JEWELFISH: 24-month results from an open-label study in non-treatment-naïve patients with SMA receiving treatment with risdiplam.

Risdiplam is a once-daily oral, survival of motor neuron 2 (SMN2) splicing modifier approved for the treatment of spinal muscular atrophy (SMA). JEWELFISH (NCT03032172) investigated the safety, tolerability, pharmacokinetics (PK), and PK/pharmacodynamic (PD) relationship of risdiplam in non-treatment-naïve patients with SMA. JEWELFISH enrolled adult and pediatric patients (N = 174) with confirmed diagnosis of 5q-autosomal recessive SMA who had previously received treatment with nusinersen (n = 76), onasemnogene abeparvovec (n = 14), olesoxime (n = 71), or were enrolled in the MOONFISH study (NCT02240355) of the splicing modifier RG7800 (n = 13).

A Mixed-method Approach to Develop an Ambulatory Module of the SMA Independence Scale.

Background: Limited qualitative data exist on the symptoms and impacts of spinal muscular atrophy (SMA) experienced by ambulant individuals. An ambulant module of the SMA Independence Scale (SMAIS) was developed to quantify the assistance required to perform everyday mobility-related activities.

Objective: The objective of this study was to develop a patient-centered module that provides key insights into what constitutes independence for ambulant and near-ambulant individuals with SMA.

Mental health impact of autism on families of children with intellectual and developmental disabilities of genetic origin.

Background: Many children with an intellectual or developmental disability (IDD) have associated autism spectrum disorders (ASD), as well as an increased risk of mental health difficulties. In a cohort with IDD of genetic aetiology, we tested the hypothesis that excess risk attached to those with ASD + IDD, in terms of both children's mental health and parental psychological distress.

Methods: Participants with a copy number variant or single nucleotide variant (5-19 years) were recruited via UK National Health Service.

Prolonged respiratory failure responds to conventional therapy in isolated homocysteine remethylation defects.

Isolated remethylation defects are rare inherited diseases caused by a defective remethylation of homocysteine to methionine, preventing various essential methylation reactions to occur. Patients present with a systemic phenotype, which can especially affect the central and peripheral nervous systems leading to epileptic encephalopathy, developmental delay and peripheral neuropathy. Respiratory failure has been described in some cases, caused by both central and peripheral neurological involvement.

Development of an International SMA Bulbar Assessment for Inter-professional Administration.

Background: Progressive weakness can affect bulbar muscles in individuals with moderate to severe forms of spinal muscular atrophy (SMA). The paucity of standardized, valid bulbar assessments capturing clinically significant deficits in SMA impedes the ability to monitor function, facilitate intervention, or detect treatment response.

Objective: To fill this void, an international multidisciplinary team gathered to develop an agreed upon consensus-derived assessment of bulbar function in SMA for inter-professional administration to enhance our ability to monitor disease progression, support clinical management, and evaluate treatment effects.

Parental help-seeking behaviour for, and care of, a sick or injured child during the COVID-19 pandemic: a European online survey.

Background: Globally, the COVID-19 pandemic had a huge impact on patients and healthcare systems. A decline in paediatric visits to healthcare settings was observed, which might have been due to lower incidence of injury and infectious illness, changes in healthcare services and parental concern. The aim of our study was to examine parental experiences of help-seeking for, and care of, a sick or injured child during COVID-19 lockdown periods in five European countries with different healthcare systems in place.

Risdiplam in Patients Previously Treated with Other Therapies for Spinal Muscular Atrophy: An Interim Analysis from the JEWELFISH Study.

Introduction: Risdiplam is a survival of motor neuron 2 (SMN2) splicing modifier for the treatment of patients with spinal muscular atrophy (SMA). The JEWELFISH study (NCT03032172) was designed to assess the safety, tolerability, pharmacokinetics (PK), and pharmacodynamics (PD) of risdiplam in previously treated pediatric and adult patients with types 1-3 SMA. Here, an analysis was performed after all patients had received at least 1 year of treatment with risdiplam.

Clinical Trial Readiness for Spinal Muscular Atrophy: Experience of an International Educational-Training Initiative.

Several successful clinical trials have been conducted in spinal muscular atrophy (SMA) over recent years which have led to the approval of splicing modifiers and gene transfer therapies. With an increasing number of other agents progressing through pre-clinical and clinical development, increasing worldwide clinical trial readiness is becoming essential.SMA Europe initiated a clinical trial readiness project, which included the development of a pilot face-to-face educational-training initiative for clinical specialists and physiotherapists involved in SMA, with an emphasis on the patient perspective.

Pembrolizumab for the treatment of progressive multifocal leukoencephalopathy following anti-CD19 CAR-T therapy: a case report.

Progressive multifocal leukoencephalopathy (PML) is an opportunistic brain infection with few treatment options and poor survival when reversal of the underlying immune dysfunction is not achievable. JC polyomavirus reactivation resulting in PML can rarely complicate chimeric antigen receptor T-cell (CAR-T) therapy. We describe successful treatment of PML with Programmed death-1 (PD-1) blockade using pembrolizumab, 4 months following axicabtagene ciloleucel.

Risdiplam in types 2 and 3 spinal muscular atrophy: A randomised, placebo-controlled, dose-finding trial followed by 24 months of treatment.

