Modern ALL therapy aims to reduce toxicity, while maintaining and improving the current high cure rates. Acute and late sequelae of anthracyclines are of major concern. The AIEOP-BFM ALL 2009 trial aimed to clarify the need for anthracyclines in low-risk patients. After 2 weeks of induction therapy, which included two daunorubicin (DNR) doses once weekly (30 mg/m2 each) as part of a 4-drug therapy, patients age 1-17 years with newly diagnosed non-high-risk B-ALL either positive for ETV6::RUNX1 or with rapid treatment response, as assessed by induction day-15 evaluation, were randomly assigned to receive either two additional doses of DNR (control arm [CA]) or no further DNR during induction (experimental arm [EA]). Patients treated as randomly assigned were included in the primary analysis on noninferiority in event-free survival (EFS). Adverse reactions of special interest (ARSI) were analyzed in the as-treated population. Of 6,136 patients enrolled in AIEOP-BFM ALL 2009, 2,514 patients (41.0%) were eligible for this random assignment, with 82.7% actually randomly assigned (EA: n = 1,040 and CA: n = 1,039). The 5-year EFS was 92.5% (SE 0.8%) in CA and 92.2% (SE 0.9%) in EA. Accordingly, cumulative incidence of relapse was 5.8% (SE 0.7%) and 5.7% (SE 0.7%), and overall survival was 97.6% (SE 0.5%) and 97.4% (SE 0.5%) in CA and EA, respectively. Life-threatening and fatal ARSI were similar in the two arms, but there was a three times lower incidence of invasive fungal infections in the EA (0.5% v 1.5%, P = .02). A reduced DNR dose during induction did not compromise the outcome of patients with favorable prognostic factors but did diminish infectious toxicity indicated by the lower rate of invasive fungal infections.

To investigate the birth prevalence, clinical manifestations, and management of congenital cytomegalovirus (CMV) infections in Australia, 1999-2023. Longitudinal observational study; analysis of prospectively collected Australian Paediatric Surveillance Unit (APSU) data. Australia, 1 January 1999 - 1 January 2024. Number of definite congenital CMV infections during study period and after the establishment of universal neonatal hearing screening (1 January 2004); clinical sequelae of definite infections; proportion of infants with symptomatic definite infections treated with antiviral medications. During 1 January 1999 - 1 January 2024, 586 cases of congenital CMV infection were reported to the APSU (8.15 [95% confidence interval, 7.50-8.83] infections per 100 000 births), including 479 definite infections (82%). The most frequent sequelae of definite infections were small for gestational age or intrauterine growth restriction (135 infants, 28.2%); neurological conditions (most frequently: deafness [183, 38.2%], microcephaly [89, 18.6%]); liver disease with jaundice (130, 27.1%), hepatomegaly (75, 15.7%), or hepatitis (85, 14.7%); and bone marrow conditions (most frequently: thrombocytopaenia [139, 29.0%], petechiae/purpura [89, 18.6%]). Of 168 Guthrie card tests (newborn blood spot screening), 154 (91.7%) were CMV-positive (polymerase chain reaction DNA detection), including 143 that provided the sole reason for classifying the cases as definite congenital CMV infections. During 1 January 2004 - 1January 2024, 447 of 506 cases (88.3%) were definite congenital CMV infections, of which 366 (81.9%) were symptomatic; 116 of these infants (32%) were treated with antiviral medications. The number of reported definite congenital CMV infections during 1 January 1999 - 1 January 2024 was only 1.0% of the number expected in Australia on the basis of their estimated prevalence in developed countries. The number of reported cases has continuously increased since 1999, as has the use of antiviral therapy. Surveillance of congenital CMV infections, the major infectious cause of congenital malformations, needs to be expanded to fully assess their prevalence and the associated disease burden, and to inform prevention strategies.

To estimate the risk of death after hospitalisation with non-fatal intentional self-poisoning in New South Wales, and to estimate the associated number of years of life lost. Retrospective observational study; analysis of Poisoning And enVenomation Linkage to evaluate Outcomes and clinical Variation in Australia (PAVLOVA) study data. All index admissions to New South Wales public and private hospitals of people after non-fatal intentional self-poisoning (ie, were discharged from the index admission alive), 1 January 2011 - 30 September 2020. Standardised mortality ratio (compared with general population mortality rate; SMR), overall, and by cause of death (data available only for 2011-2018); years of life lost (YLL) overall, and by cause of death (2011-2018), age group, and sex. Index admissions of people with non-fatal intentional self-poisoning were identified for 48 951 people; their median age was 32.8 years (interquartile range [IQR], 20.8-47.5 years), 30 274 were girls or women (61.8%), and 3449 died during follow-up (median, 4.9 years; IQR, 2.7-7.3 years). The all-cause SMR was 3.1 (95% confidence interval [CI], 3.0-3.2); by cause of death, the SMR was highest for external cause deaths (16.8; 95% CI, 15.9-17.8), including accidental poisoning (30.3; 95% CI, 27.4-33.2) and suicide deaths (25.1; 95% CI, 23.2-27.1). Among natural causes of death, the SMR was highest for infectious and parasitic diseases (5.4; 95% CI, 3.9-6.8), digestive diseases (4.2; 95% CI, 3.4-5.0), and respiratory diseases (3.0; 95% CI, 2.5-3.4). The estimated overall premature mortality burden was 110 301.4 YLL; the median value per death was similar for women (31.1 YLL; IQR, 15.0-43.0 YLL) and men (33.2 YLL; IQR, 19.7-44.9 YLL). During 2011-2018, the total mortality burden was 79 821.6 YLL; by cause of death, the major contributors were deaths from suicide (26 945.2 YLL; 33.8%), accidental poisoning (17 436.1 YLL; 21.8%), other injuries (6026.8 YLL; 7.5%), and natural causes (29 413.5 years; 36.8%). The risk of death is markedly higher after hospitalisation with intentional self-poisoning than for the general population, but suicide deaths only cause about one-third of the mortality burden in terms of lost years of life; deaths from accidental poisoning and natural causes are also major contributors. Referrals to specialist psychiatric and physical health care and brief interventions for treating psychiatric and substance use conditions are appropriate after hospitalisation with intentional self-poisoning.

