Efficacy and safety of onasemnogene abeparvovec in children with spinal muscular atrophy type 1: real-world evidence from 6 infusion centres in the United Kingdom.

Background: Real-world data on the efficacy and safety of onasemnogene abeparvovec (OA) in spinal muscular atrophy (SMA) are needed, especially to overcome uncertainties around its use in older and heavier children. This study evaluated the efficacy and safety of OA in patients with SMA type 1 in the UK, including patients ≥2 years old and weighing ≥13.5 kg. Methods: This observational cohort study used data from patients with genetically confirmed SMA type 1 treated with OA between May 2021 and January 2023, at 6 infusion centres in the United Kingdom. Functional outcomes were assessed using age-appropriate functional scales. Safety analyses included review of liver function, platelet count, cardiac assessments, and steroid requirements. Findings: Ninety-nine patients (45 SMA therapy-naïve) were treated with OA (median age at infusion: 10 [range, 0.6-89] months; median weight: 7.86 [range, 3.2-20.2] kg; duration of follow-up: 3-22 months). After OA infusion, mean ± SD change in CHOP-INTEND score was 11.0 ± 10.3 with increased score in 66/78 patients (84.6%); patients aged <6 months had a 13.9 points higher gain in CHOP-INTEND score than patients ≥2 years (95% CI, 6.8-21.0; P < 0.001). Asymptomatic thrombocytopenia (71/99 patients; 71.7%), asymptomatic troponin-I elevation (30/89 patients; 33.7%) and transaminitis (87/99 patients; 87.9%) were reported. No thrombotic microangiopathy was observed. Median steroid treatment duration was 97 (range, 28-548) days with dose doubled in 35/99 patients (35.4%). There were 22.5-fold increased odds of having a transaminase peak >100 U/L (95% CI, 2.3-223.7; P = 0.008) and 21.2-fold increased odds of steroid doubling, as per treatment protocol (95% CI, 2.2-209.2; P = 0.009) in patients weighing ≥13.5 kg versus <8.5 kg. Weight at infusion was positively correlated with steroid treatment duration (r = 0.43; P < 0.001). Worsening transaminitis, despite doubling of oral prednisolone, led to treatment with intravenous methylprednisolone in 5 children. Steroid-sparing immunosuppressants were used in 5 children to enable steroid weaning. Two deaths apparently unrelated to OA were reported. Interpretation: OA led to functional improvements and was well tolerated with no persistent clinical complications, including in older and heavier patients. Funding: Novartis Innovative Therapies AG provided a grant for independent medical writing services.

Dental drill noise reduction using a commercially-available earplug device.

AIM: The dental handpiece noise in a dental surgery is concerning to both patients and staff as a major cause of dental phobia in patients and potential hearing loss in clinical staff. High-frequency noise generated by dental handpieces is considered to be the worst of the many noises in a dental clinic. Methods to reduce this noise have been proposed and either passive or active noise reduction headphones are often suggested. However, in a dental surgery environment, the need for good verbal communication with the patient needs to be maintained. As a result, this paper aims to evaluate one proprietary anti-noise device considered suitable for this specific purpose. METHODS: Lab-based experiments were set up and carried out to evaluate QuietOn, using GRAS 43AG-1 Ear and Cheek Simulator to mimic a section of the human head and ear to represent the acoustic characteristics of an actual ear. Two types of dental drill noise recordings, one for electric motor-driven and another one for air turbine-driven, were played back through high-definition speakers. Sound data captured by the simulator are then visualised and plotted using MATLAB for analysis. MAIN FINDINGS: QuietOn is effective at low frequencies (< 1kHz). However, when dealing with high-frequency noise such as dental handpieces it is ineffective yet subdues verbal communication. CONCLUSIONS: Further development of passive or active noise cancellation earplugs is still needed to target dental handpiece noise while maintaining verbal communication.

Antineurofascin IgG2-associated paediatric autoimmune nodopathy.

