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Missense variants in the A Isoform of FGF13 as a novel cause of paroxysmal dyskinesia
Get PDFBackground: Pathogenic variants within the unique N‐terminal inactivation particle of FGF13 isoform A (FGF13A) have so far been associated only with an X‐linked dominant epileptic encephalopathy (DEE). Objective: The aim was to expand the clinical and molecular spectrum of FGF13A‐related disorder. Methods: We performed exome or genome sequencing of patients with unexplained nonepileptic paroxysmal dyskinesia (PxD). Results: Four unrelated boys with three novel de novo or inherited pathogenic missense variants in FGF13A were identified. Variants were also located within the inactivation particle, proximal to the DEE variants. Carrier mothers were unaffected, indicating an X‐linked recessive inheritance. All patients presented with PxD in infancy, consisting of both hyperkinetic and hypokinetic–hypotonic phases, and a variable neurodevelopmental disorder. The frequency of attacks was high (60–100 per day). Treatment with caffeine with or without methylphenidate partially improved PxD in 2 patients. Conclusions: FGF13A variants cause a partially caffeine‐responsive PxD phenotype with variable cognitive impairment, albeit without epilepsy. © 2026 The Author(s). Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society
MOGAD in South Wales: Diagnostic evolution and disease epidemiology
Get PDFBackground: Myelin oligodendrocyte glycoprotein antibody‐associated disease (MOGAD) is a rare antibody‐mediated inflammatory demyelinating disorder. In 2023, new international consensus diagnostic criteria were agreed. This study uses these criteria to describe epidemiological features of MOGAD in a population‐based cohort of patients from south Wales, UK. Methods: Retrospective review of case notes on all positive MOG‐IgG results in South Wales between 01 January 2011 and 30 June 2024 was undertaken, 2023 diagnostic criteria applied and standardised clinical features recorded. Paediatric MOGAD was defined as age at onset < 16 years and adult MOGAD ≥ 16 years. The incidence period was between 01 January 2015 and 31 December 2023. Results: Seventy‐six prevalent cases were identified: 53 adults and 23 children. Minimum estimated prevalence of MOGAD in south Wales on 30 June 2024 was 76/1,974,110 population (3.85/100,000 population; 95% CI 3.03–4.82). Paediatric prevalence was 6.59/100,000 population (95% CI 4.18–9.89) and adult prevalence 3.26/100,000 population (95% CI 2.44–4.27). Sex ratio was almost equal in males and females. The most frequent presentations were optic neuritis in adults (62.3%) and ADEM in children (34.8%); 64.5% had a monophasic disease course over a median follow‐up of 38 months (IQR 13–63). Mean annual incidence was 3.39 (95% CI 2.58–4.39) per million population. Conclusions: This regional study provides updated prevalence and incidence rates for MOGAD since the introduction of 2023 diagnostic criteria in a stable south Wales, UK population
The association between childhood Toxoplasma gondii, psychotic experiences and grey matter volume: A population-based cohort study
Get PDFToxoplasma gondii (T. gondii), a parasite that can be transmitted to humans by cats, has been proposed as a modifiable risk factor for schizophrenia and related disorders. However, much of the research examining this relationship has relied on cat ownership as a proxy measure for T. gondii exposure. This study examined the relationship between serum T. gondii levels and later psychotic experiences (PEs) and brain volume. We also explored the relationship between cat ownership and T. gondii serology. Using the Avon Longitudinal Study of Parents and Children (ALSPAC), we studied 3542 individuals for whom data on serum T. gondii during childhood and PEs at age 18 were available. Voxel-based morphometry assessed whether MRI measures of grey matter volume at age 20 were associated with T. gondii levels among a subset of the participants (N = 334). Serum T. gondii was not associated with PE group in adjusted models (suspected PEs risk ratio (RR) = 1.06, 95% confidence interval (CI) [0.89–1.27]; definite PEs RR = 0.86, 95% CI [0.65–1.13]; psychotic disorder RR = 1.00, 95% CI [0.73–1.38]). Exposure to cats during gestation was associated with higher T. gondii in adolescence (β = 0.08, p = 0.033), while exposure to cats during childhood was not (β = 0.05, p = 0.310). T. gondii was not associated with grey matter volume in the neuroimaging sample (pFWEs ≥ 0.882, Zs ≤ 3.86). Future work examining the relationship between T. gondii and schizophrenia-spectrum disorders should focus on serology or cat ownership during gestation as a proxy measure of T. gondii exposure, as there was no association between childhood cat ownership and T. gondii
Prognostic impact of myelodysplasia-related gene mutations in FLT3-ITD-mutated acute myeloid leukemia
