'High hopes for treatment': Australian stakeholder perspectives of the clinical translation of advanced neurotherapeutics for rare neurological diseases.

INTRODUCTION: Advanced therapies offer unprecedented opportunities for treating rare neurological disorders (RNDs) in children. However, health literacy, perceptions and understanding of novel therapies need elucidation across the RND community. This study explored healthcare professionals' and carers' perspectives of advanced therapies in childhood-onset RNDs. METHODS: In this mixed-methodology cross-sectional study, 20 healthcare professionals (clinicians, genetic counsellors and scientists) and 20 carers completed qualitative semistructured interviews and custom-designed surveys. Carers undertook validated psychosocial questionnaires. Thematic and quantitative data analysis followed. RESULTS: Participants described high positive interest in advanced therapies, but low knowledge of, and access to, reliable information. The substantial 'therapeutic gap' and 'therapeutic odyssey' common to RNDs were recognised in five key themes: (i) unmet need and urgency for access; (ii) seeking information; (iii) access, equity and sustainability; (iv) a multidisciplinary and integrated approach to care and support and (v) difficult decision-making. Participants were motivated to intensify RND clinical trial activity and access to advanced therapies; however, concerns around informed consent, first-in-human trials and clinical trial procedures were evident. There was high-risk tolerance despite substantial uncertainties and knowledge gaps. RNDs with high mortality, increased functional burdens and no alternative therapies were consistently prioritised for the development of advanced therapies. However, little consensus existed on prioritisation to treatment access. CONCLUSIONS: This study highlights the need to increase clinician and health system readiness for the clinical translation of advanced therapeutics for RNDs. Co-development and use of educational and psychosocial resources to support clinical decision-making, set therapeutic expectations and promotion of equitable, effective and safe delivery of advanced therapies are essential. PATIENT OR PUBLIC CONTRIBUTION: Participant insights into the psychosocial burden and information need to enhance the delivery of care in this formative study are informing ongoing partnerships with families, including co-production and dissemination of psychoeducational resources featuring their voices hosted on the Sydney Children's Hospitals Network website SCHN Brain-Aid Resources.

'Integrating Ethics and Equity with Economics and Effectiveness for newborn screening in the genomic age: A qualitative study protocol of stakeholder perspectives.

BACKGROUND: Newborn bloodspot screening is a well-established population health initiative that detects serious, childhood-onset, treatable conditions to improve health outcomes. With genomic technologies advancing rapidly, many countries are actively discussing the introduction of genomic assays into newborn screening programs. While adding genomic testing to Australia's newborn screening program could improve outcomes for infants and families, it must be considered against potential harms, ethical, legal, equity and social implications, and economic and health system impacts. We must ask not only 'can' we use genomics to screen newborns?' but 'should we'?' and 'how much should health systems invest in genomic newborn screening?'. METHODS: This study will use qualitative methods to explore understanding, priorities, concerns and expectations of genomic newborn screening among parents/carers, health professionals/scientists, and health policy makers across Australia. In-depth, semi-structured interviews will be held with 30-40 parents/carers recruited via hospital and community settings, 15-20 health professionals/scientists, and 10-15 health policy makers. Data will be analysed using inductive content analysis. The Sydney Children's Hospital Network Human Research Ethics Committee approved this study protocol [2023/ETH02371]. The Standards for Reporting Qualitative Research will guide study planning, conduct and reporting. DISCUSSION: Few studies have engaged a diverse range of stakeholders to explore the implications of genomics in newborn screening in a culturally and genetically diverse population, nor in a health system underpinned by universal health care. As the first study within a multi-part research program, findings will be used to generate new knowledge on the risks and benefits and importance of ethical, legal, social and equity implications of genomic newborn screening from the perspective of key stakeholders. As such it will be the foundation on which child and family centered criteria can be developed to inform health technology assessments and drive efficient and effective policy decision-making on the implementation of genomics in newborn screening.

Newborn screening for Duchenne muscular dystrophy: the perspectives of stakeholders.

