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Quantitative Sensory Testing Reveals Evidence of Altered Pain Processing in Paget’s Disease of Bone
Get PDFPain is the most common symptom of Paget’s disease of bone (PDB), but its underlying mechanisms are poorly understood. Notably, bone pain does not correlate well with metabolic activity or treatment response. This study aimed to assess whether sensory processing is altered in skin overlying Pagetic bone using quantitative sensory testing (QST). We conducted a cross-sectional study of 156 people with PDB attending secondary care referral centres in the UK. We conducted quantitative sensory testing of the skin overlying affected sites and compared the data with unaffected sites as a control. The modalities used were hot and cold rollers, pinprick, vibration and von-Frey filaments to test both spinothalamic and lemniscal pathways. There was a consistent trend for sensory perception to be increased over affected sites versus control sites in the study population. The differences were significant for vibration detection threshold (p = 0.009), pain threshold (p = 0.010) and both single and multiple pinprick testing methods (both p < 0.001). Subgroup analysis revealed similar trends when analysis was restricted to those with pain thought to be due to bone deformity or increased metabolic activity and those with and without musculoskeletal pain. Sensory processing is altered in skin overlying Pagetic bone, independent of current pain symptoms. We speculate that this may be due to abnormalities of bone shape, bone structure or metabolic abnormalities in the affected bone. The mechanisms are unclear but deserve further study
Multinational cost-utility analysis of panel-based pharmacogenetics-guided treatment of patients enrolled in the U-PGx PREPARE study
No full textBackgroundPharmacogenetics (PGx) aims to revolutionize healthcare by individualizing drug doses and medication choices. However, clinical uptake will require positive evaluation evidence of both clinical utility and cost-effectiveness. We have recently demonstrated the clinical utility of this approach, using a panel-based PGx-guided treatment of patients from various indications recruited in seven countries (PREPARE study).MethodsHere, we provide economic evidence from a multinational cost-utility analysis of PGx-guided treatment in 6930 patients participating in the PREPARE study. The study was conducted from March 2017 to June 2020. We used the national healthcare system's perspective in each participating country, including only direct medical costs that budget holders cover. A Visual Analog Scale was used to measure utility and the quality of life was estimated by averaging the Visual Analog Scale scores of participants over four specific time points in the study, namely baseline visit (day 1), week 4, week 12, and 18 months from the baseline visit.FindingsOur analysis showed that the PGx-guided treatment is marginally cost-effective at the threshold of €11,000 QALYs. Cost drivers were hospitalization and ADRs costs, accounting for most of the resources used in both groups (46% and 37.5% in the PGx-guided group versus 49% and 48% in the control group, respectively), as a result of the average duration of hospitalization [1.51 days (95% CI: 1.23-1.82) for the PGx-guided group and 2.37 days (95% CI: 1.95-2.89) for the control group, resulting in a mean difference of 0.86 days (95% CI: 0.37-1.44). The difference in QALYs gained was 0.00178 (95% CI: 0.00176-0.00180). The ICER was €12,020 (95% CI: €10,957-€13,356) per QALY on average (SD: €116). When comparing cost and effectiveness of actionable PGx-guided versus actionable control patients, the total cost for the PGx-guided group was €491 (95% CI: €384-€613), versus €767 (95% CI: €583-€982) in the control group, with an incremental cost difference of €276 (95% CI: €62-€511), favoring the PGx-guided group. Also, the difference in effectiveness was 0.007 QALYs (95% CI: -0.021 to 0.033). Lastly, the difference in the mean total cost was estimated to be €21.4 (95% CI: €19.5-€23.8), while without considering the PGx test cost, indicative of a pre-emptive genetic testing approach, the PGx-guided treatment becomes a cost-saving option, with an estimated savings of approximately €103.6 (€124-€21.4) per patient.InterpretationThese data suggest that panel-based PGx testing is cost-effective, which, together with the clinically beneficial outcomes already demonstrated in the PREPARE study, provides additional evidence of the need to implement PGx into clinical practice.FundingEuropean Union Horizon 2020
A multi-centre performance evaluation of a commercially developed liquid biopsy for the earlier detection of brain tumours
No full textBackground: Delayed diagnosis of brain cancer leads to two-thirds of patients receiving a diagnosis only after presenting to the emergency department with more severe symptoms or neurological deficits. A simple, rapid, liquid biopsy implemented in primary care could enable more efficient triage of patients with non-specific symptoms potentially related to brain cancer, prioritising patients for urgent brain imaging, and accelerating diagnosis. Patients and methods: Presented is the international, multi-centre, observational Early and tiMely detection of BRAin CancEr (EMBRACE) study. Patients were prospectively recruited across seven sites in Europe, from the United Kingdom, Belgium, Sweden and Switzerland. The target population consisted of patients with symptoms potentially associated with brain cancer. Blood serum samples were analysed by the Dxcover® Brain Cancer Liquid Biopsy Platform. Test performance was assessed by comparison of the liquid biopsy result to diagnostic imaging. Results: Two thousand five hundred and fifty-four patients were enrolled across the seven collection sites; 2324 were deemed eligible and taken forward for test assessment. There were 697 brain tumours in total, of which 395 were malignant, and 1627 non-tumour diagnoses. Overall diagnostic performance for the primary objective was 86% sensitivity for brain cancer detection with 99% negative predictive value (NPV). Sensitivity for all brain tumours combined (malignant and benign) was 77%. Notably, for the most prevalent and most aggressive brain cancer, glioblastoma, 86% of cases were successfully identified. Additionally, 94% of patients with central nervous system lymphoma, and 90% of brain metastases were predicted correctly as having tumours. Conclusions: Existing symptom-based referral pathways are ineffective for the detection of brain cancer, and there is an urgent need for new tests to help with clinical decision making. With a NPV of 99%, the Dxcover Liquid Biopsy test could assist in primary care for efficient stratification of patients toward diagnostic imaging
