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Predictive genetic testing in amyotrophic lateral sclerosis (ALS): experiences of decision-making and engagement with UK genetic counseling services
Get PDFPredictive genetic testing enables at-risk relatives of people with amyotrophic lateral sclerosis (ALS, also known as motor neuron disease or MND) to find out if they have inherited the genetic variant identified in their family member and have an increased chance of developing symptoms. As research progresses, eligibility for and interest in predictive testing is increasing. This paper explores the experiences of people making decisions about predictive testing and identifies their information needs over the process. Semi-structured interviews were carried out with 14 individuals from across the United Kingdom who had, or were considering, predictive testing for ALS. Interviews were carried out via video call or face-to-face between March and September 2023, transcribed, and analyzed using inductive framework analysis. Findings illustrate a range of experiences. Interviews suggest variation in practice in terms of the structure of the genetic counseling process and the content of information given. Some expressed positive experiences of genetic counseling, and valued feeling listened to, understood, and supported. Others perceived barriers to accessing testing, felt the information provided was directive or not sufficient to support their concerns and decision-making. Information needs varied, and whilst people felt satisfied, there were also diverse, unmet information and support needs raised throughout the decision-making process and beyond. This evidence has been used to support the development of a patient decision aid for predictive genetic testing in ALS
Ageing of human myofibres in the Vastus Lateralis muscle: A narrative review
Get PDFHuman skeletal muscle is a complex, dynamic tissue that changes profoundly with age. It comprises heterogenous cells including long, contractile, multinucleated myofibres, broadly classified into type I (slow-twitch/oxidative) fibres and type II (fast-twitch/glycolytic) fibres, as well as a variety of mononucleated cells (e.g., immune, satellite, and endothelial cells), and the extracellular matrix (ECM). Ageing as well as sarcopenia, a muscle condition characterised by progressive loss of muscle strength and mass observed mostly in older adults, appear to disproportionately affect type II fibres. In histomorphometric studies of ageing muscle this has been described as type II myofibres loss, fibre atrophy, and redistribution of fibre types, although some inconsistent findings exist. The precise mechanisms underlying this selective vulnerability remains elusive but are likely attributable to dysregulated nutrient sensing contributing to the deregulation of muscle protein synthesis and degradation cycle, and neuromuscular junction, satellite cells, ECM and mitochondrial dysfunction. This narrative review focuses on the Vastus Lateralis (VL) muscle-a major limb muscle involved in locomotion and one of the most extensively studied human skeletal muscles-and summarises key structural and phenotypic changes that occur with ageing at the organ, tissue, and cell levels, and their relevance to sarcopenia. We also briefly discuss external influences of these changes, highlight gaps in knowledge, and suggest future directions
Public acceptance of policy interventions to control transport air pollution considering nanoparticles – A study in the UK
Get PDFAmbient nanoparticles may be more harmful than PM2.5 and PM10 but currently they are not regulated. On the other hand, existing policy interventions to control PM2.5 and PM10 may not be effective enough to control nanoparticles. Therefore, there is a need to set regulations and implement policy interventions to control ambient nanoparticles emission especially from transport. However, currently there is no study on public acceptance of interventions considering nanoparticles, while such knowledge will be essential for the effective design and successful implementation of the interventions. This study thus aims to fill this research gap. An online survey was conducted in the UK (N = 482) to collect data on the general public’s environmental attitudes, moral norm, awareness of and concerns about nanoparticles, and attitudes and behavioural intentions towards different transport policy interventions. Using hierarchical clustering analysis, four distinct acceptance groups were identified: the Rejective Minority; the Resistant Car dependants; the Indecisive Car-dependants; and the Supportive Environmentalists. The groups’ socio-demographic and travel behavioural characteristics can help explain some of the differences in their acceptance but are not sufficient. Respondents’ comments further highlighted issues of (un)fairness, distrust of government, lack of public transport and forced car ownership, and the need for information campaigns on nanoparticles. Based on these findings, group-specific barriers and opportunities were discussed and interventions suggested
Efficacy and safety of oral treprostinil in patients with pulmonary arterial hypertension on background monotherapy or dual therapy
Get PDFIntroduction
Pulmonary arterial hypertension (PAH) is a progressive, often fatal disease characterized by an elevation in pulmonary arterial pressure and pulmonary vascular resistance (PVR). Oral treprostinil is indicated for the treatment of PAH and has been shown to delay disease progression and to improve exercise capacity.
