BACKGROUND:Pertussis has re-emerged in Europe, representing a major public health concern and a substantial cause of infant morbidity and mortality. The macrolide antibiotics clarithromycin and azithromycin are recommended as first-line therapy; however, their comparative effectiveness in infants remains poorly characterised. This study aimed to compare the real-world effectiveness of clarithromycin and azithromycin in infants with pertussis. METHODS:This multicentre retrospective cohort study was designed and analysed using a target trial emulation framework, following the established TARGET reporting guidelines. Infants aged 12 months or younger who were hospitalised for pertussis between Nov 1, 2023, and Dec 1, 2024, at 11 Italian health centres were included. Infants with incomplete data, concomitant severe infections at the time of hospitalisation, and previous receipt of any antibiotic potentially active against Bordetella pertussis were excluded. Treatment with either clarithromycin or azithromycin was administered according to clinical judgment. The primary outcome was a severe disease course, defined as a Pertussis Severity Score (PSS) of more than 5. Secondary outcomes included intensive care unit (ICU) admission, need for oxygen therapy, complications, length of stay, 30-day readmission, and mortality. Confounding was addressed using propensity-score-weighting methods. FINDINGS:Among 196 infants included (90 [46%] female, 106 [54%] male; median age 86 days [IQR 47-122]), 146 (74%) received clarithromycin and 50 (26%) received azithromycin. In propensity-score-weighted analyses, azithromycin was associated with higher odds of severe disease compared with clarithromycin (PSS >5: 60% [30 of 50] vs 33% [48 of 146]; odds ratio 1·80, 95% CI 1·01-3·21). Compared with infants treated with clarithromycin, infants treated with azithromycin more frequently required oxygen therapy and had more complications and ICU admissions, although median oxygen saturation levels and 30-day readmissions were comparable between groups. Two deaths occurred, both in the azithromycin group. INTERPRETATION:Clarithromycin was associated with more favourable clinical outcomes than azithromycin among infants hospitalised with pertussis. FUNDING:EU, Next Generation PNRR Extended Partnership initiative on Emerging Infectious Diseases.
BACKGROUND:Dysmenorrhoea, or pain during menstruation, is common in adolescence and is often dismissed or left untreated. Dysmenorrhoea can interfere with daily functioning and can lead to other chronic pain conditions; however, little is known about the risk factors for dysmenorrhoea. We aimed to characterise premenarche risk factors for the presence and severity of future dysmenorrhoea. METHODS:In this prospective cohort study, we obtained data for female adolescents from the population-based Adolescent Brain Cognitive Development Study (USA) who were premenarchal at baseline (age 9-10 years) and had both reached menarche and completed the Menstrual Cycle Survey at 3-year follow-up (age 12-13 years). Parents or guardians provided sociodemographic information and completed the Child Behavior Checklist, the Sleep Disturbance Scale for Children, and the Pubertal Development Scale, which captured data on non-painful somatic symptoms, attention problems, anxiety, depression, sleep disturbances, and pubertal development at baseline. Our primary objective was to analyse associations between dysmenorrhoea at 3-year follow-up (status and severity) with select symptom domains (sleep problems, attention problems, somatic symptoms, anxious or depressive symptoms, and baseline pain status) at baseline. We also investigated associations between dysmenorrhoea and participant characteristics (pubertal status, race or ethnicity, and income-to-needs ratio) that underlie social determinants of health. Differences by race were tested using Fisher exact tests. Differences by ethnicity and baseline pain status were tested using χ2 tests. Differences in continuous variables were assessed using ANOVA. Wilcoxon-Rank Sum tests were used in analyses of sleep problems, attention problems, and somatic symptoms, and ANOVA was used for pubertal status and income-to-needs ratio. Multinomial logistic regression was used to test associations with dysmenorrhoea severity, and linear regression was used to test associations with dysmenorrhoea status and menstrual pain interference. FINDINGS:2254 female adolescents were included in this study. 