Background: The rapidly evolving clinical landscape of Duchenne muscular dystrophy (DMD) is driving innovative approaches for early diagnosis through genomic newborn bloodspot screening (NBS). However, the potential impact of these programs on families and healthcare systems remains unexplored. This study assessed the perceived benefits, harms, barriers, and enablers for DMD NBS amongst primary caregivers of children with DMD and healthcare professionals (HCPs). Methods: This Australian multi-centre cross-sectional study used a mixed-methods convergent methodology. Participants completed a codeveloped questionnaire and their perceptions on the utility, model of care, and processes of DMD NBS were thematically analysed. Findings: Participants included 50 caregivers and 26 HCPs (68.5% and 53.1% response rate respectively). Most caregivers (40/50, 80%) perceived net benefits of DMD NBS and highlighted an early diagnosis as actionable knowledge, even with the current paucity of disease modifying therapies. This knowledge was valued to enable access to multidisciplinary supportive care (29/50, 58%), clinical trials (27/50, 54%), psychological support (28/50, 56%), inform reproductive planning (27/50, 54%), and facilitate financial planning based on the future needs of their child (27/50, 54%). Whilst HCPs acknowledged these opportunities, only 16/26 (61.5%) believed there were definite net benefits, with notable concerns over the psychological harms of diagnostic knowledge without a recourse to disease modifying therapeutic intervention early in life. Interpretation: Caregivers and HCPs perceived a range of potential benefits of DMD NBS. Health system readiness will be founded on developing an integrated model of care that not only supports the psychosocial and information needs of families receiving a newborn diagnosis of DMD, but also provides care and clinical surveillance for individuals for whom a diagnosis may remain uncertain. Funding: Medical Research Futures fund (GNT2017165, MRF2015965).

Getting Wheels: development and evaluation of a psychoeducational resource for parents of children with a neuromuscular condition following recommendation of wheelchair equipment.

PURPOSE: Access to credible information can facilitate parental engagement in wheelchair prescription for their child with a neuromuscular condition (NMC). In this study, we developed and evaluated acceptability, perceived usefulness and emotional responses to a psychoeducational booklet for parents of children with a NMC. METHODS: Australian parents of children who had been recommended a wheelchair and clinicians caring for children with NMCs were invited to evaluate the booklet, Getting Wheels. The booklet included 11 chapters, each covering distinct aspects of wheelchair prescription and supportive care. Participants completed one online survey including validated and study-specific measures. RESULTS: Twenty-seven parents (71% response rate, 78% mothers) and nine clinicians (90% response rate, 89% women) participated. All parents endorsed the booklet as addressing their information and support needs, and 93% agreed it would help parents engage in the wheelchair prescription process. All clinicians endorsed the booklet as addressing parents' information and support needs and agreed they could use the booklet in clinical practice. CONCLUSIONS: Parents and clinicians rate Getting Wheels as acceptable for use in the context of wheelchair recommendation for children with a neuromuscular condition. Next steps include prospective examination of booklet use in clinical practice and adaptation to culturally and linguistically diverse populations.Implications for rehabilitationThe co-designed "Getting Wheels" booklet provides tailored information for use in the context of wheelchair recommendation for children with a neuromuscular condition.The emotions elicited throughout wheelchair prescription endorse the need for integrated psychosocial multidisciplinary care to improve access and support the ongoing emotional needs of this population.Parents of children who receive wheelchair recommendation between zero and two years require greater support from clinicians regarding their thoughts and feelings about wheelchair prescription.Parents of children with a neuromuscular condition and treating clinicians support provision of a tailored psychoeducational resource when a child is recommended a wheelchair.

Exploring caregivers' attitudes and beliefs about nutrition and weight management for young people with Duchenne muscular dystrophy.