Methods
The purpose of this report is to examine and summarize the data on the use of oral treprostinil in patients already on dual therapy with an endothelin receptor antagonist (ERA) and phosphodiesterase type-5 inhibitor (PDE-5i), using data from the FREEDOM-C study, FREEDOM-C2 study, and a retrospective chart review.
Results
In this analysis, background monotherapy versus dual therapy did not have an impact on clinical parameters (6-min walk distance). Additionally, the number of background therapies did not have an impact on the dose of oral treprostinil achieved at week 16 or measures typically used to assess clinical efficacy in patients with PAH (change in 6MWD at week 16 and NT-proBNP).
Conclusion
Oral treprostinil is a safe and efficacious treatment option and has been shown to further improve clinical parameters and risk status in patients with PAH on background dual therapy.
Trial registry
ClinicalTrials.gov identifier, NCT00325442 and NCT00887978
Access-related factors and e-cigarette use among 11–17-year-olds: a thematic synthesis of European studies using the five dimensions of access
Get PDFBackground
The rapid increase in e-cigarette use among young people is a public health concern that has led to new policies being discussed. This systematic review aimed to synthesise evidence on how access-related factors influence e-cigarette use among 11–17-year-olds in Europe, framing these factors using five dimensions of access (availability, affordability, accommodation, accessibility, acceptability) to inform thinking about policy approaches in the United Kingdom.
Methods
A systematic literature search up to 31 March 2025 of studies published since 2016 was undertaken following PRISMA guidelines (PROSPERO: CRD42024614302). Studies focusing on e-cigarette access among 11–17-year-olds in European countries were eligible for inclusion. We searched EMBASE, PsycINFO, and Web of Science. Findings were narratively synthesised using a Joanna Briggs Institute (JBI) convergent integrated approach; study quality was assessed using JBI checklists. Findings were synthesised thematically using the five dimensions of access as an organising framework.
Results
Twenty-one studies met the inclusion criteria, with some relevant to more than one dimension of access. Nine studies referred to accommodation, with a focus on how key spaces such as schools could limit the ease of e-cigarette use, a challenge complicated by the inherent concealability of e-cigarettes. Ten studies referred to acceptability, as influenced by restrictions on industry promotion of e-cigarettes to young people. Six studies referred to accessibility, which highlighted a particular challenge of age verification at the point of purchase. Five studies referred to affordability, emphasising the importance of relatively low prices as a key marketing tool to young people. Three studies referred to availability, highlighting access via social networks as a key way of circumventing other restrictions. However, there was a lack of evidence on how changes to the different dimensions of access might interact to modify the effects of new regulation.