A non-iteration partitioned method with a sliding window for large-scale time-variant vehicle-track-bridge systems
Get PDFA Non-Iterative Partitioned method with Sliding Window (NP-SW) is proposed for efficiently solving time-variant dynamic systems such as Vehicle-Rail-Bridge Systems (VRBS). In contrast to conventional approaches that retain the entire rail domain, NP-SW confines rail computation to a sliding window aligned with the vehicle's position, thereby significantly reducing the problem scale while preserving high accuracy of dynamic responses. To accommodate the sliding window mechanism in the NP-SW method, the windowed multi-partitioned structural analyzers and the interface solver were formulated. Specifically, Boolean matrices were determined to relate the global rail matrices to their localized windowed matrices, and the subdomain-interface mappings were formulated accordingly. By shifting the time-variant interface from the vehicle-rail interface to the rail-bridge interface, the system's inherent time dependency is preserved. From a numerical and theoretical perspective, the stability, efficiency, accuracy, and hybrid integration schemes of the NP-SW method are investigated based on a VRBS (i.e., a single-car vehicle, a rail-sleeper-ballast track model, and a multi-span simply supported bridge). Under an appropriate selection of window length, the energy drift of the NP-SW method maintained an extremely low and negligible level across different train speeds and integration schemes. For the eight-span simply-supported beam bridge example, the NP-SW method can reduce the computational time by a factor of 277 compared to the global rail simulation while maintaining consistency about 95% for all in-window dynamic response results within the entire calculation time. The efficiency and accuracy advantages of the NP-SW method becomes more pronounced for large-scale dynamic systems
MATTERIX: toward a digital twin for robotics-assisted chemistry laboratory automation
Get PDFAccelerated materials discovery is critical for addressing global challenges. However, developing new laboratory workflows relies heavily on real-world experimental trials, and this can hinder scalability because of the need for numerous physical make-and-test iterations. Here we present MATTERIX, a multiscale, graphics processing unit-accelerated robotic simulation framework designed to create high-fidelity digital twins of chemistry laboratories, thus accelerating workflow development. This multiscale digital twin simulates robotic physical manipulation, powder and liquid dynamics, device functionalities, heat transfer and basic chemical reaction kinetics. This is enabled by integrating realistic physics simulation and photorealistic rendering with a modular graphics processing unit-accelerated semantics engine, which models logical states and continuous behaviors to simulate chemistry workflows across different levels of abstraction. MATTERIX streamlines the creation of digital twin environments through open-source asset libraries and interfaces, while enabling flexible workflow design via hierarchical plan definition and a modular skill library that incorporates learning-based methods. Our approach demonstrates sim-to-real transfer in robotic chemistry setups, reducing reliance on costly real-world experiments and enabling the testing of hypothetical automated workflows in silico
‘In the Midst of a Thunderstorm’: Young People's Experiences of Physical Restraint in Inpatient Mental Health Services in the <scp>UK</scp>
No full textABSTRACT
Within inpatient mental health services, young people who express distress through behaviours may be physically restrained. Little is known about their experiences or perspectives of this restraint. This qualitative Interpretative phenomenological analysis (IPA) study explored young people's experiences of physical restraint. Young people were recruited from three inpatient mental health units in England. Individual, face‐to‐face augmented, audio‐recorded semi‐structured interviews were undertaken. IPA data analysis facilitated the development of subordinate and superordinate themes. The study design was informed by public consultation with young people and their families. Eight young people (five boys, three girls, aged 10–13 years) shared their experiences of physical restraint. The findings are presented within the trajectory of a thunderstorm within three themes: The Gathering (‘pre‐escalation’), The Thunderstorm (the restraint), and The Aftermath (‘debriefing and making sense’). Young people talked about how feelings of being restrained could start long before any physical touch and could continue long after the physical element of the restraint had ended. They described emotional, traumatic and confusing experiences of restraint and often being left with emotional ‘debris’ for a long time after the incident. They also described situations where physical restraint was used instead of an investment in de‐escalation strategies. The current understanding of the trajectory of physical restraint for children and young people within mental health units needs to be adapted to recognise the extended gathering and aftermath stages associated with this intervention.</jats:p
