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212 Research Priorities for Cancers of the Oesophagus and Stomach: Recommendations from a United Kingdom & Ireland Patient and Healthcare Professional Partnership Exercise
No full textEffect of a peripheral substituent on the ultrafast dynamics and the rate of intersystem crossing in the charge-transfer states of platinum(ii) acetylides
Get PDFUltrafast intersystem crossing into a triplet manifold of long-lived charge-transfer states following visible-light excitation is one of the many photophysical features of transition metal complexes that make them attractive for light-harvesting applications. Yet the spin–orbit coupling alone cannot explain the vast differences in the rates of ISC observed in similar transition metal complexes, ranging from sub-100 fs to tens or even hundreds of picoseconds. Here, we investigate how the rate of intersystem crossing and overall excited state dynamics of the two seemingly similar Pt(II) donor–acceptor molecules, Cl–Pt(PBu3)2–C[triple bond, length as m-dash]C–NAP(X), where NAP = naphthalimide, are affected by peripheral changes to the acceptor. The dynamics of the systems was examined using ultrafast broadband fluorescence upconversion spectroscopy (FLUPs), femto-to-microsecond time-resolved infrared spectroscopy (TRIR), and electronic transient absorption spectroscopy (TA). Direct determination of the rate of ISC using FLUPs demonstrated that a change of the N-substituents “X” of the naphthalimide acceptor from an alkyl chain to the aromatic 4-(C(O)OMe)-Ph– group with an IR-active, electron-withdrawing substituent leads to a significant (30%) increase in the rate of intersystem crossing. The contributing factors to such an acceleration are proposed to be a decrease in the energy gap between the singlet charge-transfer state and the triplet manifold, and additional low-frequency vibrational modes associated with the phenyl-ester functional group which may act to promote intersystem crossing. Furthermore, expanding the range of the TRIR measurements into the microsecond timescale using synchronised picosecond excitation and a broad-band mid-IR femtosecond probe allowed us to directly obtain the signatures of long-lived excited states in the mid-IR region, thereby establishing that the final excited state populated in both cases is localised primarily on the acceptor ligand. Overall, this work highlights how the rates of excited state interconversion can be modulated by a seemingly benign peripheral modification
Identification of novel molecular drivers, prognostic and diagnostic biomarkers for inflammatory bowel disease (IBD): protocol for the Nottingham/AstraZeneca prospective IBD observational cohort study
Get PDFIntroduction
Crohn’s disease (CD) and ulcerative colitis (UC) are chronic, inflammatory bowel diseases (IBDs) of unknown origin, affecting the gastrointestinal tract and often causing extraintestinal symptoms. Conventional treatments (eg, glucocorticosteroids, immunomodulators) and targeted advanced treatments, including anti-TNFα, antibodies to p40 subunit of IL-12/23, antibodies to p19 subunit of IL-23, anti-α4β7 integrin, Janus kinase inhibitors (JAKis) and sphingosine-1-phosphate receptor (S1PR) modulators, do not achieve sustained responses for all patients, leaving significant unmet therapeutic needs.
Methods and analysis
This prospective, multi-centre observational study will follow a cohort of 240 patients across multiple study centres within NHS trusts in the UK who are initiating or switching biologics, specifically anti-TNFα and anti-α4β7 integrin for UC, and anti-TNFα, antibodies to p40 subunit of IL-12/2 and JAKi for CD. Through comprehensive profiling of immunological, transcriptional, microbiome, genetic and proteomic markers at baseline, week 12, and week 52, this study aims to uncover non-invasive biomarkers that predict response to these drug classes, ultimately advancing personalised medicine in IBD.