Conclusion
The five dimensions of access are a potentially useful way to structure thinking about how new regulation might affect young people’s e-cigarette use. The synthesis highlights that young people’s vaping behaviour operates in a complex system of interacting factors; and that evidence gaps remain in developing a clearer picture of this system, including interactions
Custo-efetividade da ampliação da oferta de dispositivos intrauterinos por enfermeiros na rede pública de saúde:análise de decisão econômica por modelo de Markov, Pernambuco, 2023
Get PDFQuantifying the Full Damage Profile of Focused Ion Beams via 4D‐STEM Precession Electron Diffraction and PSNR Metrics
Get PDFFocused ion beams (FIBs) are used in applications such as circuit repair, ultra-thin lamella preparation, strain engineering, and quantum device prototyping. Although the lateral spread of the probe is overlooked, it becomes critical in precision tasks such as impurity placement in host substrates, where accurate knowledge of the ion-matter interaction profile is essential. Existing techniques characterize only the beam core, where most ions land, thus underestimating the full extent of the point spread function (PSF). In this work, we use four-dimensional scanning transmission electron microscopy (4D-STEM) to resolve the ion beam tail at defect densities equivalent to < < 0.1 ions nm - 2 . Convergent beam electron diffraction (CBED) patterns were collected in calibration regions with known ion fluence and compared to patterns acquired around static dwell spots exposed to a 30 keV Ga + beam for 1-10 s. Cross-correlation using peak signal-to-noise ratio (PSNR) revealed that 4D-STEM datasets are ultra-sensitive for defect quantification and more robust against scanning artifacts than conventional dark-field imaging. By extending beyond conventional core-focused resolution metrics, this approach enables comprehensive mapping of ion-induced damage-notably at ultra-low doses-providing a more accurate picture of FIB performance for application-specific optimization
Architecture as the practice of accountability: extractivism, externalities and alternatives
Get PDFThis paper explores architecture's relations with extractivism, drawing on both recent scholarship and practical examples to seek new modes of action which disentangle those relations and move towards accountability. The vast bulk of architectural production is both dependent upon regimes of extractivism and complicit in their expansion — the networks of materials, knowledge, and labour that produce architecture rely on the production of externalities in the form of sites, networks, and epistemologies that are unaccountable. In the face of climate and ecological breakdown, such externalities become impossible to hold apart from the work that architects do, as the effects of violent extractivism reassert themselves. The first section gives a summary of the condition of extractivism, its history, and how its continuation is challenged by climate breakdown. Drawing on decolonial and psychoanalytic perspectives, it argues that the ideology of extractivism is built on infrastructures of ignorance, the operation of which is rife within the built environment. The second section further considers how architecture is implicated and bound up in extractivism, including ways in which alternative forms of architectural practice are already offering other modes of action, which emerge from unpicking those existing relations. The conclusions summarise these modes in terms of an approach to architecture as the practice of accountability, which emerges both from activist practices and a fuller acceptance of the challenge of climate
Building a diverse and inclusive plant science community
No full textFor many people, the culture of plant science, and science more broadly, can feel alienating and intimidating, which often leads to them leaving the discipline for other opportunities. However, studies show that there is a correlation between creative problem solving and increased diversity, and plant science cannot afford to lose talented individuals. Here we report on strategies to promote diversity, inclusion, and a sense of belonging for all within plant science. We address ways that institutions, organizations, communities, educators, and individuals can contribute to this needed cultural change. We urge all plant scientists to participate in these efforts; for each other, for the discipline, and for the future
Nucleobase catalysts for the enzymatic activation of 8-oxoguanine DNA glycosylase 1
Get PDFBifunctional DNA glycosylases employ an active site lysine or the N-terminus to form a Schiff base with an abasic (AP) site base excision repair intermediate. For 8-oxoguanine DNA glycosylase 1 (OGG1), cleaving this reversible structure is the rate-determining step in the initiation of 8-oxoguanine (8-oxoG) repair in DNA. Evolution has led OGG1 to use a product-assisted catalysis approach, where the excised 8-oxoG acts as a Brønsted base for cleavage of a Schiff base intermediate. However, the physicochemical properties of 8-oxoG significantly limit the inherent enzymatic turnover leading to a weak, cellularly absent, AP lyase activity. We hypothesized that chemical synthesis of purine analogues enables access to complex structures that are suitable as product-like catalysts. Herein, the nucleobase landscape is profiled for its potential to increase OGG1 Schiff base cleavage. 8-Substituted 6-thioguanines emerge as potent and selective scaffolds enabling OGG1 to cleave AP sites opposite any canonical nucleobase by β-elimination. This effectively broadens the enzymatic substrate scope of OGG1, shaping a complete, artificial AP-lyase function. In addition, a second class of compounds, 6-substituted pyrazolo-[3,4-d]-pyrimidines, stimulate OGG1 function at high pH, while thioguanines govern enzymatic control at acidic pH. This enables up to 20-fold increased enzyme turnover and a de novo OGG1 β-elimination in conditions commonly not tolerated. The tool compounds employed here are non-toxic in cells and stimulate the repair of AP sites through a natural, APE1 dependent pathway, as opposed to previously reported β,δ-lyase stimulator TH10785
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