1299 (57·6%) participants developed dysmenorrhoea at age 12-13 years, and 247 (19·0% of those with dysmenorrhoea) reported severe dysmenorrhoea. Non-painful somatic symptoms were prospectively associated with future dysmenorrhoea (odds ratio [OR] 1·17 [95% CI 1·04-1·32]; p=0·0070), whereas anxiety or depression, sleep disturbances, and attention problems were not. Sleep disturbances were prospectively associated with menstrual pain interference (β coefficient 0·16 [95% CI 0·01-0·31]). Advanced pubertal status at ages 9-10 years was prospectively associated with risk of dysmenorrhoea 3 years later (OR 1·79 [95% CI 1·47-2·17]; p<0·0001), as was lower income-to-needs ratio (0·96 [0·93-1·00]; p=0·031). Black (1·38 [1·05-1·83]; p=0·024) and Hispanic (1·34 [1·03-1·68]; p=0·010) young females were at a significantly greater risk of experiencing dysmenorrhoea than were White and non-Hispanic young females, respectively. INTERPRETATION:Sociodemographic characteristics and clinical symptoms present before menarche might help to identify at-risk individuals for dysmenorrhoea before pain becomes a lifelong issue. FUNDING:The National Institute of Nursing Research, the National Institute of Diabetes and Digestive and Kidney Diseases, and the Eunice Kennedy Shriver National Institute for Child Health and Human Development.
BACKGROUND:The Asia Pacific region is home to more than half of the world's 1·93 billion adolescents (aged 10-24 years). Addressing adolescent health in this region is of global importance, but to date a systematic analysis of key contributors to disease in adolescents has not been done, which is a barrier to responsive action. This systematic analysis of the Global Burden of Diseases, Injuries, and Risk Factors Study (GBD) 2023 aims to provide a comprehensive assessment of adolescent health across the Asia Pacific region, at both the subregional and national levels, encompassing burden of disease, mortality, and prevalence of adolescent risk factors. METHODS:As part of GBD 2023, we obtained estimates for cause-specific mortality, disability-adjusted life-years (DALYs), and risk factor prevalence by sex for adolescents aged 10-24 years and 5-year age groups (10-14 years, 15-19 years, and 20-24 years) across 44 countries and territories (hereafter referred to collectively as Asia Pacific), grouped by seven UN subregions, from 2000 to 2023. We extracted GBD 2023 population counts and estimates of number and rate (per 100 000 population) for mortality and disease burden (DALYs). Risk prevalence estimates were obtained directly from the Institute for Health Metrics and Evaluation, and binge drinking estimates were sourced from WHO. Estimates are reported with 95% uncertainty intervals (UIs) where possible. UIs were estimated by running 250 draws of the posterior distribution, ordering the draws, and selecting the 2·5th and 97·5th percentiles for each metric. FINDINGS:In 2023, in adolescents across Asia Pacific, there were 637 496 deaths and a total disease burden of 115·8 million DALYs, representing 34·1% of global adolescent deaths and 40·6% of the global adolescent burden of disease. Non-communicable diseases (NCDs; particularly mental disorders) were the leading causes of disease burden and mortality (64·8% of DALYs and 43·9% of deaths). Unintentional and transport injuries were also leading causes of death (14·7% of deaths due to transport injury and 13·3% of deaths due to unintentional injury) and leading causes of disease burden particularly among males in south-eastern Asia. In Melanesia, Micronesia, and some parts of south-eastern Asia (Cambodia, Indonesia, Laos, the Philippines, and Timor-Leste), respiratory infections and tuberculosis remained important contributors. Southern Asia had the largest reduction (1·5% per year) in all-cause DALYs over the study period, and Australia and New Zealand (0·2% per year) had the smallest, with females in Australia and New Zealand showing a slight increase contrary to regional trends. Eastern Asia had the largest reduction (2·8% per year) in all-cause mortality rate and Melanesia (0·8% per year) the smallest. Risk factors generally had between-subregion and within-subregion variation; however, some regional trends stood out, with overweight and obesity increasing in all countries across the region, and binge drinking increasing in more countries than not. In 2023, prevalence of smoking in males exceeded that in females in every country, from 40% difference in Timor-Leste to less than 1% difference in Australia. Anaemia prevalence is decreasing in all