INTRODUCTION/AIMS: Obesity disproportionately affects children and adolescents with Duchenne muscular dystrophy (DMD) and with adverse consequences for disease progression. This study aims to: explore barriers, enablers, attitudes, and beliefs about nutrition and weight management; and to obtain caregiver preferences for the design of a weight management program for DMD. METHODS: We surveyed caregivers of young people with DMD from four Australian pediatric neuromuscular clinics. Survey questions were informed by the Theoretical Domains Framework and purposefully designed to explore barriers and enablers to food and weight management. Caregivers were asked to identify their preferred features in a weight management program for families living with DMD. RESULTS: Fifty-three caregivers completed the survey. Almost half (48%) perceived their son as above healthy weight. Consequences for those children were perceived to be self-consciousness (71%), a negative impact on self-esteem (64%) and movement (57%). Preventing weight gain was a common reason for providing healthy food and healthy eating was a high priority for families. Barriers to that intention included: time constraints, selective food preferences, and insufficient nutrition information. Caregivers preferred an intensive six-week weight management program addressing appetite management and screen time. DISCUSSION: Managing weight is an important issue for caregivers of sons with DMD; yet several barriers exist. Individualized 6 week programs are preferred by caregivers to improve weight management for DMD.

Life-Saving Treatments for Spinal Muscular Atrophy: Global Access and Availability.

Background and Objectives: Spinal muscular atrophy (SMA) is a neurodegenerative disorder manifesting with progressive muscle weakness and atrophy. SMA type 1 used to be fatal within the first 2 years of life, but is now treatable with therapies targeting splicing modification and gene replacement. Nusinersen, risdiplam, and onasemnogene abeparvovec-xioi improve survival, motor strength, endurance, and ability to thrive, allowing many patients to potentially attain a normal life; all have been recently approved by major regulatory agencies. Although these therapies have revolutionized the world of SMA, they are associated with a high economic burden, and access to these therapies is limited in some countries. The primary objective of this study was to compare the availability and implementation of treatment of SMA from different regions of the world. Methods: In this qualitative study, we surveyed health care providers from 21 countries regarding their experiences caring for patients with SMA. The main outcome measures were provider survey responses on newborn screening, drug availability/access, barriers to treatment, and related questions. Results: Twenty-four providers from 21 countries with decades of experience (mean 26 years) in treating patients with SMA responded to the survey. Nusinersen was the most available therapy for SMA. Our survey showed that while genetic testing is usually available, newborn screening is still unavailable in many countries. The provider-reported treatment cost also varied between countries, and economic burden was a major barrier in treating patients with SMA. Discussion: Overall, this survey highlights the global inequality in managing patients with SMA. The spread of newborn screening is essential in ensuring improved access to care for patients with SMA. With the advancement of neurotherapeutics, more genetic diseases will soon be treatable, and addressing the global inequality in clinical care will require novel approaches to mitigate such inequality in the future.

Gene therapy-based strategies for spinal muscular atrophy-an Asia-Pacific perspective.

Onasemnogene abeparvovec has been life-changing for children with spinal muscular atrophy (SMA), signifying the potential and progress occurring in gene- and cell-based therapies for rare genetic diseases. Hence, it is important that clinicians gain knowledge and understanding in gene therapy-based treatment strategies for SMA. In this review, we describe the development and translation of onasemnogene abeparvovec from clinical trials to healthcare practice and share knowledge on the facilitators and barriers to implementation. Rapid and accurate SMA diagnosis, awareness, and education to safely deliver gene therapy to eligible patients and access to expertise in multidisciplinary management for neuromuscular disorders are crucial for health system readiness. Early engagement and intersectoral collaboration are required to surmount complex logistical processes and develop policy, governance, and accountability. The collection and utilisation of real-world evidence are also an important part of clinical stewardship, informing ongoing improvements to care delivery and access. Additionally, a research-enabled clinical ecosystem can expand scientific knowledge and discovery to optimise future therapies and magnify health impacts. Important ethical, equity, economic, and sustainability issues are evident, for which we must connect globally.

Characterizing Common Phenotypes Across the Childhood Dementia Disorders: A Cross-sectional Study From Two Australian Centers.

