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The High-Energy Physics (HEP) and Worldwide LHC Computing Grid (WLCG) communities have faced significant challenges in understanding their global network flows across the world’s research and education (R&E) networks. This article describes the status of the work carried out to tackle this challenge by the Research Technical Networking Working Group (RNTWG) and the Scientific Network Tags (Scitags) initiative, including the evolving framework and tools, as well as our plans to improve network visibility before the next WLCG Network Data Challenge in early 2024. The Scitags initiative is a long-term effort to improve the visibility and management of network traffic for data-intensive sciences. The efforts of the RNTWG and Scitags initiatives have created a set of tools, standards, and proof-of-concept demonstrators that show the feasibility of identifying the owner (community) and purpose (activity) of network traffic anywhere in the network.

HEPScore is a new CPU benchmark created to replace the HEPSPEC06 benchmark that is currently used by the WLCG for procurement, computing resource pledges, usage accounting and performance studies. The development of the new benchmark, based on HEP applications or workloads, has involved many contributions from software developers, data analysts, experts of the experiments, representatives of several WLCG computing centres and WLCG site managers. In this contribution, we review the selection of workloads and the validation of the new HEPScore benchmark.

Cloudscheduler is a system to manage resources of local and remote compute clouds and makes those resources available to HTCondor pools. It examines the resource needs of idle jobs, then starts virtual machines (VMs), sized accordingly, on allowed clouds with available resources. Using yaml files, cloudscheduler then provisions the VMs during the boot process with all necessary tools needed to register with HTCondor and run the experiment’s jobs. Although we have run cloudscheduler in its first version for ATLAS and Belle-II workloads successfully for more than 10 years, we developed cloudscheduler version 2 (CSV2), a complete overhaul and modernization of cloudscheduler. The new system is used successfully in production for Belle-II, ATLAS, DUNE, and BABAR. In addition to using cloudscheduler version 2 as a WLCG site, we also run it as a service for other WLCG sites, and the Canadian Advanced Network for Astronomical Research (CANFAR) group uses its own instance of CSV2 for their astronomy workloads. In this paper, we report on our experience in operating CSV2 for different experiment’s jobs, running on up to 10,000 cores across all experiments and clouds in North America, Australia, and Europe. We will also report on how to correctly account for the resource usage in the WLCG APEL system, how the monitoring works, as well as on the integration of different clouds and how to use resources opportunistically.

Many clinical trials involve partially clustered data, where some observations belong to a cluster and others can be considered independent. For example, neonatal trials may include infants from single or multiple births. Sample size and analysis methods for these trials have received limited attention. A simulation study was conducted to (1) assess whether existing power formulas based on generalized estimating equations (GEEs) provide an adequate approximation to the power achieved by mixed effects models, and (2) compare the performance of mixed models vs GEEs in estimating the effect of treatment on a continuous outcome. We considered clusters that exist prior to randomization with a maximum cluster size of 2, three methods of randomizing the clustered observations, and simulated datasets with uninformative cluster size and the sample size required to achieve 80% power according to GEE-based formulas with an independence or exchangeable working correlation structure. The empirical power of the mixed model approach was close to the nominal level when sample size was calculated using the exchangeable GEE formula, but was often too high when the sample size was based on the independence GEE formula. The independence GEE always converged and performed well in all scenarios. Performance of the exchangeable GEE and mixed model was also acceptable under cluster randomization, though under-coverage and inflated type I error rates could occur with other methods of randomization. Analysis of partially clustered trials using GEEs with an independence working correlation structure may be preferred to avoid the limitations of mixed models and exchangeable GEEs., (© 2024 The Author(s). Statistics in Medicine published by John Wiley & Sons Ltd.)

Pregnant women are advised to take folic acid (FA) supplements before conception and during the first trimester of pregnancy. Many women continue FA supplementation throughout pregnancy, and concerns have been raised about associations between excessive FA intake and adverse maternal and child health outcomes. Unmetabolized folic acid (UMFA) is found in serum after high FA intakes and is proposed as a biomarker for excessive FA intake. We aimed to determine if removing FA from prenatal micronutrient supplements after 12 weeks of pregnancy reduces serum UMFA concentrations at 36 weeks gestation. In this double-blind, randomized controlled trial conducted in South Australia, 103 women with a singleton pregnancy were randomly assigned at 12-16 weeks gestation to take a micronutrient supplement containing no FA or 800 µg/day FA from enrollment until 36 weeks gestation. Ninety women (0 µg/day FA n = 46; 800 µg/day FA n = 44) completed the study. Mean, UMFA concentration was lower in the women randomized to the 0 µg/day group compared to the 800 µg/day FA group, 0.6 ± 0.7 and 1.4 ± 2.7 nmol/L, respectively. The adjusted mean difference (95% CI) in UMFA between the groups was [-0.85 (-1.62, -0.08) nmol/L, p = 0.03]. Maternal serum and red blood cell folate concentrations were lower in the 0 µg/day FA group than in the 800 µg/day group (median 23.2 vs. 49.3 and 1335 vs. 1914 nmol/L, respectively; p < 0.001). Removing FA at 12-16 weeks gestation from prenatal micronutrient supplements reduced the concentration of UMFA at 36 weeks gestation., (© 2024 The Authors. Maternal & Child Nutrition published by John Wiley & Sons Ltd.)

