Determination of physical and magnetic microstructure by STEM

This thesis is concerned with the use of a dedicated scanning transmission electron microscope (STEM) to investigate the physical and magnetic microstructure of thin film specimens. The materials investigated were ferromagnetic and some of them are considered as possible media for high density perpendicular magnetic recording. The first chapter introduces the concepts of ferromagnetism and the energy contributions which determine the domain structures in thin films. The requirements for magnetic recording media are also discussed in this chapter and the reasons for interest in perpendicular, rather than longitudinal recording, as a means of achieving high information storage densities are discussed. Chapter 2 describes the STEM used in this work, which was an extended V. G. Microscopes HB5, and then goes on to explain image formation in a STEM. It is shown that the use of a non-standard detector with an asymmetric response function in the STEM allows direct information on magnetic structures within a thin film to be obtained (the differential phase contrast imaging mode). Furthermore it is seen that the very small source size of the field emission gun in the HB5 allows this information to be obtained with a high spatial resolution, and that the sequential nature of image formation in the STEM allows this information to be acquired digitally. The remainder of the chapter deals with the microscope conditions used for, and spatial resolution available with, x-ray and EELS microanalysis. Chapter 3 demonstrates the use of the STEM to characterise fully the physical and magnetic microstructure of a large grain polycrystalline cobalt foil. In this chapter it is demonstrated that electron diffraction can be used to determine the crystallography of the foil, the thickness can be determined by measuring the deflection of the electron beam as it passes through the foil, and the magnetic structure and domain wall profile can be determined using differential phase contrast imaging in the STEM. In Chapter 4 the magnetic stray fields from the cobalt foil of Chapter 3 are investigated, as are those from written tracks on a longitudinal magnetic recording medium. It is seen that the measured stray fields from the simple domain structure of the cobalt foil are in good agreement with theoretical calculations. In Chapter 5 the techniques demonstrated in Chapter 3 are applied to planar polycrystalline Co-Cr films with artificial superstructures and to CoCr alloy films. Both materials were grown so as to have a preferential crystal orientation, with a c-axis texture, in the alloys and in the Co layers of the artificial superstructure films, along the film normal. The magnetic structure observed in these films indicated that this c-axis texture had given rise to a degree of perpendicular magnetic anisotropy. In Chapters 6 and 7 cross-sections of single and double layer perpendicular magnetic recording films are investigated. In Chapter 6, elemental segregation of Cr to individual column boundaries within the columnar microstructure is demonstrated using x-ray microanalysis. When the effects of beam broadening are considered it is seen that the column boundaries are likely to be non-magnetic. In Chapter 7 the magnetic structure of the cross-sections is investigated. Although no unambiguous magnetic contrast is revealed in the CoCr layers, the magnetic structure in the backing layers, and the stray fields from the cross-sections show that there is very small scale magnetic structure within the CoCr layer. Chapter 8 is a summary of the results obtained, and contains suggestions for future investigations of magnetic recording materials. Three of the four Appendices are concerned with computer processing of STEM images, and one explains the use of the free lens controller on the CTEM used in this work for preliminary investigations

Use of CYP1B1 inhibitors for treating cancer.

CYP1B1 proteins and their role in metabolising or inactivating anti-cancer drugs are disclosed, together with compositions for treating cancer comprising a substance capable of inhibiting CYP1B1 protein and an anti-cancer drug (e.g. docetaxel, paclitaxel, flutamide, tamoxifen, mitoxantrone, doxorubicin or daunomycin)

Case Reports1. A Late Presentation of Loeys-Dietz Syndrome: Beware of TGFβ Receptor Mutations in Benign Joint Hypermobility

Background: Thoracic aortic aneurysms (TAA) and dissections are not uncommon causes of sudden death in young adults. Loeys-Dietz syndrome (LDS) is a rare, recently described, autosomal dominant, connective tissue disease characterized by aggressive arterial aneurysms, resulting from mutations in the transforming growth factor beta (TGFβ) receptor genes TGFBR1 and TGFBR2. Mean age at death is 26.1 years, most often due to aortic dissection. We report an unusually late presentation of LDS, diagnosed following elective surgery in a female with a long history of joint hypermobility. Methods: A 51-year-old Caucasian lady complained of chest pain and headache following a dural leak from spinal anaesthesia for an elective ankle arthroscopy. CT scan and echocardiography demonstrated a dilated aortic root and significant aortic regurgitation. MRA demonstrated aortic tortuosity, an infrarenal aortic aneurysm and aneurysms in the left renal and right internal mammary arteries. She underwent aortic root repair and aortic valve replacement. She had a background of long-standing joint pains secondary to hypermobility, easy bruising, unusual fracture susceptibility and mild bronchiectasis. She had one healthy child age 32, after which she suffered a uterine prolapse. Examination revealed mild Marfanoid features. Uvula, skin and ophthalmological examination was normal. Results: Fibrillin-1 testing for Marfan syndrome (MFS) was negative. Detection of a c.1270G > C (p.Gly424Arg) TGFBR2 mutation confirmed the diagnosis of LDS. Losartan was started for vascular protection. Conclusions: LDS is a severe inherited vasculopathy that usually presents in childhood. It is characterized by aortic root dilatation and ascending aneurysms. There is a higher risk of aortic dissection compared with MFS. Clinical features overlap with MFS and Ehlers Danlos syndrome Type IV, but differentiating dysmorphogenic features include ocular hypertelorism, bifid uvula and cleft palate. Echocardiography and MRA or CT scanning from head to pelvis is recommended to establish the extent of vascular involvement. Management involves early surgical intervention, including early valve-sparing aortic root replacement, genetic counselling and close monitoring in pregnancy. Despite being caused by loss of function mutations in either TGFβ receptor, paradoxical activation of TGFβ signalling is seen, suggesting that TGFβ antagonism may confer disease modifying effects similar to those observed in MFS. TGFβ antagonism can be achieved with angiotensin antagonists, such as Losartan, which is able to delay aortic aneurysm development in preclinical models and in patients with MFS. Our case emphasizes the importance of timely recognition of vasculopathy syndromes in patients with hypermobility and the need for early surgical intervention. It also highlights their heterogeneity and the potential for late presentation. Disclosures: The authors have declared no conflicts of interes

