Personalised external aortic root support (PEARS) in Marfan syndrome: Analysis of 1-9 year outcomes by intention-to-treat in a cohort of the first 30 consecutive patients to receive a novel tissue and valve-conserving procedure, compared with the published results of aortic root replacement

Objective: Among people with Marfan syndrome who have a typical aortic root aneurysm, dissection is a characteristic cause of premature death. To pre-empt Type A dissection, composite root replacement with a mechanical valve became the standard of care in the 1980s and 1990s. This is being superseded by valvesparing aortic root replacement to avoid lifelong anticoagulation. In 2004, a total root and valve-sparing procedure, personalised external aortic support, was introduced. We report here results among the first 30 recipients. Methods: From cross-sectional digital images, the patient's own aorta is modelled by computer aided design and a replica is made in thermoplastic by rapid prototyping. On this, a personalised support of a macroporous polymer mesh is manufactured. The mesh is positioned around the aorta, closely applied from the aortoventricular junction to beyond the brachiocephalic artery. The operation is performed with a beating heart and usually without cardiopulmonary bypass. Results: Between 2004 and 2011, 30 patients, median age 28 years (IQR 20-44) had this operation and have been prospectively followed for 1.4-8.8 years by February 2013. During a total of 133 patient-years there were no deaths or cerebrovascular, aortic or valve-related events. These early outcomes are better than published results for the more radical extirpative root replacement operations. Conclusions: The aortic valve, the root architecture, and the blood/endothelia interface are conserved. The perioperative burden is less and there has been freedom from aortic and valvular events. A prospective comparative study is planned

Post-stenotic aortic dilatation

Aortic stenosis is the most common valvular heart disease affecting up to 4% of the elderly population. It can be associated with dilatation of the ascending aorta and subsequent dissection. Post-stenotic dilatation is seen in patients with AS and/or aortic regurgitation, patients with a haemodynamically normal bicuspid aortic valve and following aortic valve replacement. Controversy exists as to whether to replace the aortic root and ascending aorta at the time of aortic valve replacement, an operation that potentially carries a higher morbidity and mortality. The aetiology of post-stenotic aortic dilatation remains controversial. It may be due to haemodynamic factors caused by a stenotic valve, involving high velocity and turbulent flow downstream of the stenosis, or due to intrinsic pathology of the aortic wall. This may involve an abnormality in the process of extracellular matrix remodelling in the aortic wall including inadequate synthesis, degradation and transport of extracellular matrix proteins. This article reviews the aetiology, pathology and management of patients with post-stenotic aortic dilatation

Playing with the Rules: Influences on the Development of Regulation in Sport

Sport today is a rule-governed practice: constitutive rules, both prescriptive and proscriptive, define required equipment and facilities as well as setting the formal rules of play; auxiliary rules specify and control eligibility: and regulatory rules place restraints on behaviour independent of the sport itself. This article offers a broad sweep examination of the historical process of rule development in sport including an assessment of the influence over time of gambling, fair play ideology, economic pressures, technological developments and legal intervention. En route a seven-stage scheme of constitutive rule development is postulated which it is hoped will set a research agenda for sports historians to test with case studies of particular sports

Elucidating the physical origins of the animal magnetic sense by cavity-enhanced spectroscopy

Many animal species have the ability to navigate using the Earth’s magnetic field. This is particularly true of migratory birds, who are able to fly thousands of kilometres only to nest in exactly the same place year on year. The best current hypothesis as to the method by which this magnetoreception – the ability to sense magnetic fields – takes place is that of magnetically sensitive radical pairs in cryptochromes – blue light photoreceptors found in the retinae of birds and other animals. Chapter 1 explores the theory needed for understanding the phenomenon of magnetoreception, especially spin chemistry. The study of magnetically sensitive processes requires the ability to detect tiny changes in the concentrations of the chemical species involved. This has driven the development of state-of-the-art and high-sensitivity techniques, with a particular focus on optical spectroscopy. One such method is the use of cavity-based absorption measurements which increase the optical path length by passing the probe light through the sample multiple times. In this work, a spectrometer that employs the use of an optical cavity – cavity ring-down spectroscopy (CRDS) – was entirely redesigned, rebuilt and recoded. The work to improve the spectrometer, along with an introduction to the optical technique, is described in Chapter 2. In Chapter 3, the performance of the spectrometer is scrutinised using a model system – flavin mononucleotide (FMN) and hen egg-white lysozyme (HEWL) – allowing for exploration of the detection sensitivity and stability of the apparatus. Time-resolved and magnetically altered reaction yield (MARY) experiments yield results similar to those reported previously, particularly by Dr D. Sheppard. The sensitivity of the rebuilt spectrometer is highlighted, revealing the importance of storage conditions of this widely used “calibration sample” with a slight deviation in the time- and wavelength-resolved spectra obtained when compared to previously reported results. Once shown that the spectrometer is fully functional, the effect of pump laser power on ring-down time is also explored with the hope of improving the signal-to-noise ratio by compensating for fluctuations from the laser. The core of the thesis describes the measurements performed on cryptochrome 4 from three avian species: the migratory European robin (Erithacus rubecula); the pigeon (Columba livia), which is non-migratory, but known to orient using magnetic cues; and the chicken (Gallus gallus), which is not known to use the geomagnetic field for any purpose. The cryptochromes from the three species share strongly conserved amino acid sequences, but should, to support the cryptochrome hypothesis of magnetoreception, show differences that are based on the function. A marked difference in the spectroscopic results is shown between the migratory robin and the other two species. Additional measurements are performed on a point-mutant of the three cryptochromes in which the final electron transfer partner – a tryptophan residue at position 369 – is replaced so that it cannot be involved in forming the radical pair. It is shown that, while all cryptochrome proteins show some sensitivity of their radical concentrations to applied magnetic fields, that of the migratory robin is most remarkable – both in its magnitude and lifetime. The results of this thesis, presented in Chapter 4, hence provide further support of the radical pair hypothesis of magnetoreception and the data and conclusion formed a substantial part of a Nature publication in 2021.</p

