I hereby declare that the work presented in this document is based on research carried out by me, and that no part has previously been submitted for a degree in this or any other university

Inhibitors of known transport processes, in conjunction with ion substitution were used in biochemical, physiological and microelectrode studies to investigate the mechanisms underlying ion and fluid secretion across the Malpighian tubules of Locusta migratoria. Immunocytochemical localization and cell fractionation methods used in conjunction with biochemical analyses demonstrate the presence of Na(^+)/K(^+)-ATPase activity on the basal cell membranes and HCO(_3)(^-)-stimulated and V-type ATPase activities on apical cell membranes. The biochemical properties of the HCO(_3)(^-)-stimulated and V-type ATPase activities are compared and the results discussed. Specific inhibitors of Na(^+)/K(^+)-ATPase and V-type ATPases inhibited fluid secretion whilst cAMP was found to stimulate fluid secretion. The continued secretion of K(^+) when tubules were bathed in K(^+)-free saline was attributed to the presence of mineral concretions shown in ultrastructural studies to be distributed throughout the cytoplasm. The effects of ouabain, NEM and cAMP on the cationic composition of the "urine" were studied. In control saline, ouabain and NEM increased the level of Na(^+) in the "urine" whereas cAMP caused an increase in the amount of K(^+) secreted. In Rb(^+)-saline, ouabain caused "urine" levels of Na(^+) to increase and levels of Rb(^+) to fall whereas cAMP and NEM had no effect on the cationic composition of the "urine". Ion substitution experiments used in conjunction with intracellular microelectrodes suggest the basal cell membrane contains an inward rectifying K(^+) channel. Blocking the basal inward rectifier with Rb(+) drove the potential of this membrane towards the emf of the apical membrane potential. In the presence of Rb(^+), bafilomycin A(_1), a specific V-type ATPase inhibitor, reduced this potential suggesting the apical membrane potential is produced by a V-type ATPase. The results are discussed and a hypothetical model is proposed to account for the mechanisms of ion and fluid movement across apical and basal cell surfaces

Real-world tyrosine kinase inhibitor treatment pathways, monitoring patterns and responses in patients with chronic myeloid leukaemia in the United Kingdom: the UK TARGET CML study.

Management of chronic myeloid leukaemia (CML) has recently undergone dramatic changes, prompting the European LeukemiaNet (ELN) to issue recommendations in 2013; however, it remains unclear whether real-world CML management is consistent with these goals. We report results of UK TARGET CML, a retrospective observational study of 257 patients with chronic-phase CML who had been prescribed a first-line TKI between 2013 and 2017, most of whom received first-line imatinib (n = 203). Although 44% of patients required ≥1 change of TKI, these real-world data revealed that molecular assessments were frequently missed, 23% of patients with ELN-defined treatment failure did not switch TKI, and kinase domain mutation analysis was performed in only 49% of patients who switched TKI for resistance. Major molecular response (MMR; BCR-ABL1IS ≤0·1%) and deep molecular response (DMR; BCR-ABL1IS ≤0·01%) were observed in 50% and 29%, respectively, of patients treated with first-line imatinib, and 63% and 54%, respectively, receiving a second-generation TKI first line. MMR and DMR were also observed in 77% and 44% of evaluable patients with ≥13 months follow-up, receiving a second-generation TKI second line. We found little evidence that cardiovascular risk factors were considered during TKI management. These findings highlight key areas for improvement in providing optimal care to patients with CML

The clinical effectiveness and cost-effectiveness of a ‘stepping into day treatment’ approach versus inpatient treatment as usual for anorexia nervosa in adult specialist eating disorder services (DAISIES trial): a study protocol of a randomised controlled multi-centre open-label parallel group non-inferiority trial

BACKGROUND: Anorexia nervosa (AN) is a serious and disabling mental disorder with a high disease burden. In a proportion of cases, intensive hospital-based treatments, i.e. inpatient or day patient treatment, are required, with day patient treatment often being used as a 'step-down' treatment after a period of inpatient treatment. Demand for such treatment approaches has seen a sharp rise. Despite this, the relative merits of these approaches for patients, their families, and the NHS and wider society are relatively unknown. This paper describes the rationale for, and protocol of, a two-arm multi-centre open-label parallel group non-inferiority randomised controlled trial, evaluating the effectiveness and cost-effectiveness of these two intensive treatments for adults with severe AN: inpatient treatment as usual and a stepped care day patient approach (the combination of day patient treatment with the option of initial inpatient treatment for medical stabilisation). The main aim of this trial is to establish whether, in adults with severe AN, a stepped care day patient approach is non-inferior to inpatient treatment as usual in relation to improving body mass index (BMI) at 12 months post-randomisation. METHODS: 386 patients with a Diagnostic and Statistical Manual 5th edition diagnosis of severe AN or related disorder, with a BMI of ≤16 kg/m2 and in need of intensive treatment will be randomly allocated to either inpatient treatment as usual or a stepped care day patient approach. Patients in both groups will receive treatment until they reach a healthy weight or get as close to this point as possible. Assessments will be conducted at baseline (prior to randomisation), and at 6 and 12 months post-randomisation, with additional monthly symptom monitoring. The primary outcome will be BMI at the 12-month post-randomisation assessment. Other outcomes will include psychosocial adjustment; treatment motivation, expectations and experiences; cost-effectiveness; and carer burden. DISCUSSION: The results of this study will provide a rigorous evaluation of two intensive treatment approaches which will inform future national and international treatment guidelines and service provision

