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The epigenomic landscape of primary tissues in osteoarthritis
Get PDFObjectives
Osteoarthritis is a complex joint disease, affecting more than 500 million people worldwide. We investigated DNA methylation profiles and integrated these with matching genotype and transcriptomics data in primary tissues of patients with knee osteoarthritis to enhance our understanding of the regulatory framework that modulates gene expression in osteoarthritis.
Methods
We measured matched genotype and methylation from primary chondrocytes of macroscopically intact (low-grade) and degraded (high-grade) disease cartilage as well as synovium, infrapatellar fat pad, and blood samples, for 314 patients who underwent total knee replacement for osteoarthritis. We generated methylation quantitative trait locus (mQTL) maps in cartilage, synovium, fat pad, and blood, as well as expression quantitative trait methylation (eQTM) maps in cartilage and synovium. We integrated these results with genome-wide association studies (GWAS) to identify likely effector genes of osteoarthritis.
Results
We reported widespread associations between genetic variants and methylation as well as between methylation and gene expression. Through colocalisation, we find methylation sites with a potential causal role in osteoarthritis. By tissue-specific integration of colocalisation and eQTM results, we resolved GWAS signals and identified 50 likely effector genes.
Conclusions
We provided the largest genome-wide mQTL maps of low- and high-grade osteoarthritis cartilage and synovium. We further presented the largest cartilage eQTM map for primary cartilage and the first eQTM map in synovium. We found methylation sites with a potential mechanistically causal role in osteoarthritis and associated these with likely effector genes. Together, the presented genome-wide eQTM and mQTL maps constitute relevant resources for osteoarthritis research and beyond
Magnetic field control with dual robotic tunable magnetic end effectors
No full textMagnetic manipulation is increasingly used in medical applications for its potential in remote control. However, precise magnetic field generation in large workspaces remains challenging. This paper introduces an adaptive robotic end effector, the tunable magnetic end effector (TME), capable of generating spatially controllable magnetic fields. By integrating permanent magnets, the TME enables accurate magnetic control for wireless manipulation of miniaturized medical devices. Compared to standard switchable permanent magnets, TME offers enhanced field control suited for delicate operations. Finite element (FEM) simulations and experiments confirm reliable ON/OFF field switching, showing a 7.2% average error. Key design parameters (magnet size, material, and arrangement) were optimized via simulation. An artificial neural network (ANN), trained on spatial, rotational, and magnetic data, enables adaptive control. Proof-of-concept demos include steering millimeter-scale magnetic carriers, shaping magnetic soft robots, and directing magnetic nanoparticle swarms. The dual-TME configuration further expands the effective manipulation workspace and enables dynamic switching of magnetic field directions across different regions, thereby enhancing the system’s applicability
The development and validation of the partial denture experience questionnaire (P-DEQ): reliability and validity
Get PDFIntroduction
This paper describes the development and preliminary validation of the Partial Denture Experience Questionnaire (P-DEQ), a new, condition-specific instrument designed to measure the multifaceted impacts of living with removable dentures.
Methods
The P-DEQ was developed using a multi-phase, mixed-methods design. Item generation was informed by qualitative interviews (n = 20) with denture wearers in the UK and guided by the World Health Organisation's International Classification of Functioning, Disability and Health (ICF) framework. A 34-item scale, with five core sub-scales (Body Function, Emotional Function, Daily Abilities, Social Impacts and Participation Restrictions) and a separate ‘My Denture’ sub-scale, was tested in a cross-sectional study with online panels from the UK (n-224) and US (n-224). Reliability, item-total correlations, item impacts and sub-scale correlations were assessed.
Results
The P-DEQ sub-scales demonstrated good to excellent reliability (Cronbach's α = 0.71–0.88) across both samples. Sub-scale-to-total score correlations were high and significant, with the Emotional Function (r = 0.92) and Social Participation (r = 0.92) sub-scales showing particularly strong relationships in the UK sample. Most item-total correlations exceeded the 0.4 threshold, supporting the instrument's underlying coherence. Item impact scores varied widely; items concerning psychosocial worries (e.g., the denture breaking) and functional limitations (e.g., avoiding certain foods) registered the highest impact. In contrast, items reflecting potential benefits of the denture, such as improved appearance, had lower impact scores. Furthermore, the ‘My Denture’ sub-scale, measuring personal appraisal of the prosthesis, was significantly correlated with the total P-DEQ score (r = −0.50 UK; r = −0.55 US), indicating that a more favourable personal evaluation of a denture was associated with fewer negative impacts.
Conclusions
The P-DEQ demonstrates promising reliability and content validity for assessing the complex experience of living with a removable denture. The instrument is sensitive to the nuanced, often ambivalent, emotional states of wearers. Whilst this initial validation is based on cross-sectional data, longitudinal testing is required for item reduction and to fully establish the P-DEQ as a robust measure that can detect change over time
Atypical placental site nodules: a retrospective case series.