BACKGROUND: Childhood dementias are a group of rare pediatric conditions characterized by progressive neurocognitive decline. Quantifying and characterising phenotypes to identify similarities between specific conditions is critical to inform opportunities to optimize care and advance research. METHODS: This cross-sectional study recruited primary caregivers of children (<18 years) living with a dementia syndrome from neurology and metabolic clinics in Sydney and Adelaide, Australia. Sociodemographic and clinical data were collated. Behavior, eating, sleep, pain, and neurological disability were assessed using validated tools, including Strengths and Difficulties, Child Eating Behaviour, and Children's Sleep Habits questionnaires and visual analog of pain and modified Rankin scales. Data were analyzed with descriptive statistics. RESULTS: Among 45 children with 23 different dementia syndromes, the modified Rankin Scale demonstrated at least moderate neurological disability and functional dependence in 82% (37/45). Families reported delays in receiving an accurate diagnosis following initial symptoms (mean: 1.6 ± 1.4 years, range: 0-5 years). The most prevalent phenotypes included communication, comprehension, or recall difficulties (87%, 39/45); disturbances in sleep (80%, 36/45); appetite changes (74%, 29/39); mobility issues (53%, 24/45); and hyperactive behavior (53%, 21/40). Behavioral problems had a "high" or "very high" impact on everyday family life in 73% (24/33). CONCLUSIONS: Childhood dementia disorders share substantial behavioral, motor, sensory, and socioemotional symptoms, resulting in high care needs, despite their vast heterogeneity in age of onset and progression. Considering their unifying characteristics under one collective term is an opportunity to improve treatment, provide quality care, and accelerate research.

The psychosocial impact of childhood dementia on children and their parents: a systematic review.

BACKGROUND: Childhood dementias are a group of rare and ultra-rare paediatric conditions clinically characterised by enduring global decline in central nervous system function, associated with a progressive loss of developmentally acquired skills, quality of life and shortened life expectancy. Traditional research, service development and advocacy efforts have been fragmented due to a focus on individual disorders, or groups classified by specific mechanisms or molecular pathogenesis. There are significant knowledge and clinician skill gaps regarding the shared psychosocial impacts of childhood dementia conditions. This systematic review integrates the existing international evidence of the collective psychosocial experiences of parents of children living with dementia. METHODS: We used the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines. We systematically searched four databases to identify original, peer-reviewed research reporting on the psychosocial impacts of childhood dementia, from the parent perspective. We synthesised the data into three thematic categories: parents' healthcare experiences, psychosocial impacts, and information and support needs. RESULTS: Nineteen articles met review criteria, representing 1856 parents. Parents highlighted extensive difficulties connecting with an engaged clinical team and navigating their child's rare, life-limiting, and progressive condition. Psychosocial challenges were manifold and encompassed physical, economic, social, emotional and psychological implications. Access to coordinated healthcare and community-based psychosocial supports was associated with improved parent coping, psychological resilience and reduced psychological isolation. Analysis identified a critical need to prioritize access to integrated family-centred psychosocial supports throughout distinct stages of their child's condition trajectory. CONCLUSION: This review will encourage and guide the development of evidence-based and integrated psychosocial resources to optimise quality of life outcomes for of children with dementia and their families.

Prospective assessment of vincristine-induced peripheral neuropathy in paediatric acute lymphoblastic leukemia.

OBJECTIVE: Vincristine is a mainstay treatment for paediatric cancers, particularly acute lymphoblastic leukemia (ALL), with common toxicity including vincristine-induced peripheral neuropathy (VIPN). The present study comprehensively assessed VIPN outcomes in patients receiving vincristine treatment for ALL. METHODS: Children diagnosed with ALL commencing vincristine treatment were prospectively evaluated (baseline, post-induction, pre-reinduction, post-reinduction, follow-up). VIPN was examined clinically using the Balis sensory/motor scale, neurophysiologically using axonal excitability techniques and quality-of-life using Pediatric Quality of Life Inventory. RESULTS: Thirty-one patients were recruited to this study (age = 6.8 ± 4.4; 61.3% female). Incidence of motor VIPN (motor Balis grade > 0) symptoms were higher than sensory VIPN (sensory Balis grade > 0) at post-induction (92.0% vs 36.0%) and post-reinduction (81.8% vs 22.7%) vincristine treatment. Neurophysiological assessment also demonstrated greater change in motor axonal excitability parameters compared to sensory parameters including changes in depolarising threshold electrotonus (P < 0.0125), superexcitability and subexcitability parameters (all P < 0.0125). Follow-up assessment demonstrated persisting VIPN symptoms with reduced quality-of-life scores compared to baseline. CONCLUSIONS: Clinical and neurophysiological evaluation of VIPN suggests vincristine produces a motor-prominent sensorimotor neuropathy in children which persisted at follow-up. SIGNIFICANCE: VIPN signs and symptoms develop early in the treatment course, in line with axonal excitability profiles. Early detection of significant nerve changes may support timely implementation of neuroprotection strategies.