Can we talk? The reframing of social permissions in the comedy of Joan Rivers

Theatrical performers enjoy a privileged position whereby they are permitted to perform actions and express utterances that would be generally unacceptable in everyday social communications. Stand-up comedy frames itself as a conversation between the comedian and the audience but explicitly breaches the normal rules of such interactions, notably the politeness maxims delineated by Leech, Grice, Levinson and others. In particular, Joan Rivers and other ‘insult’ comedians, such as Don Rickles, engage in what Brown and Levinson label ‘face-threatening actions’ that would normally elicit hostility but have the opposite effect in the context of the comedy performance. Comedians such as Rivers successfully reframe the rules of social interaction to grant themselves, and their audiences, permission to express, and enjoy expressing, feelings and attitudes normally branded as taboo

IVIG-EXPOSURE AND THROMBOEMBOLIC EVENT RISK: FINDINGS FROM THE UK BIOBANK

BackgroundArterial and venous thromboembolic events (TEEs) have been associated with intravenous Ig use, but the risk has been poorly quantified. We aimed to calculate the risk of TEEs associated with exposure to intravenous Ig.MethodsWe included participants from UK Biobank recruited over 3 years, data extracted September 2020.The study endpoints were incidence of myocardial infarction, other acute ischaemic heart disease, stroke, pulmonary embolism and other venous embolism and thrombosis.Predictors included known TEE risk factors: age, sex, hypertension, smoking status, type 2 diabetes mellitus, hypercholesterolaemia, cancer and past history of TEE. Intravenous Ig and six other predictors were added in the sensitivity analysis.Information from participants was collected prospectively, while data from linked resources, including death, cancer, hospital admissions and primary care records were collected retrospectively and prospectively.  FINDINGS: 14 794 of 502 492 individuals had an incident TEE during the study period. The rate of incident events was threefold higher in those with prior history of TEE (8 .7%) than those without previous history of TEE (3.0%).In the prior TEE category, intravenous Ig exposure was independently associated with increased risk of incident TEE (OR=3.69 (95% CI 1.15 to 11.92), p=0.03) on multivariate analysis. The number needed to harm by exposure to intravenous Ig in those with a history of TEE was 5.8 (95% CI 2.3 to 88.3).Intravenous Ig exposure did not increase risk of TEE in those with no previous history of TEE.InterpretationIntravenous Ig is associated with increased risk of further TEE in individuals with prior history of an event with one further TEE for every six people exposed. In practice, this will influence how clinicians consent for and manage overall TEE risk on intravenous Ig exposure

Iterative delivery of an implementation support package to increase and sustain the routine provision of antenatal care addressing alcohol consumption during pregnancy: study protocol for a stepped-wedge cluster trial

Introduction Antenatal care addressing alcohol consumption during pregnancy is not routinely delivered in maternity services. Although a number of implementation trials have reported significant increases in such care, the majority of women still did not receive all recommended care elements, and improvements dissipated over time. This study aims to assess the effectiveness of an iteratively developed and delivered implementation support package in: (1) increasing the proportion of pregnant women who receive antenatal care addressing alcohol consumption and (2) sustaining the rate of care over time.Methods and analysis A stepped-wedge cluster trial will be conducted as a second phase of a previous trial. All public maternity services within three sectors of a local health district in Australia will receive an implementation support package that was developed based on an assessment of outcomes and learnings following the initial trial. The package will consist of evidence-based strategies to support increases in care provision (remind clinicians; facilitation; conduct educational meetings) and sustainment (develop a formal implementation blueprint; purposely re-examine the implementation; conduct ongoing training). Measurement of outcomes will occur via surveys with women who attend antenatal appointments each week. Primary outcomes will be the proportion of women who report being asked about alcohol consumption at subsequent antenatal appointments; and receiving complete care (advice and referral) relative to alcohol risk at initial and subsequent antenatal appointments. Economic and process evaluation measures will also be reported.Ethics and dissemination Ethical approval was obtained through the Hunter New England (16/11/16/4.07, 16/10/19/5.15) and University of Newcastle Human Research Ethics Committees (H-2017-0032, H-2016-0422) and the Aboriginal Health and Medical Research Council (1236/16). Trial findings will be disseminated to health service decision makers to inform the feasibility of conducting additional cycles to further improve antenatal care addressing alcohol consumption as well as at scientific conferences and in peer-reviewed journals.Trial registration number Australian and New Zealand Clinical Trials Registry (ACTRN12622000295741)