Background And Purpose: Spinal muscular atrophy (SMA) is caused by reduced levels of survival of motor neuron (SMN) protein due to deletions and/or mutations in the SMN1 gene. Risdiplam is an orally administered molecule that modifies SMN2 pre-mRNA splicing to increase functional SMN protein.

Methods: SUNFISH Part 1 was a dose-finding study conducted in 51 individuals with types 2 and 3 SMA aged 2-25 years.

Integrin-Targeted, Short Interfering RNA Nanocomplexes for Neuroblastoma Tumor-Specific Delivery Achieve Silencing with Improved Survival.

The authors aim to develop siRNA therapeutics for cancer that can be administered systemically to target tumors and retard their growth. The efficacy of systemic delivery of siRNA to tumors with nanoparticles based on lipids or polymers is often compromised by their rapid clearance from the circulation by the liver. Here, multifunctional cationic and anionic siRNA nanoparticle formulations are described, termed receptor-targeted nanocomplexes (RTNs), that comprise peptides for siRNA packaging into nanoparticles and receptor-mediated cell uptake, together with lipids that confer nanoparticles with stealth properties to enhance stability in the circulation, and fusogenic properties to enhance endosomal release within the cell.

Muscle "islands": An MRI signature distinguishing neurogenic from myopathic causes of early onset distal weakness.

Muscle MRI has an increasing role in diagnosis of inherited neuromuscular diseases, but no features are known which reliably differentiate myopathic and neurogenic conditions. Using patients presenting with early onset distal weakness, we aimed to identify an MRI signature to distinguish myopathic and neurogenic conditions. We identified lower limb MRI scans from patients with either genetically (n = 24) or clinically (n = 13) confirmed diagnoses of childhood onset distal myopathy or distal spinal muscular atrophy.

Safety and efficacy of once-daily risdiplam in type 2 and non-ambulant type 3 spinal muscular atrophy (SUNFISH part 2): a phase 3, double-blind, randomised, placebo-controlled trial.

Background: Risdiplam is an oral small molecule approved for the treatment of patients with spinal muscular atrophy, with approval for use in patients with type 2 and type 3 spinal muscular atrophy granted on the basis of unpublished data. The drug modifies pre-mRNA splicing of the SMN2 gene to increase production of functional SMN. We aimed to investigate the safety and efficacy of risdiplam in patients with type 2 or non-ambulant type 3 spinal muscular atrophy.

Modeling the impact of calorie-reduction interventions on population prevalence and inequalities in childhood obesity in the Southampton Women's Survey.

Background: In the United Kingdom, rates of childhood obesity are high and inequalities in obesity have widened in recent years. Children with obesity face heightened risks of living with obesity as adults and suffering from associated morbidities. Addressing population prevalence and inequalities in childhood obesity is a key priority for public health policymakers in the United Kingdom and elsewhere.

Megadepth: efficient coverage quantification for BigWigs and BAMs.

Motivation: A common way to summarize sequencing datasets is to quantify data lying within genes or other genomic intervals. This can be slow and can require different tools for different input file types.

Results: Megadepth is a fast tool for quantifying alignments and coverage for BigWig and BAM/CRAM input files, using substantially less memory than the next-fastest competitor.

Risdiplam in Type 1 Spinal Muscular Atrophy.

Background: Type 1 spinal muscular atrophy is a rare, progressive neuromuscular disease that is caused by low levels of functional survival of motor neuron (SMN) protein. Risdiplam is an orally administered, small molecule that modifies pre-messenger RNA splicing and increases levels of functional SMN protein.

Methods: We report the results of part 1 of a two-part, phase 2-3, open-label study of risdiplam in infants 1 to 7 months of age who had type 1 spinal muscular atrophy, which is characterized by the infant not attaining the ability to sit without support.

Risdiplam treatment has not led to retinal toxicity in patients with spinal muscular atrophy.

Objective: Evaluation of ophthalmologic safety with focus on retinal safety in patients with spinal muscular atrophy (SMA) treated with risdiplam (EVRYSDI®), a survival of motor neuron 2 splicing modifier associated with retinal toxicity in monkeys. Risdiplam was approved recently for the treatment of patients with SMA, aged ≥ 2 months in the United States, and is currently under Health Authority review in the EU.

Methods: Subjects included patients with SMA aged 2 months-60 years enrolled in the FIREFISH, SUNFISH, and JEWELFISH clinical trials for risdiplam.

Areas of agreement in the management of childhood non-infectious chronic anterior uveitis in the UK.

Background/aims: There is a paucity of high-level evidence to support the management of childhood uveitis, particularly for those children without juvenile idiopathic arthritis uveitis (JIA). We undertook a modified Delphi consensus exercise to identify agreement in the management of chronic anterior uveitis (CAU), the most common manifestation of childhood disease.

Methods: A four-round, two-panel process was undertaken between June and December 2017.

Multimodal computational neocortical anatomy in pediatric hippocampal sclerosis.

Objective: In contrast to adult cohorts, neocortical changes in epileptic children with hippocampal damage are not well characterized. Here, we mapped multimodal neocortical markers of epilepsy-related structural compromise in a pediatric cohort of temporal lobe epilepsy and explored how they relate to clinical factors.

Methods: We measured cortical thickness, gray-white matter intensity contrast and intracortical FLAIR intensity in 22 patients with hippocampal sclerosis (HS) and 30 controls.