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Clinical trajectories of genetic variants in ALS: a European observational study within PRECISION-ALS
Get PDFObjective
To investigate the association between C9orf72, SOD1, FUS and TARDBP variants on the clinical trajectory of ALS patients in Europe.
Methods
Nine ALS centers with population-based registries provided data on demographic and disease characteristics – at diagnosis and longitudinally – as part of PRECISION ALS. These data were harmonized and collated for analysis.
Results
21,820 ALS patients were identified, 9,887 underwent genetic testing for at least one of the 4 genes of interest. 9.8% of patients carried a hexanucleotide expansion in C9orf72; 2.9% carried a pathogenic variant in SOD1; 1.4% carried a pathogenic variant in TARDBP; and 0.8% carried a pathogenic variant in FUS. Only one p.A5V variant was identified in this dataset. The most frequently identified SOD1 variant was p.D91A, with evidence of other variant clusters in Belgium, Italy and the United Kingdom. TARDBP variants were clustered in the Netherlands and Italy. Earlier ages of onset were demonstrated compared to wild-type populations; C9orf72 59.58 (IQR 62.5, p < 2.2e-16), SOD1 54.19 (IQR 19.4, p = 6.304e-14), TARDBP 58.30 (IQR 16.23, p = 0.00024) and FUS 51.16 (IQR 25.08, p = 1.58e-06). C9orf72 was more bulbar (p < 0.0001) in onset and SOD1 more spinal (p < 0.0001). Those carrying variants spent distinctly different periods in each of the King’s stages.
Conclusions
Genetic forms of ALS have an earlier age of onset, have distinct patterns in their sites of disease onset, and progress differently as compared to populations without such major-effect genes. There is also evidence of disease clusters across Europe suggestive of founder effects
Impact of opioid and cannabis use on low‐dose amitriptyline efficacy in cyclical vomiting syndrome: a real‐world study in the United Kingdom
Get PDFBackground
Central neuromodulators, specifically tricyclic antidepressants (TCAs), are prescribed as prophylactic treatment for cyclical vomiting syndrome (CVS). It is unclear whether opioids and/or cannabis affect the treatment response to neuromodulators. The aims of this study were to assess: (i) the prevalence of opioid and cannabis use among outpatients with CVS, (ii) clinical characteristics associated with opioid/cannabis use and response to a three-tiered neuromodulator treatment algorithm, and (iii) the effect of opioid/cannabis cessation on response to the treatment algorithm.
Methodology
Data from consecutive patients newly diagnosed with Rome IV CVS at a single tertiary care neurogastroenterology outpatient clinic (January 2016–June 2024) were retrospectively collected. Patients were advised to stop consuming opioids and/or cannabis and commenced a low-dose TCA.
Results
Sixty-one (46/75) percent of outpatients with CVS responded to the three-tiered treatment algorithm. Among responders, 42 (91%) patients responded to TCA alone (1st line therapy), 3 (7%) patients responded to TCA and selective serotonin reuptake inhibitor or serotonin norepinephrine reuptake inhibitor (2nd line therapy), and 1 (2%) patient required topiramate (3rd line therapy). The mean [SD] dosage of TCA among responders was 26.5 [18.3] mg. Twenty-five (33%) patients consumed opioids, 14 (19%) took cannabis, and five (7%) consumed both opioids and cannabis. While opioid cessation was associated with clinical response to the treatment algorithm (p = 0.03), opioid intake at the initial consultation was not (p = 0.2). Irritable bowel syndrome was independently associated with significantly greater odds (OR [95% CI]) of opioid consumption at baseline (6.59 [1.49–29.24], p = 0.01). Heartburn was independently associated with lower odds of response to the treatment algorithm (0.2 [0.05–0.65], p = 0.006).