countries, but female prevalence was higher and reducing at a slower rate than in males. Bullying prevalence was slightly higher in Polynesia, Micronesia, and Melanesia combined, Australia and New Zealand, and eastern Asia compared with southern and south-eastern Asian subregions. INTERPRETATION:Several patterns were consistent across the region: the dominance of mental disorders and NCDs, the universal rise in overweight and obesity (particularly high in Oceanic countries but increasing rapidly in south and south-eastern Asia), and persistent sex-specific challenges across subregions: unintentional injuries and smoking in males, and anaemia in females. Actions to tackle shared risk factors (while accounting for context-specific local health profiles, workforce deficits, cultural factors, and health system capacity) should not be forgone due to local variation. Future research could focus on subnational variation, intersecting inequalities, and multi-sectoral interventions targeting shared risk factors. Priority actions should include regional investment in adolescent mental health services and obesity prevention, targeted injury reduction strategies for high-risk populations, and sex-specific approaches to smoking cessation and anaemia reduction, delivered through local health systems with the capacity and cultural responsiveness to meet local needs. FUNDING:Gates Foundation and Australian Government.
Sickle cell disease remains a major cause of childhood morbidity and mortality, particularly in sub-Saharan Africa. In September, 2025, WHO convened the Paediatric Drug Optimization for Sickle Cell Disease process to review approved therapies, pipeline candidates, and potentially curative approaches, and define priorities for children and adolescents. Hydroxyurea (hydroxycarbamide) was confirmed as the leading near-term priority, with age-appropriate soluble or dispersible formulations identified as essential to improve equitable paediatric access; preferred and minimum characteristics were defined through a formal target product profile. Among investigational agents, pyruvate kinase activators and decitabine plus tetrahydrouridine (NDec) emerged as promising candidates for paediatric investigation on the basis of emerging efficacy data and programmatic potential. Intersecting research priorities included identifying appropriate clinical trial endpoints, strengthening early and inclusive paediatric investigation, and proactively ensuring that the promise of potential cure through gene therapy does not delay investment in scalable disease-modifying treatments.
Methylation profile scores (MPSs) aggregate the effects of many DNA methylation (DNAm) sites across the genome into a single continuous value per individual. These scores are rapidly gaining traction in health research, as they translate DNAm patterns into summary measures that can be used to address many clinical and epidemiological questions. Most current research, however, is focused on adults, with little consideration given to transferability to children and adolescents. In this Review, we aim to provide a practical guide introducing MPSs and to discuss the current status of MPSs in child and adolescent populations. First, we introduce the diverse applications of MPSs, including the following: (1) use as exposure proxies to estimate exposures that are missing, under-reported, or hard to measure (eg, an MPS for exposure to maternal prenatal smoking); (2) use as biological proxies to summarise physiological processes such as inflammation (eg, an MPS for C-reactive protein); (3) use in risk stratification, where MPS variation is associated with risk of a future health outcome (eg, cardiometabolic disease); (4) use in diagnostics, where MPSs are used to detect disease states (currently most established for rare Mendelian syndromes and paediatric brain tumours); and (5) use in pharmacoepigenetics and treatment monitoring, an emerging area where MPSs are used to predict treatment response or track symptom change over time. Second, we outline specific considerations that apply to the developmental context, which explain why child and adolescent MPSs often differ from their later-life counterparts. Third, we provide recommendations on how to critically judge paediatric MPS studies. Finally, we conclude that, at present, with a few notable exceptions, most MPSs are better characterised as research tools at an early stage of development rather than clinical tools, and we highlight future directions for the field.