The collective burden of childhood dementia: a scoping review.

Childhood dementia is a devastating and under-recognized group of disorders with a high level of unmet need. Typically monogenic in origin, this collective of individual neurodegenerative conditions are defined by a progressive impairment of neurocognitive function, presenting in childhood and adolescence. This scoping review aims to clarify definitions and conceptual boundaries of childhood dementia and quantify the collective disease burden. A literature review identified conditions that met the case definition. An expert clinical working group reviewed and ratified inclusion. Epidemiological data were extracted from published literature and collective burden modelled. One hundred and seventy genetic childhood dementia disorders were identified. Of these, 25 were analysed separately as treatable conditions. Collectively, currently untreatable childhood dementia was estimated to have an incidence of 34.5 per 100 000 (1 in 2900 births), median life expectancy of 9 years and prevalence of 5.3 per 100 000 persons. The estimated number of premature deaths per year is similar to childhood cancer (0-14 years) and approximately 70% of those deaths will be prior to adulthood. An additional 49.8 per 100 000 births are attributable to treatable conditions that would cause childhood dementia if not diagnosed early and stringently treated. A relational database of the childhood dementia disorders has been created and will be continually updated as new disorders are identified (https://knowledgebase.childhooddementia.org/). We present the first comprehensive overview of monogenic childhood dementia conditions and their collective epidemiology. Unifying these conditions, with consistent language and definitions, reinforces motivation to advance therapeutic development and health service supports for this significantly disadvantaged group of children and their families.

Decision-making and challenges within the evolving treatment algorithm in spinal muscular atrophy: a clinical perspective.

INTRODUCTION: The clinical application of disease modifying therapies has dramatically changed the paradigm of the management of people with spinal muscular atrophy (SMA), from sole reliance on symptomatic care directed toward the downstream consequences of muscle weakness, to proactive intervention and even preventative care. AREAS COVERED: In this perspective, the authors evaluate the contemporary therapeutic landscape of SMA and discuss the evolution of novel phenotypes and the treatment algorithm, including the key factors that define individual treatment choice and treatment response. The benefits achieved by early diagnosis and treatment through newborn screening are highlighted, alongside an appraisal of emerging prognostic methods and classification frameworks to inform clinicians, patients, and families about disease course, manage expectations, and improve care planning. A future perspective of unmet needs and challenges is provided, emphasizing the key role of research. EXPERT OPINION: SMN-augmenting therapies have improved health outcomes for people with SMA and powered the practice of personalized medicine. Within this new proactive diagnostic and treatment paradigm, new phenotypes and different disease trajectories are emerging. Ongoing collaborative research efforts to understand the biology of SMA and define optimal response are critical to refining future approaches.

The outlook for individuals with Spinal Muscular Atrophy (SMA) has transformed with the approval of three effective disease modifying therapies in the past seven years. This group of genetic diseases that cause progressive muscle weakness and present as a broad range of severity ­ from mild disease with near normal lifespan to severe with abbreviated lifespan and comorbidities ­ now have gene-based therapies that have shown (motor) functional gains, ameliorated comorbidities, and improved overall quality of life of patients and prolonged survival. With the rapid translation of early diagnostic paradigms through newborn screening and the acceleration of a therapeutic pipeline, uncertainties within clinical practice arise including the optimal time to treat, the changing clinical characteristics of the treated population, monitoring of disease progression and therapeutic response in the post-treatment era. In this article, we review the evidence base to address these challenges. The key factors that determine individual treatment choice and response are discussed. The changed clinical characteristics in treated children that need early identification and appropriate management are discussed in depth. A new classification system in keeping with the changed paradigm is provided. In these early times of the treatment era, the evidence from clinical trials and real world is combined to generate evidence base to guide management. The reader would be apprised of the recent therapeutic developments, their applications, and outcomes. Finally, the challenges to be expected along the uncharted path of prolonged lifespan are discussed and care guidelines provided.