Get PDFThe inclusion of nine myelodysplasia-related gene (MRG) mutations (ASXL1, BCOR, EZH2, RUNX1, SF3B1, SRSF2, STAG2, U2AF1, ZRSR2) as adverse risk factors in the ELN risk classification has reshaped classification in acute myeloid leukemia (AML). AML with FLT3-ITD mutations and co-occurring MRG alterations is now classified to the ELN adverse risk group although supporting evidence remains limited. Among 4,078 patients with AML with available molecular information included in the HARMONY platform, 862 harbored FLT3-ITD mutations and underwent intensive chemotherapy. Of these, 171 (20%) exhibited co-occurring MRG mutations at diagnosis. In this cohort, MRGs were not independently associated with relapse-free survival (RFS) or overall survival (OS). In the FLT3-ITD/NPM1 co-mutated subgroup, MRG mutations were rare (9%) and showed no prognostic impact. Conversely, in FLT3-ITD/NPM1 wildtype AML, MRG mutations were predictive of shorter RFS (HR 1.37, 95%CI 1.01 – 1.88, p = 0.046) and OS (HR 1.34, 95%CI 1.02–1.74, p = 0.032) in multivariable analysis with survival times comparable to the ELN adverse risk category. The allelic ratio of FLT3-ITD did not further stratify OS and RFS in this subgroup. These findings suggest that the prognostic relevance of MRG mutations in FLT3-ITD AML is modulated by NPM1 co-mutational status and mirror findings in AML lacking FLT3-ITD
Rapid plasma membrane reorganisation and endocytosis in HER2 breast cancer cells incubated with trastuzumab decorated polymer nanoparticles
Get PDFKnowledge on HER2+ breast cancer biology has informed drug design leading to targeted therapies giving improved clinical outcomes. Drug resistance and disease relapse, however still drive a continuous need for more efficacious and reliable therapeutics. Nanoparticles (NPs) as HER2 targeting nanomedicines offer new hope for selective targeting of HER2 within and beyond solid tumours, together with concomitant delivery of therapeutic cargo. For initial preclinical characterisation, studies on NP endocytosis and drug delivery are often performed in HER2+ breast cancer cell models, but information on initial NP-HER2 dynamics at the plasma membrane and how this impacts endocytic uptake and delivery efficiency is largely missing. Here using polymer poly(lactic-co-glycolide) acid NPs decorated with different valencies of the HER2 targeting monoclonal antibody trastuzumab, we have designed approaches to immediately study the impact of NP-HER2 targeting on high and low HER2 expressing breast cancer cell models. Using resonant scanning confocal imaging of live cell plasma membrane dynamics, we show in very high detail and within 10 minutes of cell exposure of the receptor to the NPs, extensive blebbing and ruffling of the plasma membrane, manifesting before much longer uptake of the NPs into the cell interior. Plasma membrane reorganisation was rapidly reversible, with cells reaching baseline morphology in 30 minutes. Our findings were confirmed at the ultrastructural level by scanning electron microscopy in cells fixed within 10 and 30 minutes of exposure to the NPs. Endocytic traffic of the NPs was in part directed to lysosomes and we discover a relationship between antibody valency and the ability of the NPs to deliver the chemotherapeutic agent doxorubicin to mediate cell death. Knowledge gained from these studies offers new approaches to study NP-cell dynamics in different NP-receptor settings and how receptor targeting influences plasma membrane organisation, endocytosis and delivery
High-temperature continuous wave operation of oxide-confined VCSELs
Get PDFWe present experimental measurements of the temperature dependence of oxide-confined vertical-cavity surface-emitting lasers under continuous wave (CW) operation and the aperture size-dependent performance at heatsink temperatures >135 ∘C. We extract the maximum CW operating temperature and internal cavity temperature at turn off and show these to be higher for narrow aperture devices. The modal properties are assessed from below threshold to turn-off and we show a tendency to low order mode lasing throughout the current sweep for narrow aperture devices, influenced by strong optical and electrical confinement
An oversampling method for addressing imbalanced data utilizing K-means clustering and membership-based data partitioning
No full textClass imbalance poses a critical challenge in real-world classification tasks, such as medical diagnosis, fraud detection, and fault monitoring, where accurate recognition of minority instances is vital. Oversampling is an effective approach to address this issue, but most existing methods tend to generate noisy synthetic samples in certain distributions, which degrades classification performance. This paper proposes a novel oversampling method called KM-MSMOTE (K-means and Membership-guided Synthetic Minority Oversampling Technique). The proposed method integrates K-means clustering with membership-based region partitioning to enhance the quality and representativeness of synthetic samples. Specifically, KM-MSMOTE filters clusters based on class dominance, adaptively assigns sampling weights, and divides each cluster into safe, overlapping, and noisy regions to control the generation of synthetic samples. Comprehensive experiments on 24 real-world datasets demonstrate that KM-MSMOTE consistently outperforms several state-of-the-art oversampling methods, achieving average improvements of 6.4–6.8 % across multiple evaluation metrics when combined with Support Vector Machine (SVM), Random Forest (RF), and K-Nearest Neighbors (KNN). Statistical analysis through Friedman and Nemenyi Post-Hoc tests confirms the significance of these improvements. Moreover, KM-MSMOTE demonstrates its superior robustness in challenging scenarios, achieving an average AUC improvement of 4.1 % under noise interference and 4.7 % under class overlap conditions compared to baseline methods. These results suggest that KM-MSMOTE provides an effective solution for engineering applications requiring reliable classification in imbalanced, noisy data environments
