis. All patients received adjuvant craniospinal irradiation (CSI) and chemotherapy. The median CSI dose was 23.4 Gy (23.4-39.6), and tumor-bed total dose 54 Gy (54-55.8). At median follow-up of 4.62 years (1.02-9.57), 10 patients relapsed, and one died. Five-year PFS and OS were 84.8±4.9% and 98.5±1.5% respectively. Five-year PFS of TP53 wild-type disease was 93.0±4.8%, compared with 51.7±13.6% in TP53 mutant (log-rank p<0.001). Multivariate Cox regression analysis showed TP53 mutation was an independent risk factor for PFS (HR=10.175, 95%CI [2.615, 39.586], p <0.001), but not OS. Metastatic status, tumor resection extent, radiotherapy and chemotherapy sequence had no statistically significant impact on PFS and OS. Conclusion WNT-MB generally has good prognosis. Patients with somatic TP53 mutation have a higher risk of recurrence, caution should be exercised when considering treatment reduction in our patient population based on subgroup alone.