Co-circulation and co-infection: parasite interactions across scales
Get PDFParasite–parasite interactions occur both within and between hosts, but the two scales are rarely considered together. Consequently, there is a gap in our ability to predict the integrated effects of interactions occurring across scales, disentangle their relative contributions to key ecological outcomes, and accurately identify the drivers of host–parasite evolutionary responses. Here, we extend the standard susceptible–infected framework of theoretical epidemiology to explicitly incorporate parasite–parasite interactions across scales. We identify where – in each step of the transmission process – such interactions may occur, at the within- or between-host levels, providing empirical examples where possible. Thus, we demonstrate how integrating the two scales provides a more complete understanding of the evolutionary ecology of multi-parasite systems and suggest future avenues of investigation
Symptom-specific alterations in subregional intrinsic connectivity of anterior cingulate cortex in major depressive disorder
No full textThe anterior cingulate cortex (ACC) is critically implicated in major depressive disorder (MDD), with distinct subregional dysfunctions related to specific aspects of emotional and cognitive dysregulation. However, its precise functional architecture, including the number, boundaries and intrinsic connectivity patterns of subdivisions, remains to be characterized in MDD. To address this, we employed data-driven connectivity-based parcellation (CBP) to delineate the optimal ACC functional partitions in 158 first-episode medication-naïve non-comorbid patients with MDD, and 152 healthy controls (HC). We generated subregion-specific ACC intrinsic connectivity maps, and analyzed group differences using diagnosis-by-subregion flexible factorial analyses of variance. We further explored the relationship between connectivity changes and clinical features. The ACC was optimally parcellated into bilateral ventral ACC (vACC) and dorsal ACC (dACC): The vACC showed preferential connections with default mode network (DMN) regions, whereas the dACC primarily connected to salience network and subcortical areas. Significant diagnosis-by-subregion interactions in ACC connectivity were mainly in the DMN regions: in HC, vACC showed stronger connectivity with DMN regions compared to the dACC, while this difference was attenuated in MDD, characterized by the vACC-DMN hypoconnectivity and a trend towards dACC-DMN hyperconnectivity. Clinically, lower vACC-DMN connectivity was related with core depressive symptoms, i.e., lower mood and longer illness duration, while higher dACC-DMN connectivity was linked to elevated maladaptive behaviors, e.g., suicide and insomnia. These findings confirm ventral-dorsal functional heterogeneity of ACC architecture and reveal symptom-specific patterns of subregional ACC-DMN dysconnectivity in MDD, which may provide insights for developing tailored interventions to address specific clinical manifestations
Taking International Law Seriously? Interpretation of the 1998 Belfast/Good Friday Agreement in the Context of Article 2(1) of the Windsor Framework
No full textAbstract
This article analyses the approach of the Northern Ireland courts to interpretation of the 1998 Belfast/Good Friday Agreement in the context of the ‘no diminution of rights’ obligation in article 2(1) of the Windsor Framework. It advances an alternative approach to the interpretation of the 1998 Agreement that is consistent with international law and provides a more robust basis for rights protection. The article sets out the sources of the rules of treaty interpretation in international law and their application in article 2(1) cases, and analyses the nature of the multi-party agreement part of the 1998 Agreement. It is argued that the multi-party agreement is neither a free-standing treaty nor an integral part of a treaty, and the rules of treaty interpretation do not apply to that instrument. The multi-party agreement, including its Rights, Safeguards and Equality of Opportunity part, should nevertheless be interpreted using a ‘generous and purposive’ approach. In accordance with existing precedents in UK constitutional law, the multi-party agreement should be interpreted generously and purposively due to its nature as a constitution for Northern Ireland.</jats:p
Experimental insights into CI engine behaviour with ternary diesel blends of treated waste oil and high-chain alcohols
No full textThe transition from conventional fossil-based fuels to renewable alternatives holds great promise in advancing more sustainable transportation. This present experimental study investigates the effects of high-chain alcohol-based fuels, octanol and butanol, under conditions of treated waste engine oil and diesel fuels in a compression ignition (CI) engine on combustion, performance and emission parameters. Three fuel blends were examined at varying pedal positions (20–50%), with a 10% increment. The tested fuel blends were a pure diesel combustion (D100), a ternary blend of diesel-treated waste engine oil (TWEO)-butanol (60:20:20-DWB20), and a ternary blend of diesel-TWEO-octanol (60:20:20-DWO20). The waste engine oil was improved by acid-clay treatment, allowing it to be used in the fuel blend. Key findings revealed that incorporating butanol and octanol into the treated waste oil–diesel blends produced in-cylinder pressure and heat release rates comparable to those of pure diesel. Additionally, CO2 emissions were lower for the octanol-containing blend at lower pedal positions, while the butanol-containing blend exhibited reduced HC and NOX emissions compared to pure diesel. The outcomes of this work are pertinent to the efforts of renewable alternative fuels in the pursuit of clean and effective combustion technologies for future powertrain systems
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