Demonstrating the value for money of implementing evidence-based treatment: the case for further investment in magnesium sulphate as a neuroprotectant for preterm births
Get PDFBackground: Effective and cost-effective treatments are not always optimally implemented. The benefit forgone due to sub-optimal implementation is often not considered or estimated. We use the economic concept of “incremental net monetary benefit” (INMB) to demonstrate how this can be valued. This approach can inform decision-making when used to estimate the value for money of potential future quality improvement (QI) programmes. We illustrate these analyses using the case of antenatal magnesium sulphate (MgSO4), a cost-effective treatment for the prevention of cerebral palsy in preterm births. We estimate the optimal implementation of MgSO4, the INMB lost due to sub-optimal implementation, and the value of future implementation initiatives to increase the use of MgSO4.
Methods: We estimated MgSO4 treatment implementation for babies under 32 weeks' gestation using routine data on its uptake between 2014 and 2022 in England, Scotland, and Wales. The optimal uptake level of MgSO4 was estimated using clinical judgment. The societal lifetime INMB of MgSO4 for the prevention of cerebral palsy in preterm births was obtained from the literature. The INMB of sub-optimal implementation over time was estimated as the difference between optimal and actual uptake over time in each country. We estimated the cost-effectiveness of a hypothetical future QI programme based on different scenarios of implementation effectiveness and costs.
Results: The optimal uptake of MgSO4 was 95%. The INMB forgone associated with sub-optimal MgSO4 uptake has reduced over time, as uptake has increased. However, in 2022, the societal lifetime INMB forgone was still £18.2 m in England, £3.7 m in Scotland, and £1.0 m in Wales. A future QI programme across all three countries achieving a 5% increase in MgSO4 uptake over one year, and costing £987,500 to implement, would be cost-effective; generating £7.5 m in INMB. Future implementation initiatives are likely to be cost-effective within a range of different implementation effectiveness and costs.
Conclusions: The case of MgSO4 treatment for preterm birth illustrates how sub-optimal implementation of evidence-based interventions can be associated with high opportunity costs measured as INMB forgone. This approach provides valuable quantification of the value for money of future QI programmes to improve the implementation of these interventions
Impact of wiping materials on the elimination from surfaces of dry surface biofilm of bacteria of food safety concern
Get PDFSalmonella spp. and Listeria monocytogenes are common foodborne pathogens that easily contaminate food preparation surfaces. Salmonella’s ability to form dry surface biofilms (DSBs) likely exacerbates surface persistence, making effective removal from food contact surfaces essential. This study is the first to evaluate the efficacy of food contact surface sanitizers against artificial L. monocytogenes DSBs, with comparisons to hydrated biofilms and dried planktonic cells. We hypothesized that the effectiveness of no-rinse, quaternary ammonium compound (QAC)-based sanitizers depends on both the wiping material used and the bacterial strain present.
Two pre-formulated no-rinse QAC sanitizers and one QAC spray were tested with six commercial wiping materials against three dried planktonic Salmonella spp. and one L. monocytogenes, as well as their DSBs, on stainless steel surfaces. Dried planktonic cells were more easily eliminated than DSBs, achieving approximately 4 log10 versus 2 log10 reductions, respectively. Although no-rinse QAC sanitizers are designed to reduce bacterial levels to acceptable limits, formulation constraints may limit their cleaning efficacy, particularly against DSBs in the presence of organic matter.
Pre-formulated QAC wipes were less effective than spraying the sanitizer followed by wiping. Wiping material type significantly influenced efficacy: paper towels significantly outperformed cloths, though performance varied among brands, and one sponge was the most effective overall.
This study underscores the need to carefully select wiping materials and no-rinse food contact surface sanitizers to eliminate Salmonella and Listeria DSBs, ensuring effective sanitation practices in foodservice settings