Background: Iron deficiency (ID) is the most common nutritional deficiency affecting young children. Serum ferritin concentration is the preferred biomarker for measuring iron status because it reflects iron stores; however, blood collection can be distressing for young children and can be logistically difficult. A noninvasive means to measure iron status would be attractive to either diagnose or screen for ID in young children., Objectives: This study aimed to determine the correlation between urinary and serum ferritin concentrations in young children; to determine whether correcting urinary ferritin for creatinine and specific gravity improves the correlation; and to determine a urine ferritin cut point to predict ID., Methods: Validation study was conducted using paired serum and urine collected from 3-y-old children (n = 142) participating in a longitudinal birth cohort study: the ORIGINS project in Perth, Western Australia. We calculated the sensitivity, specificity, positive, and negative predictive values of urinary ferritin amount in identifying those with ID at the clinical cut point used by the World Health Organization (serum ferritin concentration of <12 ng/mL)., Results: Urine ferritin, corrected for creatinine, correlated moderately with serum ferritin [r = 0.53 (0.40-0.64)] and performed well in predicting those with ID (area under the curve: 0.85; 95% confidence interval: 0.75, 0.94). Urine ferritin <2.28 ng/mg creatinine was sensitive (86%) and specific (77%) in predicting ID and had a high negative predictive value of 97%; however, the positive predictive value was low (40%) owing to the low prevalence of ID in the sample (16%)., Conclusions: Urine ferritin shows good diagnostic performance for ID. This noninvasive biomarker maybe a useful screening tool to exclude ID in healthy young children; however, further research is needed in other populations., (Copyright © 2024 American Society for Nutrition. Published by Elsevier Inc. All rights reserved.)

Background: Ingestion of prebiotics during pregnancy and lactation may have immunomodulatory benefits for the developing fetal and infant immune system and provide a potential dietary strategy to reduce the risk of allergic diseases., Objective: We sought to determine whether maternal supplementation with dietary prebiotics reduces the risk of allergic outcomes in infants with hereditary risk., Methods: We undertook a double-blind randomized controlled trial in which pregnant women were allocated to consume prebiotics (14.2 g daily of galacto-oligosaccharides and fructo-oligosaccharides in the ratio 9:1) or placebo (8.7 g daily of maltodextrin) powder from less than 21 weeks' gestation until 6 months postnatal during lactation. Eligible women had infants with a first-degree relative with a history of medically diagnosed allergic disease. The primary outcome was medically diagnosed infant eczema by age 1 year, and secondary outcomes included allergen sensitization, food allergy, and recurrent wheeze by age 1 year., Results: A total of 652 women were randomized between June 2016 and November 2021 (329 in the prebiotics group and 323 in the placebo group). There was no significant difference between groups in the percentage of infants with medically diagnosed eczema by age 1 year (prebiotics 31.5% [103 of 327 infants] vs placebo 32.6% [105 of 322 infants]; adjusted relative risk, 0.98; 95% CI, 0.77-1.23; P = .84). Secondary outcomes and safety measures also did not significantly differ between groups., Conclusions: We found little evidence that maternal prebiotics supplementation during pregnancy and lactation reduces the risk of medically diagnosed infant eczema by age 1 year in infants who are at hereditary risk of allergic disease., Competing Interests: Disclosure statement This trial was supported by a National Health and Medical Research Council (NHMRC) project grant (grant no. ID1099480) and a Telethon-Perth Children’s Hospital Research Fund grant. D.J.P. was supported by the NHMRC Medical Research Futures Fund Career Development Fellowship (ID1144544) (2018-2021) and the Telethon Kids Institute Ascend Fellowship (2022-2026). T.R.S. was supported by an NHMRC Investigator Grant (grant no. ID1173576). S.L.P. was supported by a fellowship from the Nova Institute for Health. Substantial in-kind support has been provided by Telethon Kids Institute and Joondalup Health Campus. All study powders were manufactured, packaged, and labeled by the independent company, Danone (Utrecht, The Netherlands). The trial was investigator-initiated, and Danone had no other involvement other than the provision of study powders. All funders had no role in the study design nor writing of this trial protocol article. Disclosure of potential conflict of interest: J. Garssen is a part-time employee of Danone Nutricia Research; and receives research funding/grants from the European Union, the Dutch government, Bill Gates Foundation, public and private research funding from the Netherlands, and some companies such as Danone Nutricia Research, Nutricia Research Foundation, Friesland Campina, and DSM. M. C. Jenmalm received funding for a clinical trial; received honoraria for lectures from BioGaia AB; and received consultant fees and travel support from Danone Nutricia and Abigo Medical. S. L. Prescott received speaker fees from Danone Nutricia. The rest of the authors declare that they have no relevant conflicts of interest., (Copyright © 2024 The Authors. Published by Elsevier Inc. All rights reserved.)

To obtain valid inference following stratified randomisation, treatment effects should be estimated with adjustment for stratification variables. Stratification sometimes requires categorisation of a continuous prognostic variable (eg, age), which raises the question: should adjustment be based on randomisation categories or underlying continuous values? In practice, adjustment for randomisation categories is more common. We reviewed trials published in general medical journals and found none of the 32 trials that stratified randomisation based on a continuous variable adjusted for continuous values in the primary analysis. Using data simulation, this article evaluates the performance of different adjustment strategies for continuous and binary outcomes where the covariate-outcome relationship (via the link function) was either linear or non-linear. Given the utility of covariate adjustment for addressing missing data, we also considered settings with complete or missing outcome data. Analysis methods included linear or logistic regression with no adjustment for the stratification variable, adjustment for randomisation categories, or adjustment for continuous values assuming a linear covariate-outcome relationship or allowing for non-linearity using fractional polynomials or restricted cubic splines. Unadjusted analysis performed poorly throughout. Adjustment approaches that misspecified the underlying covariate-outcome relationship were less powerful and, alarmingly, biased in settings where the stratification variable predicted missing outcome data. Adjustment for randomisation categories tends to involve the highest degree of misspecification, and so should be avoided in practice. To guard against misspecification, we recommend use of flexible approaches such as fractional polynomials and restricted cubic splines when adjusting for continuous stratification variables in randomised trials., (© 2024 The Authors. Statistics in Medicine published by John Wiley & Sons Ltd.)

Neisseria meningitidis carriage peaks in adolescents. This secondary analysis of a randomized controlled trial (NCT03089086) assessing 4CMenB herd protection in South Australia ("B-Part-of-It" study) explored school attributes linked to baseline carriage in 34,489 adolescents prevaccination. Carriage was higher in students attending single-sex [adjusted odds ratio (aOR): 1.49; 95% confidence interval (CI): 1.14-1.93], boarding (aOR: 1.92; 1.13-3.27) and government schools (aOR: 1.32, 1.09-1.61)., Competing Interests: The authors have no conflicts of interest to disclose., (Copyright © 2024 Wolters Kluwer Health, Inc. All rights reserved.)