The current gold standard for diagnosing malignant hyperthermia (MH) is an in-vitro contracture test (IVCT), which has many limitations. Here, we evaluate a newly developed test, the Ca2+ wave frequency assay (CaWFa), which aimed to directly measure Ca2+ release from the ryanodine receptors (RyR1) of single muscle fibres. A small segment of muscle (50 mg) was sectioned from 30 patients undergoing routine IVCT muscle biopsies and mechanically skinned single muscle fibres were isolated. Using Ca2+-dependent fluorescence and confocal microscopy we were able to examine RyR1 sensitivity of single fibres challenged with graded concentrations of halothane and caffeine. The induction of regenerative Ca2+ waves and wave frequencies were compared with IVCT results to assess diagnostic sensitivity and specificity. The proportion of muscle fibres that responded with regenerative Ca2+ waves on exposure to 0.5 mM and 1 mM halothane was higher in muscle from MHS patients compared with MHN patients (36.5% vs 0% and 77.5% vs 23.1%, respectively). Ca2+ wave frequency was also elevated in the MHS fibres compared to MHN in halothane at all tested concentrations. No difference in Ca2+ wave onset or frequency were demonstrated between groups exposed to caffeine. Using CaWFa, an onset concentration of 1 mM halothane in combination with a wave frequency threshold of 1.57 waves/minute achieved 92% sensitivity and 88% specificity. The CaWFa effectively discriminates MHS from MHN muscle in response to halothane, offering a comparable sensitivity and specificity to the IVCT. The CaWFa shows promising potential as a minimally invasive alternative to IVCT for diagnosing MH susceptibility.

Post-mortem detection of a medicine following suicide can be due to two main reasons: the decedent was taking that medicine therapeutically before death, and/or the medicine was involved in the suicidal act (poisoning-related suicide). We aimed to investigate how antidepressant concentrations differed between poisoning and non-poisoning suicides. We hypothesized that the predictive value of these concentrations and the separation between poisoning and non-poisoning concentrations would improve by adjusting for dose dispensed to the decedent. We analysed post-mortem toxicology results from suicides in Australia, July 2013 to October 2019, linked to the individual's dispensing history. Suicides were classified as poisoning- or non-poisoning-related by coroners. We analysed the distribution of concentrations through descriptive statistics, precision-recall curves and quantile regression to compare poisoning and non-poisoning concentrations. We adjusted concentrations by estimated daily dose and total drug quantity dispensed in 90 days and re-assessed model performance. We had sufficient sample size to analyse nine antidepressants: amitriptyline (n = 149), mirtazapine (n = 399), citalopram (n = 116), escitalopram (n = 297), fluoxetine (n = 183), sertraline (n = 253), duloxetine (n = 122), venlafaxine (n = 261), desvenlafaxine (n = 194). Selective Serotonin Reuptake Inhibitor non-poisoning and poisoning concentrations were similar, with no high certainty threshold for poisoning for citalopram and sertraline. Amitriptyline had the best separation between poisoning and non-poisoning concentrations. Adjustment by estimated daily dose improved the separation of lower quantiles through quantile regression but did not help identify thresholds that separated poisonings and non-poisonings. Dose adjustment generally did not improve the separation of poisoning vs non-poisoning suicides, indicating that post-mortem concentrations may not have clear dose-concentration relationships.