Conclusion
Low-dose neuromodulators, along with opioid and cannabis cessation, may be important strategies in the management of CVS
Intestinal parasitic infections are related to micronutrient status and body composition in Mexican school-age children:results from a cross-sectional study
Get PDFIntestinal parasitic infections remain a significant public health issue, particularly in low-resource settings. They have been linked to poor micronutrient status and body composition, which are critical determinants of child health and development. The aim of this cross-sectional study was to determine the relationship between intestinal parasitic infections and micronutrient status, and whether these differ according to the body composition. Serum concentrations of zinc, iron, ferritin, vitamins A, E, C, D, folate, B12 and CRP, were determined in 269 school-aged children from rural Mexico. Infection with soil transmitted helminths (STHs) and intestinal protozoa was screened in a fecal sample. Anthropometric and body composition measurements were taken. Lower ferritin, zinc and vitamin C concentrations were found in children infected with any STHs or A. lumbricoides compared to parasite-free children (p < 0.05). Children infected with any intestinal protozoa, Endolimax nana or Entamoeba coli had higher concentrations of ferritin and B12 than parasite-free children (p < 0.05). Vitamin E: lipid concentration was higher in children infected with any intestinal protozoa and E. nana. Among the children with high body fat percentage, those infected with STH had lower zinc, and those infected with intestinal protozoa had lower vitamin A than parasite-free children (p < 0.05). STH infection was associated with lower concentrations of ferritin, zinc and vitamin C, whereas intestinal protozoa infection with higher concentrations of ferritin, vitamin E: lipids, and B12. These associations differed according to body fat percentage
Digital Twins in Fusion Energy Research:Current State and Future Directions
Get PDFThis review paper explores the pivotal role of digital twin (DT) technology in advancing nuclear fusion research and its potential to address key challenges in achieving fusion energy as a sustainable power source. Whilst DTs have been developed to tackle complex issues in data analysis, real-time control, optimisation, and simulation, existing efforts are largely fragmented and constrained to isolated applications due to the experimental and evolving nature of fusion reactors. To bridge this gap, there is a pressing need for an integrated, end-to-end DT framework that can unify these capabilities, enabling a more holistic approach to reactor design and operation. This paper systematically reviews the current state of DT development, focusing on its application to critical components such as the divertor, breeder blanket, and magnets, which serve as ideal candidates for modular DT instances. By leveraging high-performance computing and vast datasets generated by fusion experiments worldwide, we identify opportunities to create scalable, data-driven surrogate models that can continuously refine live DT systems. The findings highlight the potential for centralised storage of the data and models to accelerate simulation-based testing (in silico) and optimisation of reactor components, ultimately contributing to the faster realisation of commercially viable fusion reactors. This integration of DT technology promises to significantly reduce the need for costly, iterative physical testing, paving an efficient pathway to achieving fusion as a reliable energy source
A Study of Changing Automated Teller Machine (ATM) Accessibility and its Implications in England and Wales
Get PDFThe ways that people choose to pay for products and services is changing, with many people having a greater desire to pay using electronic means in preference to using cash. However for a significant section of society cash remains an important option, for budgetary, technical and sociological reasons. One of the primary ways to make cash available is through Automated Teller Machines (ATMs) and the United Kingdom’s financial industry and the government are keen to maintain a viable network of ATMs. In this study a refinement to the Floating Catchment Area technique, the Modified Huff Variable Three Step Floating Catchment Area (MHV3SFCA), is used to assess the accessibility of ATMs in England and Wales. The MHV3SFCA approach better accounts for competition, and ensures equity through a minimum threshold for access. How this accessibility has changed over time and how the definition of the network has an impact is shown. The results are illustrated with maps that identify potential ATM deserts and a case study of the City of York. Trends are summarised using the typographies of an area classification, a deprivation index and an urban/rural indicator. The results show better accessibility in deprived and urban locations. Over a 3 year time period the accessibility has deteriorated for all locations, however this was least in deprived areas, where accessibility is already good. In locations where there has been an attempt to protect ATMs, the level of accessibility has remained stable
Simultaneous observation of bright and dark polariton states in subwavelength gratings made from quasi-bulk WS2
Get PDFOver the last decade, layered crystals, referred to as van der Waals (vdW) materials, have attracted tremendous interest due to their unique properties in their single and few layer forms. Their bulk counterparts, however, have only been recently explored as building blocks for nanophotonics. Indeed, bulk vdW materials offer promising properties such as high refractive indices and adherence to any type of substrate. We present here a variety of 1D grating structures composed of bulk transition metal dichalcogenide (TMD) WS2 as a highly tunable and versatile platform for observation of a multi-level polaritonic system. The WS2 excitons are simultaneously strongly coupled with the two grating photonic modes, including the bound state in the continuum (BIC) of the lower energy mode, giving rise to polariton-BICs. The polaritonic dispersion shapes can be varied in a straightforward fashion by choosing WS2 films of different thicknesses and changing the gratings periods
Respiratory function, survival, and NIV prevalence over time in ALS - a PRECISION ALS study
Get PDFIntroduction: Respiratory function typically deteriorates as ALS progresses and is associated with shorter survival. This study aims to describe respiratory function and the prevalence of noninvasive ventilation (NIV) along the disease trajectory using prospective data from the PRECISION ALS project.
Methods: We included 3449 ALS patients from six European population-based cohorts. All had comparable assessments of vital capacity, percent predicted (VC%) (58.1% had multiple assessments) and 56% had assessments of the revised ALS Functional Rating Scale (ALSFRS-R). The data were analyzed in relation to survival, NIV, and genetic status (C9orf72, SOD1, FUS, and TARDBP).