Background and Objectives: Difficulty recruiting individuals from minoritized and underserved populations for clinical research is well documented and has health equity implications. Previously, we reported findings from interviews with research staff about pediatric research recruitment processes. Respondents raised equity concerns related to recruitment and enrollment of participants from minoritized, low resourced, and underserved populations. We therefore decided to perform a secondary coding of the transcripts to examine equity-related issues systematically., Methods: We conducted a process of secondary coding and analysis of interviews with research staff involved in recruitment for pediatric clinical research. Through consensus we identified codes relevant to equity and developed a conceptual framework including 5 stages of research., Results: We analyzed 28 interviews and coded equity-related items. We report 6 implications of our findings. First, inequitable access to clinical care is an upstream barrier to research participation. Second, there is a need to increase research opportunities where underserved and under-represented populations receive care. Third, increasing research team diversity can build trust with patients and families, but teams must ensure adequate support of all research team members. Fourth, issues related to consent processes raise institutional-level opportunities for improvement. Fifth, there are numerous study procedure-related barriers to participation. Sixth, our analysis illustrates that individuals who speak languages other than English face barriers across multiple stages., Conclusions: Research staff members identified equity-related concerns and recommended potential solutions across 5 stages of the research process, which may guide those endeavoring to improve research recruitment for pediatric patients from minoritized and underserved populations., Competing Interests: Declaration of Competing Interest The authors have no conflicts of interest relevant to this article to disclose., (Copyright © 2023 Academic Pediatric Association. Published by Elsevier Inc. All rights reserved.)

Introduction: Children with chronic medical diseases are at an unacceptable risk of hospitalisation and death from influenza and SARS-CoV-2 infections. Over the past two decades, behavioural scientists have learnt how to design non-coercive 'nudge' interventions to encourage positive health behaviours. Our study aims to evaluate the impact of multicomponent nudge interventions on the uptake of COVID-19 and influenza vaccines in medically at-risk children., Methods and Analyses: Two separate randomised controlled trials (RCTs), each with 1038 children, will enrol a total of approximately 2076 children with chronic medical conditions who are attending tertiary hospitals in South Australia, Western Australia and Victoria. Participants will be randomly assigned (1:1) to the standard care or intervention group. The nudge intervention in each RCT will consist of three text message reminders with four behavioural nudges including (1) social norm messages, (2) different messengers through links to short educational videos from a paediatrician, medically at-risk child and parent and nurse, (3) a pledge to have their child or themselves vaccinated and (4) information salience through links to the current guidelines and vaccine safety information. The primary outcome is the proportion of medically at-risk children who receive at least one dose of vaccine within 3 months of randomisation. Logistic regression analysis will be performed to determine the effect of the intervention on the probability of vaccination uptake., Ethics and Dissemination: The protocol and study documents have been reviewed and approved by the Women's and Children's Health Network Human Research Ethics Committee (HREC/22/WCHN/2022/00082). The results will be published via peer-reviewed journals and presented at scientific meetings and public forums., Trial Registration Number: NCT05613751., Competing Interests: Competing interests: HM acknowledges support from the National Health and Medical Research Council of Australia: Practitioner Fellowship (APP1155066). CCB acknowledges support from the National Health and Medical Research Council of Australia: Investigator Grant (APP1173163). HM is an independent investigator on clinical trials of investigational vaccines manufactured by pharmaceutical companies including Pfizer, ILiAD Biotechnologies and Merck. The institution at which HM, BW and PA are employed has received funding for investigator-led research from GlaxoSmithKline, Sanofi-Pasteur and Pfizer Vaccines. All authors receive no personal payments from industry. There are no other conflicts of interest to declare., (© Author(s) (or their employer(s)) 2024. Re-use permitted under CC BY. Published by BMJ.)