BACKGROUND:Ataxia telangiectasia is a rare, multisystem disorder with progressive cerebellar neurodegeneration and no approved treatments. The efficacy of corticosteroids, including erythrocyte encapsulated dexamethasone sodium phosphate (eDSP), which have been studied for two decades in this disease, has not yet been proven in randomised trials. We aimed to investigate the safety and efficacy of eDSP in children aged 6-9 years with ataxia telangiectasia. METHODS:NEAT was a multicentre, randomised, double-blind, placebo-controlled phase 3 study, conducted at 20 sites across nine countries (Denmark, Germany, Italy, Norway, Poland, Spain, Switzerland, UK, and USA). Eligible participants were children aged 6 years or older weighing at least 15 kg, with a genetic diagnosis of ataxia telangiectasia and presence of neurological symptoms. Participants were randomly assigned (1:1) to the eDSP or placebo group via an independent interactive web response system and were stratified by age (6-9 years or ≥10 years), sex, and region (USA vs other countries). All participants, investigators, sponsors, and raters were masked to treatment assignments. eDSP was given intravenously every 21-30 days for six doses. All randomly assigned participants were included in the intention-to-treat (ITT) and safety populations; the primary and secondary efficacy analyses were conducted in participants aged 6-9 years in the ITT population. The primary efficacy endpoint was the change in Rescored Modified International Cooperative Ataxia Rating Scale (RmICARS) score between baseline and month 6, and a mixed-model-repeated-measures analysis was used. The trial was registered at ClinicalTrials.gov, NCT06193200, and is completed. FINDINGS:Between June 24, 2024, and Dec 17, 2025, we screened 125 participants for eligibility, of whom 105 (84%) were randomly assigned to the eDSP group (n=51 [49%]) or the placebo group (n=54 [51%]) and received at least one dose of treatment. The mean age was 8·5 years (SD 1·9) in the eDSP group and 8·6 years (2·3) in the placebo group (overall age range 6-17 years). In the eDSP group, 24 (47%) of 51 participants were girls and 27 (53%) were boys and, in the placebo group, 26 (48%) of 54 were girls and 28 (52%) were boys. Of ITT participants aged 6-9 years, 38 (95%) of 40 in the eDSP group and 41 (95%) of 43 in the placebo group completed the study. Compared with the placebo group, no significant differences were identified in change in RmICARS score from baseline to 6 months in participants aged 6-9 years: least squares mean difference -1·30 (95% CI -2·77 to 0·18; p=0·085). Adverse events were reported in 47 (92%) of 51 participants in the eDSP group and in 50 (93%) of 54 participants in the placebo group. The most common treatment-emergent adverse events were vomiting, pyrexia, pruritus, nasopharyngitis, cough, headache, and fatigue. There were no reports of treatment-related serious adverse events or deaths. Safety laboratory parameters did not identify adverse effects on growth, metabolism, bone mineral density, or endocrine function in any of the treatment groups. INTERPRETATION:The primary efficacy endpoint was not achieved, because the effect of eDSP on neurological symptoms did not reach statistical significance. The favourable safety profile of eDSP, previously described in a large study of children with ataxia telangiectasia, was confirmed in this trial. The eDSP programme, comprising two randomised studies and treating the largest cohort of patients with ataxia telangiectasia to date, underscores the need for rigorously designed trials of sufficient duration to detect sustained clinical benefit. FUNDING:Quince Therapeutics.
