922017 research outputs found
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ALBI grade predicts suitability for further systemic therapy following sorafenib in patients with advanced hepatocellular carcinoma.
No full textBackground & Aims: Preserved performance status (PS) and liver function are required for systemic therapy in patients with advanced hepatocellular carcinoma (aHCC). We investigated the frequency of suitability for further systemic therapies following sorafenib in aHCC.Methods: Demographic, tumour, and therapy-related data were collected retrospectively for patients with aHCC who received sorafenib at a UK tertiary referral centre (training cohort), and an independent French centre (validation cohort). The primary end point was percentage of patients with Child-Pugh class A (CP-A) liver disease and PS 0-1 after sorafenib discontinuation.Results: Sorafenib was received by 182 patients. After sorafenib discontinuation, 93 patients (51%) were CP-A and 60 patients (33%) were PS 0-1; 43 patients (24%) were both CP-A and PS 0-1. On multivariable analysis, patients with Albumin-Bilirubin (ALBI) score of 1 at time of sorafenib commencement were more likely to be suitable for post-sorafenib therapy, (44% grade 1 vs 15% grade 2) (OR 3.76, 95%CI 1.72-8.25, p=0.0009). In the validation cohort of 216 patients baseline ALBI grade was also significantly associated with suitability for further systemic therapy (p=0.008). Conclusions: Most patients with aHCC are not suitable for further systemic therapy after sorafenib, but those with ALBI grade 1 have a greater likelihood of suitability.<br/
Bounds for the chi-square approximation of Friedman’s statistic by Stein’s method
No full textFriedman’s chi-square test is a non-parametric statistical test for r treatments across n trials to assess the null hypothesis that there is no treatment effect. We use Stein’s method with an exchangeable pair coupling to derive a bound on the distance between the distribution of Friedman’s statistic and its limiting chi-square distribution, measured using smooth test functions. Our bound is of the optimal order n−1, and also has an optimal dependence on the parameter r, in that the bound tends to zero if and only if r/n→0. From this bound, we deduce a Kolmogorov distance bound that decays to zero under the weaker condition r1/2/n→0
Time restricted feeding – a free and effective method of managing hypertension by ameliorating inflammation?
No full textAngiotensin receptor blockade is associated with increased risk of giant cell arteritis
No full textBackground. Angiotensin II is implicated in giant cell arteritis (GCA) pathology. We examined whether the use of angiotensin receptor blockers (ARB) is associated with GCA risk, compared with ACE inhibitors (ACEi) or other antihypertensives.Methods. We performed a matched cohort study including adults who were initiators of antihypertensives in UK primary care data between 1995 and 2019. Treatment naïve individuals without prior GCA or polymyalgia rheumatica (PMR) were categorised into three groups – ARB initiators, ACEi initiators, or other antihypertensive initiators (beta-blockers, calcium channel blockers, diuretics or alpha-adrenoceptor blockers) – and followed for up to 5 years. Incident GCA was defined using validated Read codes, with age of onset ≥50 years and ≥2 glucocorticoid prescriptions. Inverse-probability-weighted Cox models were used to model outcome risk, adjusting for lifestyle parameters, comorbidities, and comedications.Results. Among over a million new starters of antihypertensives (81,780 ARB, 422,940 ACEi, and 873,066 other antihypertensives), the incidence rate of GCA per 10,000 patient-years was 2.73 (95%CI 2.12-3.50) in the ARB group, 1.76 (95%CI 1.25-2.39) in the ACEi group, and 1.90 (95%CI 1.37-2.56) in other antihypertensive group. The hazard of GCA was higher in ARB initiators (HR 1.55; 95%CI 1.16-2.06) than initiators of ACEi, but similar between initiators of other antihypertensives and ACEi (HR 1.08; 95%CI 0.87-1.35).Conclusions. Initiation of ARB is associated with higher risk of GCA compared to ACEi or other antihypertensives. Mechanistic studies of angiotensin receptor biology will provide further clarity for our findings
Filament Formation via Collision-induced Magnetic Reconnection – Formation of a Star Cluster
No full textA collision-induced magnetic reconnection (CMR) mechanism was recently proposed to explain the formation of a filament in the Orion A molecular cloud. In this mechanism, a collision between two clouds with antiparallel magnetic fields produces a dense filament due to the magnetic tension of the reconnected fields. The filament contains fiber-like sub-structures and is confined by a helical magnetic field. To show whether the dense filament is capable of forming stars, we use the Arepo code with sink particles to model star formation following the formation of the CMR-filament. First, the CMR-filament formation is confirmed with Arepo. Second, the filament is able to form a star cluster after it collapses along its main axis. Compared to the control model without magnetic fields, the CMR model shows two distinctive features. First, the CMR-cluster is confined to a factor of ∼ 4 smaller volume. The confinement is due to the combination of the helical field and gravity. Second, the CMR model has a factor of ∼ 2 lower star formation rate. The slower star formation is again due to the surface helical field that hinders gas inflow from larger scales. Mass is only supplied to the accreting cluster through streamers
Pre-sleep alpha brainwave entrainment by audio or visual stimulation for people with chronic pain and sleep disturbance; a feasibility study
No full textMechanisms of Electron Transfer Rate Modulations in Cytochrome P450 BM3.