Background: This analysis investigated longitudinal changes in meningococcal carriage in adolescents in South Australia over 4 years., Methods: Data from the "B Part of It" study, which included a state-wide cluster randomized controlled trial in secondary-school students (n = 34,489 in 2017 and 2018) and serial cross-sectional studies in school leavers aged 17-25 years (n = 4028 in 2019-2020). Individuals had oropharyngeal swabs collected annually. This study included two unique cohorts: (1) individuals enrolled in 2019, with three consecutive annual swabs taken in 2017, 2018 and 2019; and (2) individuals enrolled in 2020, with swabs taken in 2017, 2018, and 2020. Disease-associated N. meningitidis genogroups were identified using PCR and whole genome sequencing. Univariate analysis identified risk factors for recurrent carriage (≥2)., Results: Among school leavers, 50 (1.7%, total n = 2980) had carriage detected at successive visits. In participants with meningococcal carriage at successive visits, 38/50 (76.0%) had the same genogroup detected by porA PCR. Of those, 19 had the same MLST type and demonstrated minimal variation, indicating they most likely had sustained carriage of the same isolate (range 226 to 490 days, mean duration 352 [SD 51] days). In the 2019 school leaver cohort, 6.7% acquired carriage in their first year out of school compared to 3.3% in their final school year. Compared to single carriage detection, recurrent carriage was potentially more likely in older adolescents (16 compared to ≤15 years; OR = 1.97 (95%CI 1.0, 3.86); p = 0.048)., Conclusion: Whilst carriage is typically transient, some adolescents/young adults may have persistent carriage and are likely to be an important group in the transmission of meningococci., Competing Interests: Declaration of Competing Interest H.S.M. is an investigator on vaccine trials sponsored by the GSK group of companies, Novavax, and Pfizer. H.S.M.’s, M.M.’s, and H.M.’s institution receives funding for investigator-led studies from Pfizer and the GSK. H.S.M. and M.M. receive no personal payments from industry., (Copyright © 2024 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Importance: Children born at less than 29 weeks' gestation are at risk of behavioral difficulties. This may be due in part to the lack of transplacental supply of docosahexaenoic acid (DHA), a key fatty acid with structural and functional roles in the brain., Objective: To determine whether meeting the neonatal DHA requirement through supplementation is associated with improved behavioral functioning of children born at less than 29 weeks' gestation., Design, Setting and Participants: This was a follow-up of children from 10 Australian participating centers in a multi-center, blinded, parallel group randomized clinical trial of infants born at less than 29 weeks' gestation conducted from June 2012 and September 2015, excluding those with additional fatty acid supplementation or major congenital or chromosomal abnormalities. Follow-up took place from August 2018 to May 2021. Parents of surviving children who had not withdrawn from the original trial were invited to complete questionnaires when the child turned 5 years' corrected age., Interventions: Infants were randomized to receive daily enteral emulsions providing 60 mg/kg/d of DHA or a soy-oil emulsion (with no DHA) from within the first 3 days of enteral feeding until 36 weeks' postmenstrual age or discharge home, whichever occurred first., Main Outcomes and Measures: The primary outcome of this follow-up was parent-rated behavior and emotional functioning as indicated by the Total Difficulties score of the Strengths and Difficulties Questionnaire. Parents also completed questionnaires about their child's behavioral manifestations of executive functioning, as well as a range of health outcomes to assess potential longer-term side effects of DHA intervention., Results: Primary outcome data were available for 731 children (76% of 958 surviving eligible children; 361 in the intervention group and 370 in the control group). Of these 731, 452 (47%) were female, and the mean (SD) corrected age at follow-up was 5.4 (0.5) years. Following imputation for missing data, the mean Total Difficulties score was the same in both groups (intervention group, n = 465; mean [SD], 11.8 [6.3]; control group, n = 493; mean [SD], 11.8 [6.0]; mean difference adjusted for sex, gestational age stratum, and hospital, 0.01; 95% CI, -0.87 to 0.89; P = .98). There was no evidence for differences between the groups in any secondary outcomes of behavior, executive functioning, or health., Conclusions and Relevance: In this follow-up of a randomized clinical trial, enteral DHA supplementation at the equivalent of the estimated in utero dose for infants born at less than 29 weeks' gestation did not improve behavioral functioning at age 5 years. There were no indications of adverse effects with DHA supplementation., Trial Registration: Australian New Zealand Clinical Trial Registry: ACTRN12612000503820.

Background: In 2009, the Australian government mandated the fortification of bread salt with iodine. In 2010, pregnant and lactating women were also advised to take an iodine-containing supplement. Our assessment of this policy in an iodine-sufficient population showed that children whose mothers were in the highest and lowest quartiles of iodine intake performed more poorly on early childhood tests of cognition and language than those in the second quartile. However, we did not quantify the iodine intake associated with optimal neurodevelopment., Objectives: The aim was to establish the iodine intake range in pregnancy associated with optimal child neurodevelopment., Methods: A prospective cohort study of pregnant women and their young children (n = 699). Iodine intake was assessed by a validated food frequency questionnaire at 16 and 28 wk of gestation. Child neurodevelopment at 18 mo of age was measured using the Bayley Scales of Infant and Toddler Development, Third Edition (Bayley-III). The relationship between average iodine intake during pregnancy and child neurodevelopment was assessed using linear regression with fractional polynomials and adjustment for confounders., Results: Mean (SD) iodine intake was similar at study entry and 28 wk, 308 (120) μg/d, with 82% of women taking iodine supplements at study entry. The relationship between iodine intake during pregnancy and Bayley-III cognitive and language scores was curvilinear (P = 0.001 and P = 0.004, respectively), with the lowest Bayley-III scores observed at lower and higher iodine intakes. The inflection point that drove the association between lower iodine intake in pregnancy and poorer child neurodevelopment scores was around 185 μg/d; for the higher pregnancy iodine intakes, language and cognitive scores were negatively affected from ∼350 μg/d to 370 μg/d, respectively. Higher iodine intakes were being driven by supplement use., Conclusions: Targeted, not blanket, iodine supplementation may be needed for pregnant women with low-iodine intake from food., (Copyright © 2023 American Society for Nutrition. Published by Elsevier Inc. All rights reserved.)

Background: Intention-to-treat analyses of the Omega-3 to Reduce the Incidence of Prematurity (ORIP) trial found that omega-3 (n-3) fatty acid supplementation reduces the risk of prematurity in the subgroup of women with a singleton pregnancy and low n-3 status early in pregnancy, but not overall. However, results may have been influenced by less-than-optimal compliance., Objectives: To identify predictors of compliance with n-3 supplementation and determine treatment effects among compliers., Design: Exploratory analyses of a multicentre-blinded randomised trial., Setting: 6 tertiary care centres in Australia., Participants: 5328 singleton pregnancies., Interventions: Daily capsules containing 900 mg n-3 long-chain polyunsaturated fatty acids or vegetable oil, consumed from before 20 weeks gestation until 34 weeks gestation., Outcome Measures: Early preterm (<34 weeks gestation) and preterm birth (<37 weeks gestation). Women were considered compliant if they reported missing less than a third of their allocated capsules in the previous week during a mid-pregnancy appointment., Results: Among 2654 singleton pregnancies in the n-3 intervention group, 1727 (65%) were deemed compliant with supplementation. Maternal characteristics associated with compliance included age, years of full-time education, consuming alcohol but not smoking in the 3 months leading up to pregnancy, fewer previous births and taking dietary supplements at enrolment. Based on complier average causal effects, n-3 supplementation reduced the risk of preterm birth in compliers (relative risk=0.76; 95% CI 0.60 to 0.97), but not early preterm birth (relative risk=0.80; 95% CI 0.44 to 1.46). Consistent with intention-to-treat analyses, the lack of an overall effect on early preterm birth in compliers appeared to be due to beneficial effects in women with low n-3 status at enrolment but not women with replete status., Conclusions: Results in compliers were similar to those from intention-to-treat analyses, suggesting that non-compliance was not a major factor in explaining outcomes from the ORIP trial., Trial Registration Number: ACTRN12613001142729., Competing Interests: Competing interests: RAG has received supplies from Croda UK, prepared supplies for a trial for Efamol/Wassen UK and holds a patent (WO2013/10 40 25 A1) on stabilising and analysing fatty acids in a biologic sample stored on solid media, owned by Adelaide Research and Innovation, the University of Adelaide, and licensed to Xerion. SKT, FH, SD and ISZ are employees of Société des Produits Nestlé (SPN). MM has received supplies from Croda UK, and prepared supplies for a trial for Efamol/Wassen UK. The other authors do not have any competing interests., (© Author(s) (or their employer(s)) 2023. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Many trials use stratified randomisation, where participants are randomised within strata defined by one or more baseline covariates. While it is important to adjust for stratification variables in the analysis, the appropriate method of adjustment is unclear when stratification variables are affected by misclassification and hence some participants are randomised in the incorrect stratum. We conducted a simulation study to compare methods of adjusting for stratification variables affected by misclassification in the analysis of continuous outcomes when all or only some stratification errors are discovered, and when the treatment effect or treatment-by-covariate interaction effect is of interest. The data were analysed using linear regression with no adjustment, adjustment for the strata used to perform the randomisation (randomisation strata), adjustment for the strata if all errors are corrected (true strata), and adjustment for the strata after some errors are discovered and corrected (updated strata). The unadjusted model performed poorly in all settings. Adjusting for the true strata was optimal, while the relative performance of adjusting for the randomisation strata or the updated strata varied depending on the setting. As the true strata are unlikely to be known with certainty in practice, we recommend using the updated strata for adjustment and performing subgroup analyses, provided the discovery of errors is unlikely to depend on treatment group, as expected in blinded trials. Greater transparency is needed in the reporting of stratification errors and how they were addressed in the analysis., (© 2023 The Authors. Statistics in Medicine published by John Wiley & Sons Ltd.)