Get PDFINTRODUCTION: Atypical placental site nodule (APSN) is a rare diagnosis, representing remnants of a previous pregnancy and extravillous trophoblast tissue. These lesions are potential precursor lesions to rare forms of Gestational trophoblastic neoplasia (GTN). Recent data suggest up to a 15% risk of malignancy occurring either concurrently or manifesting within a few months of diagnosis. These patients are often young with future fertility considerations. Prognosis, treatment, and clinical follow-up of APSN cases currently remain a matter of debate. This study aimed to address and explore some of these issues.
MATERIAL AND METHODS: Retrospective case series analysis was performed between 1st January 2000 and 31st December 2023 at the Sheffield Trophoblastic Disease Centre, Sheffield, UK. Patients on conservative management were asked at routine follow-up telephone consultations if they would consider a completion hysterectomy in light of the risk of progression to GTN.
RESULTS: Twenty-two cases of APSN were registered, of which 10 (45%) received surgical management. Two (20%) cases were incidentally diagnosed following total abdominal hysterectomy (TAH) for other indications and eight (80%) had a TAH within twelve months of their initial diagnosis as part of primary management. None had histological evidence of GTN. Of the twelve (55%) patients initially opting primarily for conservative management, three (25%) decided to have a TAH performed based on the current evidence for risk of malignant transformation, eight (67%) indicated they would have a TAH based on advice from the center, and one (8%) was uncertain. No patients were diagnosed with GTN.
CONCLUSIONS: In this study, we found no evidence of malignant transformation in our patients, which conflicts with other published data conferring an 11%-14% risk of malignant transformation. An international consensus opinion needs to be reached within the Gestational trophoblastic community regarding the optimal advice, management, and follow-up regimens for patients diagnosed with APSN
Evidence-based steps towards climate resilient development pathways:insights across levels and sectors
Get PDFClimate-Resilient Development Pathways (CRDP) proposed by the Intergovernmental Panel on Climate Change underscore the urgent need for effective adaptation and mitigation while sustaining socio-economic development. Achieving CRDP requires coordinated action across local, national, and international levels. In the European Union (EU), this multilevel challenge is embodied in frameworks including the European Green Deal, Climate Law, and Adaptation Strategy, which collectively seek a climate-resilient society by 2050. While Member States are mandated to pursue CRDP at a local level, empirical evidence on the enabling conditions that facilitate CRDP transitions remains limited, revealing a globally critical research gap. This paper targets that gap by drawing on 124 semi-structured interviews with policymakers and practitioners, complemented by a review of scientific literature and policy documents. Focusing on three climate-vulnerable Italian regions – Aosta Valley, Basilicata, and Sardinia – it explores CRDP across sectors at local and national scales. It asks: (i) What forms of integrated adaptation and mitigation are being pursued across sectors in these regions to address climate impacts and enhance resilience? (ii) What enabling conditions have supported transitions toward CRDP at multiple scales? Italy offers a compelling case due to its exposure to multiple climate hazards and its policy alignment with EU and global resilience agendas. Findings highlight the importance of holistic, context-specific, and long-term strategies that integrate human, water, and land systems across scales and sectors. Key enablers applicable to the pursuit of global resilience include supportive institutional frameworks, financial mechanisms, cross-sector collaboration, socio-cultural engagement, and investment in technological and infrastructural innovation
Multimodal time–space-interaction analysis of content creators’ translocal trajectories
Get PDFThis paper examines social media content creators’ practices development over time and across platforms, through the case of @foodqood, an Italy-based food content creator who achieved megainfluencer status. An integrated multimodal time–space-interaction analysis of the creator’s 3-year long production on TikTok, Instagram and YouTube maps shifts in semiotic resources and audience engagement. Findings identify three phases in the creator’s practices, showing a trajectory from experimentation to institutionalisation. Changes through time and variations across spaces, cross-checked with followers’ prompts and responses, reveal shifts in identity performances and prioritised audience segments. The time–space-interaction analysis evidences complex dynamics of influence between grassroots and institutional practices, and between agency in sign-making and dominant semiotic regimes, including ethnoracialised linguistic ideologies. The study advances a social semiotic approach that includes translanguaging for the analysis of translocality. Using provenance to identify the cultural dimensions in semiotic assemblages allows for nuanced considerations of the import of dimensions such as lifestyles and space-specific affiliations alongside geopolitical and ethnolinguistic provenances. It mitigates the risks of unbalanced analyses towards named languages, and reductionist interpretations of cultural phenomena solely/chiefly along a geopolitically-defined local–global continuum. The study addresses gaps in research on content creators by integrating a longitudinal perspective to multimodal analysis. It also raises questions regarding the (self-)exploitation and (self-)erasure of minoritized identities in social media ecosystems increasingly shaped by corporate interests