Structural and functional characterization of capsid binding by anti-AAV9 monoclonal antibodies from infants after SMA gene therapy.

Success in the treatment of infants with spinal muscular atrophy (SMA) underscores the potential of vectors based on adeno-associated virus (AAV). However, a major obstacle to the full realization of this potential is pre-existing natural and therapy-induced anti-capsid humoral immunity. Structure-guided capsid engineering is one possible approach to surmounting this challenge but necessitates an understanding of capsid-antibody interactions at high molecular resolution. Currently, only mouse-derived monoclonal antibodies (mAbs) are available to structurally map these interactions, which presupposes that mouse and human-derived antibodies are functionally equivalent. In this study, we have characterized the polyclonal antibody responses of infants following AAV9-mediated gene therapy for SMA and recovered 35 anti-capsid mAbs from the abundance of switched-memory B (smB) cells present in these infants. For 21 of these mAbs, seven from each of three infants, we have undertaken functional and structural analysis measuring neutralization, affinities, and binding patterns by cryoelectron microscopy (cryo-EM). Four distinct patterns were observed akin to those reported for mouse-derived mAbs, but with early evidence of differing binding pattern preference and underlying molecular interactions. This is the first human and largest series of anti-capsid mAbs to have been comprehensively characterized and will prove to be powerful tools for basic discovery and applied purposes.

CSF neopterin, quinolinic acid and kynurenine/tryptophan ratio are biomarkers of active neuroinflammation.

BACKGROUND: Defining the presence of acute and chronic brain inflammation remains a challenge to clinicians due to the heterogeneity of clinical presentations and aetiologies. However, defining the presence of neuroinflammation, and monitoring the effects of therapy is important given its reversible and potentially damaging nature. We investigated the utility of CSF metabolites in the diagnosis of primary neuroinflammatory disorders such as encephalitis and explored the potential pathogenic role of inflammation in epilepsy. METHODS: Cerebrospinal fluid (CSF) collected from 341 paediatric patients (169 males, median age 5.8 years, range 0.1-17.1) were examined. The patients were separated into a primary inflammatory disorder group (n = 90) and epilepsy group (n = 80), who were compared with three control groups including neurogenetic and structural (n = 76), neurodevelopmental disorders, psychiatric and functional neurological disorders (n = 63), and headache (n = 32). FINDINGS: There were statistically significant increases of CSF neopterin, kynurenine, quinolinic acid and kynurenine/tryptophan ratio (KYN/TRP) in the inflammation group compared to all control groups (all p < 0.0003). As biomarkers, at thresholds with 95% specificity, CSF neopterin had the best sensitivity for defining neuroinflammation (82%, CI 73-89), then quinolinic acid (57%, CI 47-67), KYN/TRP ratio (47%, CI 36-56) and kynurenine (37%, CI 28-48). CSF pleocytosis had sensitivity of 53%, CI 42-64). The area under the receiver operating characteristic curve (ROC AUC) of CSF neopterin (94.4% CI 91.0-97.7%) was superior to that of CSF pleocytosis (84.9% CI 79.5-90.4%) (p = 0.005). CSF kynurenic acid/kynurenine ratio (KYNA/KYN) was statistically decreased in the epilepsy group compared to all control groups (all p ≤ 0.0003), which was evident in most epilepsy subgroups. INTERPRETATION: Here we show that CSF neopterin, kynurenine, quinolinic acid and KYN/TRP are useful diagnostic and monitoring biomarkers of neuroinflammation. These findings provide biological insights into the role of inflammatory metabolism in neurological disorders and provide diagnostic and therapeutic opportunities for improved management of neurological diseases. FUNDING: Financial support for the study was granted by Dale NHMRC Investigator grant APP1193648, University of Sydney, Petre Foundation, Cerebral Palsy Alliance and Department of Biochemistry at the Children's Hospital at Westmead. Prof Guillemin is funded by NHMRC Investigator grant APP 1176660 and Macquarie University.