Introduction: Severe bronchopulmonary dysplasia (BPD) is a well-known factor consistently associated with impaired cognitive outcomes. Regarding reported benefits on long-term neurodevelopmental outcomes, the potential adverse effects of high-dose docosahexaenoic acid (DHA) supplementation on this short-term neonatal morbidity need further investigations in infants born very preterm. This study will determine whether high-dose DHA enteral supplementation during the neonatal period is associated with the risk of severe BPD at 36 weeks' postmenstrual age (PMA) compared with control, in contemporary cohorts of preterm infants born at less than 29 weeks of gestation., Methods and Analysis: As part of an Australian-Canadian collaboration, we will conduct an individual participant data (IPD) meta-analysis of randomised controlled trials targeting infants born at less than 29 weeks of gestation and evaluating the effect of high-dose DHA enteral supplementation in the neonatal period compared with a control. Primary outcome will be severe grades of BPD (yes/no) at 36 weeks' PMA harmonised according to a recent definition that predicts early childhood morbidities. Other outcomes will be survival without severe BPD, death, BPD severity grades, serious brain injury, severe retinopathy of prematurity, patent ductus arteriosus and necrotising enterocolitis requiring surgery, sepsis, combined neonatal morbidities and growth. Severe BPD will be compared between groups using a multivariate generalised estimating equations log-binomial regression model. Subgroup analyses are planned for gestational age, sex, small-for-gestational age, presence of maternal chorioamnionitis and mode of delivery., Ethics and Dissemination: The conduct of each trial was approved by institutional research ethics boards and written informed consent was obtained from participating parents. A collaboration and data sharing agreement will be signed between participating authors and institutions. This IPD meta-analysis will document the role of DHA in nutritional management of BPD. Findings will be disseminated through conferences, media interviews and publications to peer-reviewed journals., Prospero Registration Number: CRD42023431063., Trial Registration Number: NCT05915806., Competing Interests: Competing interests: IsM, PML, AJM, CTC, IbM, TRS and MM were investigators of RCTs expected to be included in this IPD meta-analysis., (© Author(s) (or their employer(s)) 2023. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Introduction: Many extremely preterm newborns develop anaemia requiring a transfusion, with most receiving three to five transfusions during their admission. While transfusions save lives, the potential for transfusion-related adverse outcomes is an area of growing concern. Transfusion is an independent predictor of death and is associated with increased morbidity, length of hospital stay, risk of infection and immune modulation. The underlying mechanisms include adverse pro-inflammatory and immunosuppressive responses. Evidence supports an association between transfusion of washed red cells and fewer post-transfusion complications potentially through removal of chemokines, lipids, microaggregates and other biological response modifiers. However, the clinical and cost-effectiveness of washed cells have not been determined., Methods and Analysis: This is a multicentre, randomised, double-blinded trial of washed versus unwashed red cells. Infants <28 weeks' gestation requiring a transfusion will be enrolled. Transfusion approaches will be standardised within each study centre and will occur as soon as possible with a recommended fixed transfusion volume of 15 mL/kg whenever the haemoglobin is equal to or falls below a predefined restrictive threshold, or when clinically indicated. The primary outcome is a composite of mortality and/or major morbidity to first discharge home, defined as one or more of the following: physiologically defined bronchopulmonary dysplasia; unilateral or bilateral retinopathy of prematurity grade >2, and; necrotising enterocolitis stage ≥2. To detect a 10% absolute reduction in the composite outcome from 69% with unwashed red blood cell (RBCs) to 59% with washed RBCs with 90% power, requires a sample size of 1124 infants (562 per group). Analyses will be performed on an intention-to-treat basis with a prespecified statistical analysis plan. A cost-effectiveness analysis will also be undertaken., Ethics and Dissemination: Ethics approval has been obtained from the Women's and Children's Health Network Human Research Ethics Committee (HREC/12/WCHN/55). The study findings will be disseminated through peer-reviewed articles and conferences., Trial Registration Number: ACTRN12613000237785 Australian New Zealand Clinical Trials Registry., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2023. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Background: Influenza and COVID-19 infections during pregnancy may have serious adverse consequences for women as well as their infants. However, uptake of influenza and COVID-19 vaccines during pregnancy remains suboptimal. This study aims to assess the effectiveness of a multi-component nudge intervention to improve influenza and COVID-19 vaccine uptake among pregnant women., Methods: Pregnant women who receive antenatal care at five tertiary hospitals in South Australia, Western Australia and Victoria will be recruited to two separate randomised controlled trials (RCTs). Women will be eligible for the COVID-19 RCT is they have received two or less doses of a COVID-19 vaccine. Women will be eligible for the influenza RCT if they have not received the 2023 seasonal influenza vaccine. Vaccination status at all stages of the trial will be confirmed by the Australian Immunisation Register (AIR). Participants will be randomised (1:1) to standard care or intervention group (n = 1038 for each RCT). The nudge intervention in each RCT will comprise three SMS text message reminders with links to short educational videos from obstetricians, pregnant women and midwives and vaccine safety information. The primary outcome is at least one dose of a COVID-19 or influenza vaccine during pregnancy, as applicable. Logistic regression will compare the proportion vaccinated between groups. The effect of treatment will be described using odds ratio with a 95% CI., Discussion: Behavioural nudges that facilitate individual choices within a complex context have been successfully used in other disciplines to stir preferred behaviour towards better health choices. If our text-based nudges prove to be successful in improving influenza and COVID-19 vaccine uptake among pregnant women, they can easily be implemented at a national level., Trial Registration: ClinicalTrials.gov Identifier NCT05613751. Registered on November 14, 2022., (© 2023. Crown.)