Results: In those with a survival time of 1–4 years from diagnosis, the median VC% declined from 91 to 97% at the first assessment to 47–50% at the last assessment 6 months before death. In those with longitudinal assessments, the median VC% declined an average of 24 percentage points per year. Over time, there was an increase in respiratory symptoms relative to general functional impairment, as measured by the ALSFRS-R, and VC% was strongly associated with shorter survival. The confirmed prevalence of NIV was approximately 3%, 15%, and 25% in patients with a VC% of >80, 50-80, and <50, respectively.
Conclusion: There was a trend of worsening respiratory function over time and an increase in respiratory symptoms relative to general functional impairment. Survival was strongly associated with respiratory function. In those with impaired respiratory function, there was significant variation in the introduction of NIV
Prenatal diagnosis of tracheo-oesophageal fistula/oesophageal atresia: is MRI helpful?
Get PDFBackground
Oesophageal atresia (OA) with or without tracheo-oesophageal fistula (TOF) affects 2.75 per 10,000 births within the UK. It is most frequently suspected on antenatal imaging when the stomach is absent or appears small. Studies have shown fetal magnetic resonance imaging (MRI) has greater diagnostic accuracy than ultrasound; however, there remains uncertainty over what size constitutes a small stomach and how frequently this correlates with a diagnosis of TOF/OA.
Methods
A retrospective study of patients referred for fetal MRI due to suspicions of TOF/OA on antenatal ultrasound from 2011 to 2022. We also included patients with a fetal MRI suspecting TOF/OA who had been referred for other reasons. The indication, MRI findings and postnatal outcome were compared to assess diagnostic accuracy. For each case, the size of the stomach bubble was measured on MRI, and stomach volumes in a control group were measured for comparison.
Results
The positive predictive value for USS was 45.5% and 51.7% for fetal MRI. Fetal MRI had a negative predictive value and sensitivity of 100% (p = 0.027). The control group showed a strong positive correlation between stomach size and increasing gestational age (R2 = 0.69, p < 0.001), but this correlation was less positive in the TOF/OA group (R2 = 0.26, p = 0.03), and the stomach volumes in TOF/OA were consistently lower than the control group. The receiver operating characteristic curve illustrates that an absent stomach or unmeasurably small stomach is more diagnostic of TOF/OA as volumes ≤0.06 ml had 90% sensitivity.
Conclusion
Fetal MRI can accurately exclude TOF/OA but only has marginally improved positive predictive value over ultrasound. Research with larger numbers is required to further aid the development of a cut-off value for what can be considered a pathologically small stomach.
Impact
There are several features on imaging that raise the suspicion of TOF/OA.
Fetal MRI has some improved diagnostic accuracy compared with antenatal ultrasound alone; however, it is only marginally better.
Absence of stomach bubble and presence of oesophageal dilatation combined on fetal MRI are more diagnostic of TOF/OA
Targeting metastasis in paediatric bone sarcomas
Get PDFPaediatric bone sarcomas (e.g. Ewing sarcoma, osteosarcoma) comprise significant biological and clinical heterogeneity. This extreme heterogeneity affects response to systemic therapy, facilitates inherent and acquired drug resistance and possibly underpins the origins of metastatic disease, a key component implicit in cancer related death. Across all cancers, metastatic models have offered competing accounts on when dissemination occurs, either early or late during tumorigenesis, whether metastases at different foci arise independently and directly from the primary tumour or give rise to each other, i.e. metastases-to-metastases dissemination, and whether cell exchange occurs between synchronously growing lesions. Although it is probable that all the above mechanisms can lead to metastatic disease, clinical observations indicate that distinct modes of metastasis might predominate in different cancers. Around 70% of patients with bone sarcoma experience metastasis during their disease course but the fundamental molecular and cell mechanisms underlying spread are equivocal. Newer therapies such as tyrosine kinase inhibitors have shown promise in reducing metastatic relapse in trials, nonetheless, not all patients respond and 5-year overall survival remains at ~ 50%. Better understanding of potential bone sarcoma biological subgroups, the role of the tumour immune microenvironment, factors that promote metastasis and clinical biomarkers of prognosis and drug response are required to make progress. In this review, we provide a comprehensive overview of the approaches to manage paediatric patients with metastatic Ewing sarcoma and osteosarcoma. We describe the molecular basis of the tumour immune microenvironment, cell plasticity, circulating tumour cells and the development of the pre-metastatic niche, all required for successful distant colonisation. Finally, we discuss ongoing and upcoming patient clinical trials, biomarkers and gene regulatory networks amenable to the development of anti-metastasis medicines
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