In this case series of four paediatric patients, we present the first described cases of immunotherapy-responsive autoimmune nodopathy with IgG2 antineurofascin antibodies. In three cases, the antineurofascin antibodies were predominantly of the IgG2 subclass, a novel finding in comparison to previously described adult cases where IgG4 and/or IgG1/3 have typically been described. One patient had low signal for IgG2 with predominant IgG1 and IgG4 antibodies, a pattern commonly seen in adult patients. Two patients had antibodies targeting all three neurofascin isoforms (155, 186, and 140), whereas antibodies in the sera from the third targeted only the nodal isoforms 186 and 140, and the fourth patient only neurofascin 155. The three patients with IgG2 predominant antibodies appear to be responsive to intravenous immunoglobulin (IVIG) to varying degrees thus far, whereas the patient with IgG1/4 antibodies had poor response to IVIG but good response to steroids. Although the full clinical significance of IgG2 predominant antineurofascin antibodies in the context of childhood polyneuropathy remains unclear, emerging evidence of serological-phenotypic correlation may inform prognostication and therapeutic decision-making, warranting further study into this area. WHAT THIS PAPER ADDS: Paediatric immunotherapy-responsive nodopathies were associated with antineurofascin antibodies predominantly of the IgG2 subclass in 3 out of 4 patients. Identification of antibodies and understanding their phenotypic relevance could predict response to treatment and guide therapeutic decision-making in children.

How paediatricians investigate early developmental impairment in the UK: a qualitative descriptive study.

BACKGROUND: Early developmental impairment (EDI) is common and has many aetiologies and, therefore, potential investigations. There are several published guidelines recommending aetiological investigations, and paediatricians' views of them varies. Little is known on the thought processes underlying clinical decisions in investigating EDI. This study aimed to describe the thought processes affecting clinical decisions on the investigation of EDI within a nationalised health care system. METHODS: A qualitative descriptive study using semi-structured qualitative interviews performed in person or via video link with paediatricians who see children with EDI in England. As part of the interview, a case study of a fictional disease, Cavorite deficiency, modelled on biotinidase deficiency, was given to participants with the cost of testing, incidence and likelihood it would respond to treatment. This allowed exploration of cost without encumbrance from predisposing views and training on the condition. Thematic analysis was performed by iterative approach. Where participants stated they wanted to redirect money from investigations to treatment, were that even possible, we asked which services they would like to be better funded in their area. RESULTS: Interviews were conducted with 14 consultant paediatricians: 9 Community / Neurodisability, 2 General paediatricians, and 3 Paediatric Neurologists. Two themes were identified: the value of an aetiological diagnosis to families and managing risk and probability when investigating EDI. The latter contained 4 subthemes: 'circumspection' involved blanket investigations chosen irrespective of phenotype and high regard for guidelines; 'accepting appropriate risk' involved participants choosing investigations based on clinical phenotype, recognising some aetiologies would be missed; consultants found they 'transitioned between practices' during their career; and 'improved practice' was thought possible with better evidence on how to stratify investigations based on phenotype. Services that were most frequently reported to need additional funding were therapy services, early community developmental services, management of behaviour, sleep and mental health, and educational support. CONCLUSIONS: There are many factors that influence paediatricians' choice of aetiological investigation in EDI, but clinical factors are the most important. Paediatricians want better evidence to allow them to select the right investigations for each child without a significant risk of missing an important diagnosis.

The association of peak systolic velocity in the carotid artery with coronary heart disease: A study based on portable ultrasound.

Cardiovascular disease (CVD) is the highest cause of death globally with more people dying annually from it than from any other cause. CVD is associated with modifiable risk factors (dyslipidaemia, hypertension and diabetes) and treating each of these factors lowers the risk of CVD. It is impossible to estimate the benefit of risk factor modification in the individual patient and extrapolating data from multiple trials is difficult. It would be useful to have a marker of risk that accurately estimates real time risk by measuring blood flow factors associated with the pathogenesis of atheroma. The aim of this preliminary study was to validate a low-cost measurement technique for obtaining blood flow velocity profiles and assess whether any of the measured and calculated factors, based on computational fluid dynamics (CFD) simulation, known to be associated with atheroma was associated with coronary heart disease (CHD), thus establishing its feasibility and acceptability as a clinical tool and suggesting areas for future research. Our study identified (i) that mean peak systolic (PS) velocity being associated with CHD; individuals without CHD: mean (SD) = 62.8 (16.1) cm/s, with CHD: mean (SD) = 53.6 (17.3) cm/s, p = 0.042; and (ii) that low-cost, portable ultrasound, which is routinely available in general practice, is a suitable assessment tool.

Design for invention: annotation of functional geometry interaction for representing novel working principles.