BACKGROUND:Rotavirus accounts for an estimated 25% of diarrhoea deaths in children under 5 years globally, and more than 140 countries have included rotavirus vaccines in their routine national infant vaccination programmes. We aimed to calculate rotavirus vaccine effectiveness against rotavirus-positive and all-cause acute gastroenteritis deaths. METHODS:The Multi-National Subpopulations Study to Evaluate Rotavirus Vaccines (MNSSTER-V) dataset combines child-level data from test-negative case-control studies of rotavirus vaccine effectiveness that enrolled children under 5 years of age seeking care for acute gastroenteritis at hospitals or emergency departments in 24 countries between July 1, 2007, and Aug 24, 2023. Children were included in this study if they were: younger than 5 years, met the acute gastroenteritis case definition (had at least three episodes of diarrhoea in a 24-h period, had non-bloody and non-chronic diarrhoea, and were enrolled within 7 days of diarrhoea onset), met vaccine card quality metrics, had vaccine delivery dates if the child was reported to have received a rotavirus vaccine, and had a reported outcome of death or discharge. In-hospital acute gastroenteritis deaths were characterised, and rotavirus vaccine effectiveness against all-cause and rotavirus-positive acute gastroenteritis mortality was calculated using an unconditional logistic regression model with adjustment for national under-5 mortality strata and child's age. Vaccine effectiveness analyses against all-cause and rotavirus-positive acute gastroenteritis mortality were restricted to children aged at least 3 months who received any routine vaccines from countries reporting at least one acute gastroenteritis death. FINDINGS:From the MNSSTER-V dataset, we included 27 252 children younger than 5 years enrolled from 22 countries; outcomes of patients were not available for two countries. At least one in-hospital acute gastroenteritis death was reported from 16 countries including 21 522 children; in total, 183 all-cause acute gastroenteritis deaths and 25 rotavirus-positive deaths were reported. Among children aged at least 3 months who had received any routine vaccines, receiving at least one dose of a rotavirus vaccine had an adjusted vaccine effectiveness of 75·8% (95% CI 28·4 to 91·8; n=13 630) against rotavirus-positive acute gastroenteritis mortality and 20·8% (-47·0 to 57·3; n=20 005) against all-cause acute gastroenteritis mortality. INTERPRETATION:Rotavirus vaccines are effective in preventing rotavirus-positive acute gastroenteritis mortality. Continued efforts to improve vaccine delivery could help to reduce acute gastroenteritis mortality due to rotavirus worldwide. FUNDING:None.
Concerns persist regarding the potential long-term effects of general anaesthesia on brain development in children. This narrative review summarises recent preclinical and clinical evidence (2019-25) and updates consensus messages. Preclinical studies show that commonly used anaesthetic agents can interfere with neurodevelopmental processes during vulnerable developmental periods. Clinical evidence is less clear. Randomised trials indicate that a single, short exposure in infancy is not associated with measurable impairment in cognitive outcomes, whereas observational studies report mixed findings. Several large population-based studies consistently identified a small, increased risk of attention-deficit hyperactivity disorder following early exposure to general anaesthesia. Emerging evidence also suggests modifications in visual development and processing, including preferential processing of global visual information, although these findings remain preliminary. Interpretation is limited by confounding related to surgery, comorbidity, and environmental factors. Communication with families should emphasise acknowledgment of parental concerns, individualised anaesthetic care, physiological stability, and that necessary procedures should not be delayed because of theoretical neurodevelopmental risks.
Survival from congenital heart disease (CHD) strongly depends on local health system capacity and lesion complexity, yet the extent to which CHD is recognised within national health policy frameworks remains poorly understood. We aimed to assess the presence, framing, and level of policy commitment to CHD within national health priority documents across countries of different income levels. We conducted a cross-sectional policy content analysis using publicly available national health strategies, child health plans, non-communicable disease strategies, and universal health coverage roadmaps. Documents were sourced from government websites and international repositories. References to CHD were classified as explicit, implicit, or absent, and policy commitment was categorised as none or actionable. Analysis was stratified by the country's World Bank income group. Among 193 UN countries and two observer states, CHD was absent from national policy documents in 109 countries, implicitly mentioned in 48 countries, and explicitly referenced in 38 countries. Overall, 44% of countries mentioned CHD in any form within their national health policies. Actionable commitments were identified in 19% of countries; of those that referenced CHD, 42% progressed to actionable measures. Countries that have explicit reference to CHD more often had actionable commitment (79%), compared with countries with implicit framing (13%). Recognition increased with income, from 19% in low-income countries to 59% in high-income countries, yet actionable commitment did not follow a clear income gradient. CHD is inconsistently represented within national health priority frameworks despite its substantial global burden. Where explicitly recognised, CHD is more likely to be accompanied by structured commitments than when implictly referenced. Strengthening policy positioning of CHD within national strategies represents a crucial step towards coordinated congenital cardiac care systems.