Ethics and dissemination
Ethical approval for the Nottingham/AstraZeneca study was granted by the West of Scotland Research Ethics Committee. Recruitment began in December 2022 and is currently ongoing at 10 NHS Trust sites across the UK. Study findings will be disseminated by publication in peer-reviewed journals and presentations at relevant national and international conferences
Analytical investigation of a novel joist‐to‐stud web connection in light steel framed buildings
Get PDFIn typical light steel framed (LSF) buildings, floor joists are connected to studs through web connections assuming pinned behaviour. This often results in deeper joist sections, as the design is primarily governed by mid-span deflections. Consequently, the full load-bearing capacity of cold-formed steel (CFS) elements is underutilized, leading to heavier structures and increased environmental impact. This paper investigates the behaviour of a novel semi-rigid joist-to-stud connection, where the joist and stud webs are screwed together. The semi-rigid nature of this connection allows for the development of rotational stiffness and bending resistance, enabling the use of smaller joist sections and more efficient utilisation of structural capacity. To this end, detailed experimentally validated Finite Element (FE) models are developed in ABAQUS software to assess the influence of key design parameters, including connecting element sizes, screw arrangements, construction methods and gravity loads, on the structural performance of joist-to-stud connections. The performance of the connections is compared in terms of initial stiffness and flexural strength. Depending on the screw configurations and the section sizes, two main failure mechanisms are anticipated: (i) shear failure in the screwed connection; (ii) local buckling of the stud or joist flanges near the connection zone. The results indicate that implementing a semi-rigid connection led to an average 25% reduction in the steel weight of the structure of six storey case study buildings compared to its conventionally designed counterpart with simple connections
Achieving 3D Attention via Triplet Squeeze and Excitation Block
Get PDFThe emergence of ConvNeXt and its variants has reaffirmed the conceptual and structural suitability of CNN-based models for vision tasks, re-establishing them as key players in image classification in general, and in facial expression recognition (FER) in particular. In this paper, we propose a new set of models that build on these advancements by incorporating a new set of attention mechanisms that combines Triplet attention with Squeeze-and-Excitation (TripSE) in four different variants. We demonstrate the effectiveness of these variants by applying them to the ResNet18, DenseNet and ConvNext architectures to validate their versatility and impact. Our study shows that incorporating a TripSE block in these CNN models boosts their performances, particularly for the ConvNeXt architecture, indicating its utility. We evaluate the proposed mechanisms and associated models across four datasets, namely CIFAR100, ImageNet, FER2013 and AffectNet datasets, where ConvNext with TripSE achieves state-of-the-art results with an accuracy of 78.27% on the popular FER2013 dataset, a new feat for this dataset
Experimental investigation into cracking in edge restrained concrete walls
Get PDFThe paper describes an experimental investigation into cracking in edge-restrained reinforced concrete walls cast onto concrete bases. The aim of the investigation was to study the mechanics of cracking in relatively thin edge-restrained walls (< ∼ 500 mm) in which through thickness temperature variations due to heat of hydration can be neglected. Twelve walls, each 5.2 m in length, but with varying thickness, height, concrete mix design, reinforcement, and formwork insulation were monitored over a period of at least 3 months. Detailed measurements were made of the temperature rise during heat of hydration, strain and crack width. The paper describes the experimental results in detail, including the development of cracking with time. The measured restrained strains, time of cracking and crack widths are compared with those calculated with EC2–04, EC2–23 and Ciria Report C766 which all adopt the same unrealistic model for calculation of crack width. EC2–04 gives the greatest crack widths and C766 the least due to the lower adopted restraint factor. Significantly, C766 was found to greatly underestimate the maximum measured crack widths with EC2–04 and EC2–23 providing more realistic estimates. Based on the observed cracking behaviour, the paper proposes a simplified mechanical model for the calculation of crack width in relatively thin edge-restrained walls