In some mechanical engineering devices the novelty or inventive step of a patented design relies heavily upon how geometric features contribute to device functions. Communicating the functional interactions between geometric features in existing patented designs may increase a designer's awareness of the prior art and thereby avoid conflict with their emerging design. This paper shows how functional representations of geometry interactions can be developed from patent claims to produce novel semantic graphical and text annotations of patent drawings. The approach provides a quick and accurate means for the designer to understand the patent that is well suited to the designer's natural way of understanding the device. Through several example application cases we show the application of a detailed representation of functional geometry interactions that captures the working principle of familiar mechanical engineering devices described in patents. A computer tool that is being developed to assist the designer to understand prior art is also described.

Aetiological investigations in early developmental impairment: are they worth it?

OBJECTIVE: To study the frequency a diagnosis is made in children with early developmental impairment (EDI), and the contribution made to diagnosis by specific investigations. DESIGN: Retrospective case note review. SETTING: Community, neurodisability and neurology department at a UK tertiary centre. PARTICIPANTS: Children referred to determine the aetiology of EDI where a cause was not evident on history and examination. Participants were divided into two groups: EDI and no additional features (EDI-) and EDI with additional features (EDI+). MAIN OUTCOME MEASURES: The frequency a cause was found for the child's EDI and which tests contributed to a diagnosis. RESULTS: 699 participants, 68.8% boys, median age at investigation 2 years 8 months (range 3 months to 11 years 5 months). 61 (8.7%) of participants had no investigations, and children with EDI- were less likely to be investigated (χ2=12.5, p<0.05). A diagnosis was made in 166 children (23.7%) and was more frequent in EDI+ (EDI- 9.9%, EDI+ 27.3%, χ2=19.0; p<0.05). Full blood count, zinc protoporphyrin, renal or liver function, bone profile, biotinidase, creatine kinase or lead level revealed no diagnoses. The following investigations found causes for EDI: MRI (23.1%), microarray (11.5%), Fragile X (0.9%), plasma amino acids (1.2%), urine organic acids (0.9%) and thyroid function tests (0.5%). CONCLUSIONS: The majority of 'screening' investigations for EDI do not contribute to a diagnosis, highlighting an area of cost saving for the NHS and reduced burden for patients and families. We propose a streamlined guideline for the investigation of EDI based on our data.

Dimensional analysis using toric ideals: primitive invariants.

Classical dimensional analysis in its original form starts by expressing the units for derived quantities, such as force, in terms of power products of basic units [Formula: see text] etc. This suggests the use of toric ideal theory from algebraic geometry. Within this the Graver basis provides a unique primitive basis in a well-defined sense, which typically has more terms than the standard Buckingham approach. Some textbook examples are revisited and the full set of primitive invariants found. First, a worked example based on convection is introduced to recall the Buckingham method, but using computer algebra to obtain an integer [Formula: see text] matrix from the initial integer [Formula: see text] matrix holding the exponents for the derived quantities. The [Formula: see text] matrix defines the dimensionless variables. But, rather than this integer linear algebra approach it is shown how, by staying with the power product representation, the full set of invariants (dimensionless groups) is obtained directly from the toric ideal defined by [Formula: see text]. One candidate for the set of invariants is a simple basis of the toric ideal. This, although larger than the rank of [Formula: see text], is typically not unique. However, the alternative Graver basis is unique and defines a maximal set of invariants, which are primitive in a simple sense. In addition to the running example four examples are taken from: a windmill, convection, electrodynamics and the hydrogen atom. The method reveals some named invariants. A selection of computer algebra packages is used to show the considerable ease with which both a simple basis and a Graver basis can be found.

Loss of MIR15A and MIR16-1 at 13q14 is associated with increased TP53 mRNA, de-repression of BCL2 and adverse outcome in chronic lymphocytic leukaemia.