Treatment of severe acute necrotizing encephalopathy of childhood with interleukin-6 receptor blockade in the first 24 h as add-on immunotherapy shows favorable long-term outcome at 2 years.

BACKGROUND: Acute necrotizing encephalopathy (ANE) of childhood is a rare and devastating infection-associated acute encephalopathy. While there are no consensus treatments for ANE, recent case reports suggest a beneficial role for the use of tocilizumab, a recombinant humanized monoclonal antibody against the interleukin-6 (IL-6) receptor. The correlation of the timing of add-on tocilizumab in relation to long-term outcome has not been reported. METHODS: We report on the timing of administration of tocilizumab in two patients classified as high-risk using the ANE severity score (ANE-SS) with respect to the long-term outcome at 2 years. RESULTS: Case 1 was a 19-month-old previously well boy who presented to a tertiary children's hospital with seizures, evolving status dystonicus and shock. Case 2 was a three-year-old boy who presented to a peripheral hospital with fever, sepsis and encephalopathy. The patients were transferred to the tertiary intensive care unit and MRI confirmed ANE with extensive brainstem involvement. Case 1 received intravenous immunoglobulin (IVIg), methylprednisolone and tocilizumab at 21, 39 and 53 h respectively. His modified Rankin scale (mRS) at discharge and two years was unchanged at 5. The functional independence measure - for children (WeeFIM) at two years was very low (19/126). Case 2 received dexamethasone at 1 h, methylprednisolone at 21 h and IVIg and tocilizumab at 22 h. The mRS at discharge and two years was 4 and 3 respectively. The WeeFIM score at two years showed substantial improvement (96/126). CONCLUSION: The very early use of interleukin-6 blockade as 'add-on' immunotherapy in the first 24 h demonstrates potential for improving the long-term outcome in patients classified as high-risk using the ANE-SS.

Newborn screening for spinal muscular atrophy in Australia: a non-randomised cohort study.

BACKGROUND: In light of a new therapeutic era for spinal muscular atrophy (SMA), newborn screening has been proposed as a gateway to facilitate expedient diagnosis and access to therapeutics. However, there is paucity of evidence on health outcomes outside the homogenous populations in clinical trials to justify broader implementation of newborn screening for SMA. In this real-world study, we aimed to investigate the effectiveness of newborn screening coupled with access to disease-modifying therapeutics, as an intervention for SMA. METHODS: In this prospective, non-randomised cohort study done at Sydney Children's Hospital Network (NSW, Australia), we included children younger than 16 years with homozygous exon 7 deletions of survival motor neuron 1 gene (SMN1) mutations, non-selectively assigned to a screening group (incident population diagnosed by newborn screening) from Aug 1, 2018, to Aug 1, 2020, or a comparator group (incident population diagnosed by clinical referral) from Aug 1, 2016, to July 31, 2018. We excluded infants with compound heterozygous SMN1 mutations and those participating in ongoing and unpublished clinical trials. Effectiveness of newborn screening for SMA was compared using motor development milestone attainment defined by WHO Multicentre Growth Reference Study at 2 years post diagnosis. Secondary outcome measures included mortality and change in Hammersmith Infant Neurological Examination-2 (HINE-2) score, ventilation requirements, and enteral requirements 2 years from the time of diagnosis. FINDINGS: 34 children met the study inclusion criteria, but 33 children were included in the study population after one neonate was excluded due to participation in an ongoing unpublished clinical trial. 15 children were included in the screening group (seven [47%] male and eight [53%] female; median age 2·1 weeks [IQR 1·9-2·7]) and 18 children (nine [50%] male and nine [50%] female) were included in the comparator group (median age 47·8 weeks [13·0-99·9]). The 2-year survival rate was 93% (14 of 15 children) in the screening group and 89% (16 of 18) in the comparator group. Among survivors, 11 (79%) of 14 walked independently or with assistance in the screening group, compared with one (6%) of 16 children in the comparator group (χ2=16·27; p<0·0001). A significantly greater change in motor function was observed in the screening group compared with the comparator group over 2 years (HINE-2 score group difference, 12·32; p<0·0001). The requirement for non-intensive ventilation or feeding support at follow-up was higher in the comparator group than in the screening group (odds ratio 7·1 [95% CI 0·7-70·2]). Significant predictors of functional motor outcomes as determined by HINE-2 score at 2 years post diagnosis were HINE-2 score (p=0·0022), CHOP-INTEND (p=0·0001), compound muscle action potential (CMAP; p=0·0006), and disease status (p=0·023) at diagnosis. INTERPRETATION: Newborn screening for SMA, coupled with early access to disease-modifying therapies, effectively ameliorates the functional burden and associated comorbidities for affected children. For children diagnosed through newborn screening, motor score, CMAP, and disease status at diagnosis has clinical utility to determine functional independence. FUNDING: Brain Foundation and National Health and Medical Research Council.