Importance: High-dose omega-3 docosahexaenoic acid (DHA) supplementation of children born at less than 29 weeks' gestation has been shown to improve IQ despite increasing the risk of bronchopulmonary dysplasia (BPD). Given that BPD is associated with poorer cognitive outcomes, it is unclear whether the increased risk of BPD with DHA supplementation is associated with decreased benefit to IQ., Objective: To investigate whether the increased risk of BPD with DHA supplementation was associated with diminished IQ benefit., Design, Setting, and Participants: This cohort study used data collected from a multicenter, blinded, randomized controlled trial of DHA supplementation in children born at less than 29 weeks' gestation. Participants were recruited from 2012 to 2015 and followed up until 5 years' corrected age. Data were analyzed from November 2022 to February 2023., Interventions: Enteral DHA emulsion (60 mg/kg/d, to match the estimated in-utero requirement) or a control emulsion from the first 3 days of enteral feeds until 36 weeks' postmenstrual age or discharge home., Main Outcomes and Measures: Physiological BPD was assessed at 36 weeks' postmenstrual age. IQ was assessed at 5 years' corrected age using the Wechsler Preschool and Primary Scale of Intelligence, 4th Edition; children from the 5 highest-recruiting Australian hospitals were assessed. The total effect of DHA supplementation on IQ was divided into direct and indirect effects using mediation analysis, with BPD as the presumed mediating variable., Results: Among 656 surviving children from hospitals involved in IQ follow-up (mean [SD] gestational age at birth, 26.8 [1.4] weeks; 346 males [52.7%]), there were 323 children with DHA supplementation and 333 children in the control group. Mean IQ was 3.45 points (95% CI, 0.38 to 6.53 points) higher in the DHA group than the control group, despite an increase in the risk of BPD (160 children [49.7%] vs 143 children [42.8%] with BPD). The indirect effect of DHA on IQ via BPD was not statistically significant (-0.17 points; 95% CI, -0.62 to 0.13 points), with most of the effect of DHA on IQ occurring independently of BPD (direct effect = 3.62 points; 95% CI, 0.55 to 6.81 points)., Conclusions and Relevance: This study found that associations of DHA with BPD and IQ were largely independent. This finding suggests that if clinicians supplement children born preterm with high-dose DHA, any resulting increase in BPD risk would not be associated with meaningful reductions in the IQ benefit.

Objectives: The risk factors for prematurity are multifactorial and include low omega-3 status. Omega-3 supplementation in pregnancy has been found to reduce prematurity risk, particularly among women with low omega-3 levels. This study aimed to identify maternal characteristics that predict whether women with a singleton pregnancy will benefit from omega-3 supplementation to reduce their risk of prematurity., Design: Exploratory analyses of a multicentre, double-blind randomised trial., Setting: 6 tertiary care centres in four states in Australia., Participants: 5328 singleton pregnancies in 5305 women recruited before 20 weeks of gestation., Interventions: Fish oil capsules containing 900 mg omega-3 long-chain polyunsaturated fatty acids per day versus vegetable oil capsules consumed from enrolment until 34 weeks' gestation., Outcome Measures: Early preterm birth (EPTB, <34 weeks' gestation) and preterm birth (PTB, <37 weeks' gestation) analysed using logistic regression models with interactions between treatment group and a range of maternal biological, clinical and demographic characteristics., Results: Omega-3 supplementation reduced the odds of EPTB for women with low total omega-3 status in early pregnancy (OR=0.30, 95% CI 0.10-0.93). No additional maternal characteristics influenced whether omega-3 supplementation reduced the odds of EPTB. For PTB, women were more likely to benefit from omega-3 supplementation if they were multiparous (OR=0.65, 95% CI 0.49-0.87) or avoided alcohol in the lead up to pregnancy (OR=0.62, 95% CI 0.45-0.86)., Conclusions: Our results support previous findings that women with low total omega-3 levels in early pregnancy are most likely to benefit from taking omega-3 supplements to reduce their risk of EPTB. Understanding how other maternal characteristics influence the effectiveness of omega-3 supplementation on reducing PTB requires further investigation., Trial Registration Number: ACTRN12613001142729., Competing Interests: Competing interests: RAG has received supplies from Croda UK, prepared supplies for a trial for Efamol/Wassen UK and holds a patent (WO2013/104025A1) on stabilising and analysing fatty acids in a biological sample stored on solid media, owned by Adelaide Research and Innovation, The University of Adelaide, and licensed to Xerion. SKT, FH, SD and ISZ are employees of Société des Produits Nestlé (SPN). MM has received supplies from Croda UK and prepared supplies for a trial for Efamol/Wassen UK., (© Author(s) (or their employer(s)) 2023. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Introduction: Clinical trial designs based on the assumption of independent observations are well established. Clustered clinical trial designs, where all observational units belong to a cluster and outcomes within clusters are expected to be correlated, have also received considerable attention. However, many clinical trials involve partially clustered data, where only some observational units belong to a cluster. Examples of such trials occur in neonatology, where participants include infants from both singleton and multiple births, and ophthalmology, where one or two eyes per participant may need treatment. Partial clustering can also arise in trials of group-based treatments (e.g. group education or counselling sessions) or treatments administered individually by a discrete number of health care professionals (e.g. surgeons or physical therapists), when this is compared to an unclustered control arm. Trials involving partially clustered data have received limited attention in the literature and the current lack of standardised terminology may be hampering the development and dissemination of methods for designing and analysing these trials., Methods and Examples: In this article, we present an overarching definition of partially clustered trials, bringing together several existing trial designs including those for group-based treatments, clustering due to facilitator effects and the re-randomisation design. We define and describe four types of partially clustered trial designs, characterised by whether the clustering occurs pre-randomisation or post-randomisation and, in the case of pre-randomisation clustering, by the method of randomisation that is used for the clustered observations (individual randomisation, cluster randomisation or balanced randomisation within clusters). Real life examples are provided to highlight the occurrence of partially clustered trials across a variety of fields. To assess how partially clustered trials are currently reported, we review published reports of partially clustered trials., Discussion: Our findings demonstrate that the description of these trials is often incomplete and the terminology used to describe the trial designs is inconsistent, restricting the ability to identify these trials in the literature. By adopting the definitions and terminology presented in this article, the reporting of partially clustered trials can be substantially improved, and we present several recommendations for reporting these trial designs in practice. Greater awareness of partially clustered trials will facilitate more methodological research into their design and analysis, ultimately improving the quality of these trials.