This study was conducted to investigate the possibility that TP53 mRNA is variably expressed in chronic lymphocytic leukaemia (CLL) and that under-expression is associated with TP53 dysfunction and adverse outcome. Although TP53 mRNA levels did indeed vary among the 104 CLL samples examined, this variability resulted primarily from over-expression of TP53 mRNA in 18 samples, all of which lacked TP53 deletion/mutation. These patients had higher lymphocyte counts and shorter overall and treatment-free survival times compared to cases with low TP53 mRNA expression and no TP53 deletion/mutation. Furthermore, TP53 mRNA levels did not correlate with levels of TP53 protein or its transcriptional target CDKN1A. We speculated that the adverse outcome associated with TP53 mRNA over-expression might reflect variation in levels of MIR15A and MIR16-1, which are encoded on chromosome 13q14 and target TP53 and some oncogenes including BCL2. In keeping with our hypothesis, 13q14 copy number and levels of MIR15A/MIR16-1 correlated positively with one another but negatively with levels of TP53 mRNA and BCL2 mRNA. Our findings support a model in which loss of MIR15A/MIR16-1 at chromosome 13q14 results in adverse outcome due to de-repression of oncogenes such as BCL2, and up-regulation of TP53 mRNA as a bystander effect.

The gene expression signature associated with TP53 mutation/deletion in chronic lymphocytic leukaemia is dominated by the under-expression of TP53 and other genes on chromosome 17p.

In chronic lymphocytic leukaemia (CLL), TP53 mutation and deletion are strongly associated with one another and with adverse clinical outcome. Mutant TP53 protein typically accumulates to high levels and has been reported to have transcriptional regulatory activity distinct from that of wild-type TP53. To investigate whether such an effect is relevant to CLL, carefully balanced primary CLL samples with or without TP53 mutation/deletion were compared for their gene expression profiles using high-density DNA microarrays. Ninety-six and eight differentially expressed genes were identified, respectively, using two alternative statistical approaches with different stringencies. None of the differentially expressed genes were known to be regulated by mutant TP53, and only four of the 67 under-expressed genes were known transcriptional targets of wild-type TP53. Significantly, both approaches showed that gene under-expression was the dominant feature of TP53-mutant CLL samples. Furthermore, a disproportionate number of the under-expressed genes were located on chromosome 17p, the most significant being TP53 itself. Together, these results indicate that any transcriptional regulatory effects of mutant TP53 in CLL cells are overshadowed by the under-expression of co-deleted TP53 and other genes on chromosome 17p. Our findings have implications for emerging therapeutic strategies that target mutant TP53.

Beyond the Virtual Intracranial Stenting Challenge 2007: non-Newtonian and flow pulsatility effects.

The Virtual Intracranial Stenting Challenge 2007 (VISC'07) is becoming a standard test case in computational minimally invasive cerebrovascular intervention. Following views expressed in the literature and consistent with the recommendations of a report, the effects of non-Newtonian viscosity and pulsatile flow are reported. Three models of stented cerebral aneurysms, originating from VISC'07 are meshed and the flow characteristics simulated using commercial computational fluid dynamics (CFD) software. We conclude that non-Newtonian and pulsatile effects are important to include in order to discriminate more effectively between stent designs.

Five members of the CEBP transcription factor family are targeted by recurrent IGH translocations in B-cell precursor acute lymphoblastic leukemia (BCP-ALL).

CCAAT enhancer-binding protein (CEBP) transcription factors play pivotal roles in proliferation and differentiation, including suppression of myeloid leukemogenesis. Mutations of CEBPA are found in a subset of acute myeloid leukemia (AML) and in some cases of familial AML. Here, using cytogenetics, fluorescence in situ hybridization (FISH), and molecular cloning, we show that 5 CEBP gene family members are targeted by recurrent IGH chromosomal translocations in BCP-ALL. Ten patients with t(8;14)(q11;q32) involved CEBPD on chromosome 8, and 9 patients with t(14;19)(q32;q13) involved CEBPA, while a further patient involved CEBPG, located 71 kb telomeric of CEBPA in chromosome band 19q13; 4 patients with inv(14)(q11q32)/t(14;14)(q11;q32) involved CEBPE and 3 patients with t(14;20)(q32;q13) involved CEBPB. In 16 patients the translocation breakpoints were cloned using long-distance inverse-polymerase chain reaction (LDI-PCR). With the exception of CEBPD breakpoints, which were scattered within a 43-kb region centromeric of CEBPD, translocation breakpoints were clustered immediately 5' or 3' of the involved CEBP gene. Except in 1 patient with t(14;14)(q11;q32), the involved CEBP genes retained germ-line sequences. Quantitative reverse transcription (RT)-PCR showed overexpression of the translocated CEBP gene. Our findings implicate the CEBP gene family as novel oncogenes in BCP-ALL, and suggest opposing functions of CEBP dysregulation in myeloid and lymphoid leukemogenesis.