BackgroundArterio-venous malformations (AVMs) have been associated with somatic genetic variants in the RAS-MEK pathway, generating interest in the role of MEK inhibitors. However, open biopsy for molecular characterisation carries a potentially life-threatening bleeding risk.MethodsWe utilized liquid biopsy from the AVM efferent draining vein in 10 children and young adults (female 7, age range 7.3-22.2 years) with extracranial AVMs to identify the underlying somatic variants.ResultsHere we show identification of somatic mosaic variants in 8 of 10 patients. There were no procedural complications. Two patients with spinal arteriovenous metameric syndrome (Cobb syndrome) demonstrated somatic activating KRAS variants. Two additional patients had somatic in-frame deletion-insertion variants of HRAS. Three patients had other variants involving the RAS-MEK pathway and one within PIK3CA. Five patients have commenced molecularly directed pharmacotherapy leading to reduced disability. Variant allele frequency was inversely correlated with sampling distance from the nidus. One patient who underwent sampling at two separate embolization sessions demonstrated a higher variant allele frequency in the sample obtained after embolization was completed.ConclusionsOur study further supports the role of the RAS-MEK pathway in AVM pathophysiology. In addition, we demonstrate the effective use of liquid biopsy to genotype extracranial AVMs in children. Finally, we provide insights into how the localized high-pressure high-flow conditions within the AVM distinctly shape cell free DNA fragmentation patterns.

Children living with chronic kidney disease (CKD) often experience significant psychological challenges, including emotional and behavioural difficulties linked to both the condition and its treatment. This study aimed to characterise the emotional, behavioural and adaptive functioning of children with CKD and to explore its relationship with CKD stage. Participants aged 6-18years with any stage of CKD were recruited, and the Behaviour Assessment System for Children (BASC-2) was used to assess emotional, behavioural and adaptive functioning. Multivariable logistic regression was used to assess the association of CKD stage with emotional and behavioural outcomes. The study included 53 participants, with a mean age of 12years (s.d. 2.5). Among them, 27 (51%) were in CKD stages 1-5, 3 (6%) were receiving dialysis, and 22 (42%) had undergone kidney transplantation. In parent-report scales, an increased proportion of children with CKD were at risk for specific emotional difficulties (somatisation (n = 25, 47%), withdrawal (18, 33%), depression (17, 32%) and reduced adaptive skills (social skills and activities of daily living (17, 32%)) compared to general population norms. Children receiving kidney replacement therapy (KRT) were at an increased risk of adaptive skill deficits (OR 5.7, 95% CI 1.07-30.5) when compared to children with CKD stages 1-5, but there were uncertain differences between these groups for internalising (OR 1.1, 0.3-2.6) and externalising problems (OR 5.0, 0.85-29.5) and behavioural symptoms (OR 2.0, 0.4-9.4). Children with CKD are at increased risk of emotional difficulties (withdrawal, depression) and reduced social skills and activities of daily living compared to population norms. Adaptive skill deficits were more prevalent among children with KRT compared to children with CKD stages 1-5.

Studies of traditional Indigenous compared to ‘Western’ gut microbiomes are underrepresented, and lacking in young children, limiting knowledge of early-life microbiomes in different cultural contexts. Here we analyze the gut metagenomes of 50 Indigenous Australian infants (median age <one year) living remotely with variable access to Western foods, compared to age- and sex-matched non-Indigenous infants living in urban Australia. Indigenous infants had greater alpha diversity and significant differences in bacterial beta diversity, with 114 species and 38 genera differing in abundance. Indigenous infants almost exclusively had higher carriage of Megaspaera, Streptococcus, Caecibacter, Parolsenella and Prevotella species, and markedly higher numbers of gut viruses and fungi. Bifidobacteria ssp. were dominant in Indigenous infants. Despite encroaching Westernisation, the gut microbiome of Indigenous infants retains key features of traditional societies worldwide, attesting to the dominant influence of remote environment and traditional lifestyle in maintaining microbiome diversity.

IntroductionIncremental peritoneal dialysis (PD) may confer environmental benefits compared to full-dose PD due to reduced resource use. We aimed to quantify and compare carbon emissions, water consumption, and waste generation between incremental and full-dose PD in a cohort of incident PD patients.MethodsWe compared environmental metrics, including carbon emissions, water consumption, and waste generation between incremental and full-dose PD, using prospectively collected data between June 2019 and May 2024 at the Western Renal Service, Sydney, Australia. Carbon emissions were quantified using standardized coefficients from a published life-cycle analysis, while water and waste volumes were estimated using literature-based assumptions. Group comparisons were conducted using the Mann-Whitney U test, with a two-sided p-value <0.05 considered statistically significant.ResultsAmong 365 incident patients (187 incremental, 178 full-dose), followed for a median of 20 months (interquartile range 13-37), incremental PD had lower median annual per-patient carbon dioxide equivalent emissions (1016 vs. 1360 kg), blue water consumption (24,090 vs. 25,548 L), landfill waste (212 vs. 271 kg), gray water generation (8213 vs. 10,549 L), and recycling volume (73 vs. 131 kg), compared to full-dose PD (all p < 0.001). Incremental PD yielded estimated savings of 201,087 kg carbon dioxide equivalent emissions, over 5 million liters of blue water, 1.8 million liters of gray water, 27,223 kg of landfill waste, and 16,219 kg of recyclable materials.ConclusionIncremental PD was associated with a lower environmental impact than full-dose PD, highlighting its potential contribution to environmentally sustainable dialysis care.