Personalised external aortic root support (PEARS) in Marfan syndrome: analysis of 1-9 year outcomes by intention-to-treat in a cohort of the first 30 consecutive patients to receive a novel tissue and valve-conserving procedure, compared with the published results of aortic root replacement

Objective Among people with Marfan syndrome who have a typical aortic root aneurysm, dissection is a characteristic cause of premature death. To pre-empt Type A dissection, composite root replacement with a mechanical valve became the standard of care in the 1980s and 1990s. This is being superseded by valve-sparing aortic root replacement to avoid lifelong anticoagulation. In 2004, a total root and valve-sparing procedure, personalised external aortic support, was introduced. We report here results among the first 30 recipients. Methods From cross-sectional digital images, the patient's own aorta is modelled by computer aided design and a replica is made in thermoplastic by rapid prototyping. On this, a personalised support of a macroporous polymer mesh is manufactured. The mesh is positioned around the aorta, closely applied from the aortoventricular junction to beyond the brachiocephalic artery. The operation is performed with a beating heart and usually without cardiopulmonary bypass. Results Between 2004 and 2011, 30 patients, median age 28 years (IQR 20-44) had this operation and have been prospectively followed for 1.4-8.8 years by February 2013. During a total of 133 patient-years there were no deaths or cerebrovascular, aortic or valve-related events. These early outcomes are better than published results for the more radical extirpative root replacement operations. Conclusions The aortic valve, the root architecture, and the blood/endothelia interface are conserved. The perioperative burden is less and there has been freedom from aortic and valvular events. A prospective comparative study is planned

Involving patients and the public in healthcare operational research—The challenges and opportunities

Interest is growing internationally in the potential benefits of patient and public involvement (PPI) in research. In the United Kingdom (UK) health and social care services are now committed to involving patients and service users in the planning, development and evaluation of their services. Many funders require PPI as a prerequisite for funding. What does healthcare operational research miss by not involving patients and the public in the development, refinement and implementation of models? We believe PPI is important for healthcare OR for model design and validation, and ethical and economic reasons. It also has a distinct contribution that goes beyond the incorporation of behavioural parameters into models. Case studies in neonatal care and a fractured neck of femur pathway highlight PPI's contribution to model design and validation, but a recent conference session also identified a number of obstacles. We suggest a provisional model for the implementation of PPI in healthcare OR that emphasises a facilitative approach. We acknowledge this is a significant challenge, but argue that it must be met for ethical and economic reasons that are ultimately rooted in modellers' construction of valid models. Crucially, it has the potential to enhance our ability to bring about change which can benefit health services and, most importantly, the patients they serve. © 2013 Elsevier Ltd

Detection of magnetic field effects by confocal microscopy

Certain pairs of paramagnetic species generated under conservation of total spin angular momentum are known to undergo magnetosensitive processes. Two prominent examples of systems exhibiting these so-called magnetic field effects (MFEs) are photogenerated radical pairs created from either singlet or triplet molecular precursors, and pairs of triplet states generated by singlet fission. Here, we showcase confocal microscopy as a powerful technique for the investigation of such phenomena. We first characterise the instrument by studying the field-sensitive chemistry of two systems in solution: radical pairs formed in a cryptochrome protein and the flavin mononucleotide/hen egg-white lysozyme model system. We then extend these studies to single crystals. Firstly, we report temporally and spatially resolved MFEs in flavin-doped lysozyme single crystals. Anisotropic magnetic field effects are then reported in tetracene single crystals. Finally, we discuss the future applications of confocal microscopy for the study of magnetosensitive processes with a particular focus on the cryptochrome-based chemical compass believed to lie at the heart of animal magnetoreception

Age effects on diffusion tensor magnetic resonance imaging tractography measures of frontal cortex connections in schizophrenia

Diffusion tensor magnetic resonance imaging (DT-MRI) has previously been used to investigate white matter tracts in schizophrenia, with inconsistent results. The aim of the study was to use a novel method for tract-specific measurements of fronto-temporal fasciculi in early-onset schizophrenia. We hypothesized that by making tract-specific measurements, clear diffusion abnormalities would be revealed in specific fasciculi in schizophrenia. Measurements of diffusion anisotropy and mean diffusivity were localized within fronto-temporal fasciculi by forming 3-D reconstructions of the cingulum, uncinate, superior longitudinal, and inferior fronto-occipital fasciculi using diffusion tensor tractography. We were limited in our ability to test our hypothesis by the important and surprising finding that age affected DT-MRI-based measures in schizophrenia patients in a different way from comparison subjects, most notably in the left superior longitudinal fasciculus. The youngest schizophrenia patients that we studied had lower diffusion anisotropy than age-matched comparison subjects, but this difference diminished with increasing age. The main conclusion of this study was that direct comparisons of absolute DT-MRI-based measures between individuals with schizophrenia and comparison subjects may be problematic and misleading because of underlying age-related differences in brain maturation between groups