No full textThe bacterial cytochromes P450 BM3 (CYP450 BM3) catalyzes reactions of industrial importance. Despite many successful biotransformations, robust re(design) for novel applications remains challenging. Rational design and evolution-ary approaches are not always successful highlighting a lack of complete understanding of the mechanisms of electron trans-fer (ET) modulations. Thus, the full potential of CYP450 reactions remains under-exploited. In this work, we report the first MD-based explicit prediction of BM3 ET parameters (reorganization energies; λ and ET free energies; ΔG°), and log ET rates (log kET) using Marcus theory. Overall, the calculated ET rates for the BM3 wild-type (WT), mutants (F393 and L86), ligand-bound state, and ion concentrations agree well with experimental data. In ligand-free (LF) BM3, mutations modulate kET via ET ΔG°. Simulations show that the experimental ET rate enhancement is due to increased driving force (more negative ΔG°) upon ligation. This increase is related to the protein reorganization required to accommodate the ligand in the binding pocket, rather than binding interaction with the ligand. Our methodology (CYPWare 1.0) automates all the stages of MD simulation step-up, energy calculations, and estimation of ET parameters. CYPWare 1.0 and this work, thus represent an important advancement in the CYP450 ET rate predictions which has the potential to guide the redesign of ET enzymes. This program and a web tool are available on GitHub for academic research
The Cold Futures of Mouse Genetics: Modes of Strain Cryopreservation since the 1970s
No full textCryopreservation, or the freezing of embryos or sperm, has become a routine part of many research projects involving laboratory mice. In this article, we combine historical and sociological methods to produce a cryopolitical analysis of this less explored aspect of animal research. We provide a longitudinal account of mouse embryo and semen storage and uses in the UK and show that cryopreservation enabled researchers to overcome particular challenges—fears of strain loss, societal disapproval, and genetic drift—in ways which enabled the continued existence of strains and contributed to the scaling up of mouse research since World War II. We use the theoretical lens of cryopolitics to explore three different, yet overlapping, cryopolitical strategies that we identify. All share the ability to ensure the continued maintenance of genetically-defined strains without the need for continually breeding colonies of mice. We argue that, in contrast to more common imaginaries of species conservation, the cryopolitical rationale can best be understood as purposefully not letting the strain die without requiring animals to live. The ability to freeze mice, then, had the potential to unsettle who the objects of care are in mouse research, from individual animals to the concept of the strain itself
‘Enter Parliament but never become part of it’: How have the Greens in the UK Approached Opposition?
No full textThe Greens in the UK have benefited from the fragmentation of the party system and the creation of devolved institutions, achieving consistent representation at multiple levels of British politics in recent years. However, we know little about what they have done in these positions. This study uses interviews with Green legislators to investigate how they have interpreted the task of opposition at Westminster, Holyrood and Stormont. We show that Green legislators’ approaches to opposition have been influenced by their party identity, and that differences in approach between the institutions have largely been determined by contrasting political opportunity structures, rather than parliamentary rules. These findings highlight the importance of party as a factor shaping opposition strategy and the varied roles which opposition parties can play within the UK political system
Quantifying the Impacts of Modelling Assumptions on Accuracy and Computational Efficiency for Integrated Water-Energy System Simulations Under Uncertain Climate
No full textJointly managing water and energy systems, rather than treating each system independently, is recognised as an approach that can lead to a more cost-effective and reliable supply, which is particularly critical in water-rich and developing countries. This has motivated the development of various integrated water-energy simulators, each one catering for specific modelling needs through the use of specific sets of modelling assumptions, e.g., representing water and energy with balance equations, or dedicated river flow and power network equations. In this context, it becomes critical to assess the effectiveness of different modelling assumptions to improve the design of water-energy simulators. In particular, it is important to develop a methodology that can identify, based on a systematic assessment process, the portfolios of modelling assumptions that better capture the uncertain future conditions in the water and energy sectors, e.g., climate-driven stresses and shocks such as water scarcity, temperature rise, etc. To address this challenge, this paper proposes a Mixed Integer Linear Programming (MILP) integrated water-energy system simulation methodology designed to adapt and quantify different modelling assumptions under various weather-related conditions (e.g., water scarcity and high temperatures). The models were developed to capture the characteristics of non-pressurised water systems (e.g., channels and rivers) and electricity systems. The methodology is used to investigate typical modelling assumptions (e.g., temporal resolutions and water and power system models) and novel approaches to model the impacts of high temperatures on generation capacity to capture the effects of extreme weather on power generation. The methodology is demonstrated on the Ghanaian integrated water-energy system. The results highlight the benefits in terms of computational costs and modelling accuracy, of the customisable simulation, and provide guidance to select adequate modelling assumptions