Identification of Novel CSF-Derived miRNAs in Treated Paediatric Onset Spinal Muscular Atrophy: An Exploratory Study.

The availability of disease modifying therapies for spinal muscular atrophy (SMA) have created an urgent need to identify clinically meaningful biomarkers that provide insight into disease progression and therapeutic response. microRNAs (miRNA) have been shown to be involved in the pathogenesis of SMA and have the potential to provide insight within the field of SMA. miRNA-sequencing was utilized to identify differential miRNA expression in the cerebrospinal fluid (CSF) in six children with SMA treated with nusinersen in this exploratory study. Fourteen differentially expressed miRNAs were significantly altered in CSF from baseline to follow-up during treatment with nusinersen. The greatest magnitude of change was noted in miR-7-5p, miR-15a-5p, miR-15b-3p/5p, miR-126-5p, miR-128-2-5p and miR-130a-3p which encompassed a spectrum of functions predominantly in neurogenesis, neuronal differentiation and growth. The dominant signaling pathways identified in this study were the mammalian target of rapamycin and the mitogen-activated protein kinase signaling pathways. This study identified multiple miRNAs that were involved in the complex interplay between neurodevelopment and neurodegeneration.

"The usual challenges of work are all magnified": Australian paediatric health professionals' experiences during the COVID-19 pandemic.

Background: The COVID-19 pandemic has significantly increased stress and strain on health professionals. With a focus on paediatric cardiac care, this study explored health professionals' concerns about COVID-19, perceptions of the impact of pandemic on healthcare, and experiences of psychological stress. Methods: Paediatric health professionals working at a large quaternary hospital in Australia were invited to complete a survey between June 2020 and February 2021. Demographic factors, clinical role characteristics, and anxiety and depressive symptoms were assessed. Qualitative data on experiences and perceived effects of the pandemic on paediatric cardiac care were also collected. Results: 228 health professionals (152 nurses, 37 medical doctors, 22 allied and mental health professionals, 17 medical research and administrative staff) participated in the survey (54.4% response rate, 85% women). Half the sample (52.2%) endorsed 'moderate' to 'extreme' worry about COVID-19 and 38% of participants perceived healthcare services as adversely impacted by the pandemic to a 'great' or 'very great' extent. Almost one in five health professionals reported anxiety (18%) and 11% reported depressive symptoms indicative of a need for clinical intervention. Six themes were identified in the qualitative data: (1) Concern about the consequences of visitor restrictions and disrupted patient services, (2) Intensified strain on healthcare workers, (3) Feelings of fear and loss, (4) Social isolation and disconnection, (5) Adapting to change, and (6) Gratitude. Conclusion: Timely, tailored policies, supports, and interventions are needed to address health professionals' mental health needs during and beyond the pandemic, to minimize the far-reaching impact of situational stressors.