Localized asymmetric behavior of common-mode current through bearing balls
Get PDFThe high-frequency pulse width modulation in voltage source inverters generates common-mode voltage and current in inverter-fed electrical machine drive systems, leading to high-frequency bearing currents and potential bearing damage. Due to the enclosed structure of bearings and the distributed nature of bearing currents, accurate measurement remains challenging. This paper reviews existing measurement methods and identifies a previously unreported bearing current component caused by uneven potential distribution on the end-caps, termed the “end-cap bearing current.” The “end-cap bearing current” occurs exclusively when the bearings are in a conducting state, which can happen during low-speed operation or bearing breakdown. Experimental results from a modified end-cap setup with multiple connection wires reveal asymmetric radial current flow through bearing balls, which is not captured by conventional single-wire measurement methods. A 3D finite element model and an enhanced circuit model are developed to illustrate the underlying mechanism. The study demonstrates that up to 25% of the high-frequency common-mode current in the end-cap may flow through the bearing balls under conductive conditions, highlighting the limitations of existing measurement techniques and the need for more accurate bearing current assessment
Long-term tofersen in SOD1 amyotrophic lateral sclerosis
Get PDFImportance Approximately 2% of amyotrophic lateral sclerosis (ALS) cases are attributable to a pathogenic variant in the superoxide dismutase 1 (SOD1) gene. Tofersen, an intrathecal antisense oligonucleotide designed to reduce SOD1 protein synthesis, is the first and only approved therapy for the treatment of ALS in adults who have a variant in the SOD1 gene.
Objective To evaluate the long-term effects of tofersen in adults with SOD1-ALS.
Design, Setting, and Participants The phase 3, randomized, double-blind, placebo-controlled VALOR trial (A Study to Evaluate Efficacy, Safety, Tolerability, Pharmacokinetics and Pharmacodynamics of Tofersen in SOD1-ALS; conducted from March 2019 to July 2021) evaluated tofersen use over 28 weeks in adults (18 years and older) with weaknesses attributable to ALS and a confirmed SOD1 pathogenic variant at 32 sites in 10 countries; participants could then enroll in an open-label extension (OLE; completed August 2024).
Intervention and Exposure Adults with SOD1-ALS were randomly assigned 2:1 to receive tofersen (100 mg) or placebo over a 24-week period in the VALOR study. All participants in the OLE were treated with tofersen.
Main Outcomes and Measures Integrated analysis of VALOR and the OLE study aimed to compare early start vs placebo/delayed start (approximately 6 months later) treatment with tofersen. Key efficacy end points included measures of axonal injury and neurodegeneration (neurofilament), function and strength, quality of life, and survival.
Results VALOR enrolled 108 participants with 42 unique SOD1 pathogenic variants (mean [SD] age: placebo/delayed-start group 51.2 [11.6] [n = 36]; early-start group: 48.1 [12.6] [n = 72]) with 19 (53%) and 43 (60%) of participants being male in the placebo/delayed- and early-start groups, respectively. Overall, 95/108 participants (88%) enrolled in the OLE, and 46 participants completed the OLE (early-start group, 34 [47%]; placebo/delayed-start group, 12 [33%]). At OLE completion, participants could have accumulated 3.5 years or more (range, 192-276 weeks) of follow-up from the start of VALOR. Over 148 weeks, earlier initiation of tofersen (compared to later initiation) was associated with numerically less decline in measures of clinical function (Amyotrophic Lateral Sclerosis Functional Rating Scale–Revised score, −9.9 vs −13.5 points), respiratory function (slow vital capacity, −13.8% vs −18.1%), muscle strength (handheld dynamometry megascore, −0.38 vs −0.43 points), and quality of life (Amyotrophic Lateral Sclerosis Assessment Questionnaire 5 score, 17.0 vs 22.5 points; EuroQol 5 Dimension, 5 Level Questionnaire score, −0.1 vs −0.2 points). Tofersen prolonged survival relative to the expected natural history of SOD1-ALS. Most adverse events were consistent with ALS progression or known procedural adverse effects. All serious neurological adverse events were reversible; few led to tofersen discontinuation.
Conclusions and Relevance Final data from VALOR and the OLE demonstrated the benefit of tofersen in SOD1-ALS and provide clear rationale for its use in this population
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