Importance: Children with chronic medical conditions are at increased risk of severe influenza. Uptake of influenza vaccination in children and adolescents with these identified special risk medical conditions (SRMCs) is suboptimal., Objective: To assess the effectiveness of Flutext-4U, a parent short message service (SMS) reminder nudge intervention, in increasing influenza immunization in children and adolescents with SRMCs., Design, Setting, and Participants: This randomized clinical trial was conducted at a tertiary pediatric hospital in Adelaide, South Australia, from April 15 to September 30, 2021. Children and adolescents aged 6 months to younger than 18 years with SRMCs and a subspecialist outpatient appointment over a 5-month period during the Australian seasonal influenza vaccination season (April-August 2021) were eligible to participate. Follow-up was until September 30, 2021., Interventions: Participants were randomly assigned (1:1 ratio) to control: clinician nudges (hospital vaccine availability, ease of access, and recommendation from hospital subspecialists) or SMS intervention (control conditions plus an additional SMS reminder nudge to parents), with randomization stratified by age group (<5 years, 5-14 years, or >14 to <18 years)., Main Outcomes and Measures: The primary outcome was influenza vaccination, as confirmed by the Australian Immunisation Register., Results: A total of 600 participants (intervention group: 298 [49.7%]; mean [SD] age, 11.5 [4.6] years; 162 female participants [54.4%]; control group: 302 [50.3%]; mean [SD] age, 11.4 [4.7] years; 155 female participants [51.3%]) were included. Influenza vaccination was 38.6% (113 of 293) in the SMS intervention group compared with 26.2% (79 of 302) in the control group (adjusted odds ratio [aOR], 1.79; 95% CI, 1.27-2.55; P = .001). Time to vaccine receipt was significantly lower among SMS participants (adjusted hazard ratio, 1.67; 95% CI, 1.25-2.22; P < .001). For participants randomly assigned by June 15, a significantly greater proportion receiving the SMS intervention were vaccinated during the optimal delivery period April to June 30 (SMS group: 40.0% [76 of 190] vs 25.4% [50 of 197]; aOR, 1.97; 95% CI, 1.28-3.06; P = .002)., Conclusions and Relevance: Results of this randomized clinical trial suggest that an additional SMS reminder nudge for parents delivered in the tertiary care hospital setting to children and adolescents with SMRCs resulted in higher influenza vaccine uptake compared with clinician nudges alone., Trial Registration: ANZCTR Identifier: ACTRN12621000463875.

Background: Preterm infants suffer higher morbidity and mortality rates compared to full-term infants, but little is known about how changes to oral and respiratory tract microbiota may impact disease development., Methods: Here, very preterm neonates (n = 50) were selected to study oral and respiratory microbiota development during the first few months post-birth, where 26 individuals were diagnosed with BPD and/or sepsis. These infants were compared to 14 healthy full-term infants and 16 adults. Microbiota diversity, composition, and species abundances were calculated from 16S ribosomal RNA gene sequences in buccal swabs and tracheal aspirates at two time points (within a week and 1-3 months post-birth)., Results: Collection time point was the biggest factor to significantly influence the preterm oral microbial diversity and composition. In addition, BPD and sepsis were linked to distinct preterm oral microbiota diversity and composition, and opportunistic pathogens previously associated with these diseases were identified in the initial sample for both healthy preterm neonates and those with the disease. Compared to the full-term infant and adult dataset, preterm infant diversity and composition was initially significantly different, but resembled full-term infant diversity and composition over time., Conclusion: Overall, consequences of microbiota development need further examination in preterm infant infections and later development., Impact: Non-gut microbiota research on preterm infants is limited. At one week post-birth, preterm infants harbor distinct oral microbiota that are not shared with full-term children or adults, eventually becoming similar to full-term infants at 36 weeks postmenstrual age. DNA from potential opportunistic pathogens was observed in the mouth and lungs of preterm infants within a week of birth, and microbes associated with BPD were identified in the lungs. Oral microbiota in preterm infants over the first 2-3 months is unique and may be connected to short- and long-term health outcomes in these children., (© 2023. The Author(s).)