Fragmentation analysis for underwater ordnance disposal
Get PDFExplosive weapons may cause damage through both blast loading and fragmentation of their casings. Although air-detonated ordnance has been extensively studied, fragmentation hazards from underwater munitions remain underexplored, and therefore no standardised procedure exists to calculate safe standoff distances as a function of depth and charge mass in naval environments. This significantly hampers the safety planning process for underwater explosives ordnance disposal activities. Building on prior laboratory investigations of underwater fragmentation, this study extends the analysis toward full-scale applicability by estimating maximum fragmentation ranges and applying injury-criteria models to assess associated hazard limits. A series of well-controlled small-scale experiments compared cased explosive charges detonated in air and at varying submersion depths. Three casing configurations were tested to quantify the influence of depth and casing configuration type on fragment generation, in-flight behaviour, and size–velocity distributions. High-speed videography and in-situ witness panels were utilised to track fragmentation post-detonation and estimate velocities during flight and after impact. An in-house analysis code with optical and panel data was developed to compute fragment trajectories, maximum ranges, and soft-tissue penetration probabilities using established injury thresholds. Results indicate a pronounced reduction in fragment count, velocity and launch angle with increasing submersion depth, producing substantially shorter predicted penetration distances for all tested submerged charges. This paper outlines a practical methodology for scaling experimental observations toward larger charge masses and discusses implications for risk assessment and mitigation during underwater munitions clearance operations
Atomic-scale observation of vacancy ordering in magnetite nanoparticles
No full textMagnetic nanoparticles have been extensively investigated for use in various advanced technologies. Among them, magnetite nanoparticles garner significant attention owing to their biocompatibility and superior magnetic properties. However, their performance can be affected by the presence of discrepancies from the ideal bulk structure. In this study, we carried out an atomistic microscopy observation of magnetite nanoparticles by high-angle annular dark field scanning transmission electron microscopy (HAADF-STEM), which demonstrates the formation of vacancies in their structure reflected in changes in the atomic column contrast. In addition, the HAADF-STEM images, acquired along the [111] orientation, demonstrate the tendency of symmetric ordering of the observed vacancies in opposite atomic columns around the central brightest atomic columns. Atomic crystal structure optimization simulations confirm the lowest energies for such ordering configurations, in a good agreement with the experimental observations
Bi-allelic intermediate ATXN2 repeat expansions are associated with slow progressing, leg-onset familial ALS
Get PDFObjectives
The identification of bi-allelic intermediate ATXN2 repeat expansions in a pedigree with amyotrophic lateral sclerosis (ALS) through clinical testing prompted us to investigate its relevance in the wider ALS population.
Methods
ATXN2 repeat size was assessed in a large international cohort of ALS patients (n=6653 from Project MinE) and in neurologically intact control populations (n=13 515 controls from Project MinE and gnomad). For bi-allelic cases, we retrieved medical records, family history and MRI imaging. For familial cases, we obtained DNA samples from relatives for segregation analyses.
Results
In total, we identified bi-allelic intermediate ATXN2 repeat expansions in five familial cases from three different pedigrees and five apparently sporadic cases. There is a relatively homogeneous phenotype characterised by lower limb onset and long survival (median 6 years) without significant cerebellar atrophy. Bi-allelic expansions were absent in controls (0 out of 13 515).
Discussion
Here we report an apparently novel autosomal recessive form of familial ALS caused by bi-allelic intermediate ATXN2 repeat expansions, which is characterised by high penetrance, lower limb onset and slow progression. Although rare, testing for ATXN2 expansions should be performed in the clinical setting given its relevance to prognosis and genetic counselling
Crosstalk-mitigated microelectronic control for optically active spins
Get PDFTo exploit the subnanometer dimensions of qubits for large-scale quantum information processing, corresponding control architectures require both energy and space efficiency, with the on-chip footprint of
unit-cell electronics ideally being micrometer scale; however, the spin coherence of qubits in close packing is severely deteriorated by microwave crosstalk from neighboring control sites. Here, we present a
crosstalk-mitigation scheme using foundry microelectronics to address solid-state spins at sub-100-µm
spacing without the need for qubit detuning. Using nitrogen-vacancy centers in nanodiamonds as qubit
prototypes, we first demonstrate 10-MHz Rabi oscillations at milliwatt-level microwave power. By implementing active cancellation, we then demonstrate that the crosstalk field from neighboring lattice sites
can be reduced to undetectable levels. We finally extend the scheme to show increased qubit control, or,
effectively, enhanced spin coherence under crosstalk mitigation. Compatible with integrated optics, our
results present a step toward scalable control across quantum platforms using silicon microelectronics
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