Heterozygous variants in SLC12A6 have recently been shown to cause dominant Charcot-Marie-Tooth disease (CMT). We aim to characterise the phenotype of patients with previously reported and novel heterozygous variants in the gene and understand any genotype-phenotype correlation. Patients were clinically and genetically assessed in sites from Europe, Australia, Brazil and the USA. All patients underwent whole exome or whole genome sequencing. Variants were classified using American College of Medical Genetics and Genomics criteria. Twenty-three individuals from 13 families carried nine variants classified either as pathogenic/likely pathogenic or variants of uncertain significance segregating in multiple family members, including five novel variants. Forty-eight percent (11/23) were male with a mean age of disease onset of 15.7 years (range 1-45 years). Clinical phenotype varied dramatically with genotype; Arg207His and Ser647Pro caused a severe childhood-onset, sensory and motor, conduction-slowing neuropathy, whereas Gly552Asp caused a mild, adult-onset, sensory-predominant neuropathy, Thr991Ala an infantile-onset motor neuropathy, and the Met282Lys/Gly286Cys locus a complex, axonal neuropathy. Heterozygous variants in SLC12A6 can cause CMT of all clinical phenotypes, severity and age of onset, depending on the genotype. Such phenotypic diversity has not been described for any other CMT gene, and more work is needed to understand disease mechanisms to guide future therapeutic options.

To evaluate disease severity, age distribution, and seasonal patterns of human metapneumovirus (hMPV) infection among hospitalized children <5 years across pre-, during and post-coronavirus disease 2019 pandemic. We conducted a retrospective study using electronic medical records of acute lower respiratory infection (ALRI) hospitalizations in children <5 years at the Sydney Children's Hospitals Network from 2015 to 2023. Analyses were restricted to hospitalizations for only laboratory-confirmed hMPV. Severity outcomes-extended length of stay (>median), intensive care unit admission and/or mechanical ventilation-were compared across pre-pandemic (2015-2019), pandemic (2020-2021) and post-pandemic (2022-2023) using multivariable logistic regression. Seasonal patterns were assessed using monthly hMPV positivity rates. Among 32,618 ALRI hospitalizations, 1081 (3.3%) were hMPV-positive. hMPV hospitalizations declined during the pandemic (4.3% pre-pandemic, 2.0% pandemic and 3.2% post-pandemic (P < 0.001). Median age of hMPV hospitalization shifted from 1.1 years (interquartile range [IQR] 0.5-2.3) pre-pandemic to 1.5 years (IQR 0.5-2.6) during and 1.6 years (IQR 0.6-2.8) post-pandemic (P < 0.001). Odds of extended length of stay were lower during (adjusted odds ratio [aOR] 0.61, 95% confidence interval [CI] 0.39-0.93) and post-pandemic (aOR 0.53, 95% CI 0.40-0.69) compared with pre-pandemic. Odds of intensive care unit admission and/or mechanical ventilation were lower during (aOR 0.70, 95% CI 0.33-1.49; P = 0.358) and post-pandemic (aOR 0.65, 95% CI 0.40-1.05; P = 0.080). Pre-pandemic, hMPV peaked in July-October; circulation disappeared in 2020, re-emerged in 2021 and returned to near pre-pandemic seasonality in 2023. Post-pandemic hMPV accounted for 3.2% of ALRI hospitalizations in children <5 years, highlighting the need for prevention, treatment and continued surveillance.

Genomic investigation is playing an increasing role in the management of cystic kidney diseases, reflecting a broader shift towards precision medicine in Nephrology. Recent updates to the KDIGO Clinical Practice Guideline emphasize diagnostic genomics as a core component of Autosomal Dominant Polycystic Kidney Disease (ADPKD) care in particular, recognizing its utility across a range of clinical scenarios. Traditionally, diagnosis of ADPKD has been clinical, using age-dependent imaging criteria for at risk individuals via ultrasound and Magnetic Resonance Imaging (MRI). While these imaging modalities have good sensitivity, there are pitfalls in clinical diagnosis, particularly in patients with atypical clinical features, those without family history or those at a young age. A confirmed genetic diagnosis can guide screening of at-risk family members, inform reproductive decisions, support safe selection of living-related kidney donors and provide the opportunity to utilize genotype-specific prognostication tools. In addition, as genotype-specific therapies enter the landscape, accurate genotyping will become essential for identifying which patients will benefit from treatment. This narrative review aims to provide a practical approach for the general Nephrologist of when to offer genetic testing to patients with cystic kidney disease and outline the technical and genetic counselling considerations in the provision of patient-centered genetic investigation.

ABSTRACT Active vaccine safety surveillance, which involves directly engaging with vaccine recipients to actively solicit information on adverse events following immunization, complements spontaneous reporting systems. This commentary provides a comparative overview of three national active vaccine safety surveillance systems: AusVaxSafety (Australia), CANVAS (Canada) and V-safe (United States) across six key surveillance system evaluation attributes. Each system played an essential role during the COVID-19 pandemic and continues to contribute to global post-marketing vaccine safety surveillance. Each has various strengths and limitations. AusVaxSafety, established in 2014, is well integrated with routine healthcare settings for opt-out surveillance and offers frequent public reporting. CANVAS, established in 2009, offers a unique cohort-based design with inclusion of control groups. V-safe, established in 2020, has proven scalability and broad population reach due to its accessible web-based design. The various features of each system offer insights to inform future vaccine safety surveillance efforts.

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.