Importance: High-dose docosahexaenoic acid (DHA), a long-chain polyunsaturated fatty acid, may affect the risk of bronchopulmonary dysplasia (BPD). However, high-level summative evidence supporting such clinical association in very preterm infants is lacking., Objective: To examine the association between enteral supplementation with high-dose DHA during the neonatal period and the risk of BPD in preterm infants born at less than 29 weeks' gestation., Data Sources: PubMed, Embase, Web of Science, Cochrane Central Register of Controlled Trials, medRxiv, and ClinicalTrials.gov were searched from inception to August 1, 2022, for eligible articles with no language restrictions., Study Selection: Randomized clinical trials (RCTs) were eligible for inclusion (1) if their interventions involved direct administration of a minimum DHA supplementation of 40 mg/kg/d or breast milk or formula feeding of at least 0.4% of total fatty acids, and (2) if they reported data on either BPD, death, BPD severity, or a combined outcome of BPD and death., Data Extraction and Synthesis: Two investigators completed independent review of titles and abstracts, full text screening, data extraction, and quality assessment using the Cochrane Risk of Bias 2.0. Risk ratios (RRs) with 95% CIs were pooled using random-effect meta-analyses., Main Outcomes and Measures: Primary outcome was BPD using trial-specific definitions, which was further stratified for RCTs that used a more stringent BPD definition based on systematic pulse oximetry assessment at 36 weeks' postmenstrual age. Other outcomes were BPD, death, BPD severity, or combined BPD and death., Results: Among the 2760 studies screened, 4 RCTs were included, which involved 2304 infants (1223 boys [53.1%]; mean [SD] gestational age, 26.5 [1.6] weeks). Enteral supplementation with high-dose DHA was associated with neither BPD (4 studies [n = 2186 infants]; RR, 1.07 [95% CI, 0.86-1.34]; P = .53; I2 = 72%) nor BPD or death (4 studies [n = 2299 infants]; RR, 1.04 [95% CI, 0.91-1.18]; P = .59; I2 = 61%). However, an inverse association with BPD was found in RCTs that used a more stringent BPD definition (2 studies [n = 1686 infants]; RR, 1.20 [95% CI, 1.01-1.42]; P = .04; I2 = 48%). Additionally, DHA was inversely associated with moderate-to-severe BPD (3 studies [n = 1892 infants]; RR, 1.16 [95% CI, 1.04-1.29]; P = .008; I2 = 0%)., Conclusions and Relevance: Results of this study showed that enteral supplementation with high-dose DHA in the neonatal period was not associated overall with BPD, but an inverse association was found in the included RCTs that used a more stringent BPD definition. These findings suggest that high-dose DHA supplementation should not be recommended to prevent BPD in very preterm infants.

Aim: To determine if supplementation of infants born <33 weeks’ gestation with higher dose docosahexaenoic acid (DHA) affects growth, body composition, and blood pressure at 7 y corrected age (CA) and if treatment effects differed by infant sex at birth and birth weight strata (<1250 and ≥1250 g). Methods: Seven-year follow-up of an Australian multicenter randomized controlled trial in which 657 infants were fed high-DHA (≈1% total fatty acids) enteral feeds or standard-DHA (≈0.3% total fatty acids) from age 2−4 d until term CA. Seven-year CA outcomes were growth (weight, height), body composition (lean body mass, fat mass, waist, and hip circumference), and blood pressure. Results: There was no effect of high-DHA enteral feeds compared with standard-DHA on growth, body composition, and blood pressure at 7-year CA either overall or in subgroup analysis by sex. There was a significant interaction between high-DHA and birthweight strata on height at 7-y CA (p = 0.03). However, the post-hoc analyses by birthweight strata did not reach significance (p > 0.1). High-DHA group infants were more likely to be classified as obese (relative risk 1.6 (95% CI 1.0, 2.6); p = 0.05). Conclusions: DHA supplementation of premature infants did not affect growth, body composition, or blood pressure at 7-year CA overall by sex and birthweight strata. The finding of a higher risk of obesity in children who receive high-DHA needs to be interpreted with caution due to the small number of children classified as obese.

Background: Docosahexaenoic acid (DHA) is a component of neural tissue. Because its accretion into the brain is greatest during the final trimester of pregnancy, infants born before 29 weeks' gestation do not receive the normal supply of DHA. The effect of this deficiency on subsequent cognitive development is not well understood., Methods: We assessed general intelligence at 5 years in children who had been enrolled in a trial of neonatal DHA supplementation to prevent bronchopulmonary dysplasia. In the previous trial, infants born before 29 weeks' gestation had been randomly assigned in a 1:1 ratio to receive an enteral emulsion that provided 60 mg of DHA per kilogram of body weight per day or a control emulsion from the first 3 days of enteral feeds until 36 weeks of postmenstrual age or discharge home, whichever occurred first. Children from 5 of the 13 centers in the original trial were invited to undergo assessment with the Wechsler Preschool and Primary Scale of Intelligence (WPPSI) at 5 years of corrected age. The primary outcome was the full-scale intelligence quotient (FSIQ) score. Secondary outcomes included the components of WPPSI., Results: A total of 1273 infants underwent randomization in the original trial; of the 656 surviving children who had undergone randomization at the centers included in this follow-up study, 480 (73%) had an FSIQ score available - 241 in the DHA group and 239 in the control group. After imputation of missing data, the mean (±SD) FSIQ scores were 95.4±17.3 in the DHA group and 91.9±19.1 in the control group (adjusted difference, 3.45; 95% confidence interval, 0.38 to 6.53; P = 0.03). The results for secondary outcomes generally did not support that obtained for the primary outcome. Adverse events were similar in the two groups., Conclusions: In infants born before 29 weeks' gestation who had been enrolled in a trial to assess the effect of DHA supplementation on bronchopulmonary dysplasia, the use of an enteral DHA emulsion until 36 weeks of postmenstrual age was associated with modestly higher FSIQ scores at 5 years of age than control feeding. (Funded by the Australian National Health and Medical Research Council and Nu-Mega Ingredients; N3RO Australian New Zealand Clinical Trials Registry number, ACTRN12612000503820.)., (Copyright © 2022 Massachusetts Medical Society.)