A mutation in the mitochondrial fission gene Dnm1l leads to cardiomyopathy

Mutations in a number of genes have been linked to inherited dilated cardiomyopathy (DCM). However, such mutations account for only a small proportion of the clinical cases emphasising the need for alternative discovery approaches to uncovering novel pathogenic mutations in hitherto unidentified pathways. Accordingly, as part of a large-scale N-ethyl-N-nitrosourea mutagenesis screen, we identified a mouse mutant, Python, which develops DCM. We demonstrate that the Python phenotype is attributable to a dominant fully penetrant mutation in the dynamin-1-like (Dnm1l) gene, which has been shown to be critical for mitochondrial fission. The C452F mutation is in a highly conserved region of the M domain of Dnm1l that alters protein interactions in a yeast two-hybrid system, suggesting that the mutation might alter intramolecular interactions within the Dnm1l monomer. Heterozygous Python fibroblasts exhibit abnormal mitochondria and peroxisomes. Homozygosity for the mutation results in the death of embryos midway though gestation. Heterozygous Python hearts show reduced levels of mitochondria enzyme complexes and suffer from cardiac ATP depletion. The resulting energy deficiency may contribute to cardiomyopathy. This is the first demonstration that a defect in a gene involved in mitochondrial remodelling can result in cardiomyopathy, showing that the function of this gene is needed for the maintenance of normal cellular function in a relatively tissue-specific manner. This disease model attests to the importance of mitochondrial remodelling in the heart; similar defects might underlie human heart muscle disease

Implementable Deep Learning for Multi-sequence Proton MRI Lung Segmentation:A Multi-center, Multi-vendor, and Multi-disease Study

Background: Recently, deep learning via convolutional neural networks (CNNs) has largely superseded conventional methods for proton (1H)-MRI lung segmentation. However, previous deep learning studies have utilized single-center data and limited acquisition parameters.Purpose: Develop a generalizable CNN for lung segmentation in 1H-MRI, robust to pathology, acquisition protocol, vendor, and center.Study type: Retrospective.Population: A total of 809 1H-MRI scans from 258 participants with various pulmonary pathologies (median age (range): 57 (6–85); 42% females) and 31 healthy participants (median age (range): 34 (23–76); 34% females) that were split into training (593 scans (74%); 157 participants (55%)), testing (50 scans (6%); 50 participants (17%)) and external validation (164 scans (20%); 82 participants (28%)) sets.Field Strength/Sequence: 1.5-T and 3-T/3D spoiled-gradient recalled and ultrashort echo-time 1H-MRI.Assessment: 2D and 3D CNNs, trained on single-center, multi-sequence data, and the conventional spatial fuzzy c-means (SFCM) method were compared to manually delineated expert segmentations. Each method was validated on external data originating from several centers. Dice similarity coefficient (DSC), average boundary Hausdorff distance (Average HD), and relative error (XOR) metrics to assess segmentation performance.Statistical Tests: Kruskal–Wallis tests assessed significances of differences between acquisitions in the testing set. Friedman tests with post hoc multiple comparisons assessed differences between the 2D CNN, 3D CNN, and SFCM. Bland–Altman analyses assessed agreement with manually derived lung volumes. A P value of &lt;0.05 was considered statistically significant.Results: The 3D CNN significantly outperformed its 2D analog and SFCM, yielding a median (range) DSC of 0.961 (0.880–0.987), Average HD of 1.63 mm (0.65–5.45) and XOR of 0.079 (0.025–0.240) on the testing set and a DSC of 0.973 (0.866–0.987), Average HD of 1.11 mm (0.47–8.13) and XOR of 0.054 (0.026–0.255) on external validation data.Data Conclusion: The 3D CNN generated accurate 1H-MRI lung segmentations on a heterogenous dataset, demonstrating robustness to disease pathology, sequence, vendor, and center.Evidence Level: 4.Technical Efficacy: Stage 1.</p

Social prescribing for people living with dementia (PLWD) and their carers: what works, for whom, under what circumstances and why – protocol for a complex intervention systematic review

Introduction: Dementia is a complex medical condition that poses significant challenges to healthcare systems and support services. People living with dementia (PLWD) and their carers experience complex needs often exacerbated by social isolation and challenges in accessing support. Social prescribing (SP) seeks to enable PLWD and their carers to access community and voluntary sector resources to support them address such needs. Existing research, however, does not describe what SP interventions are currently in place in dementia care. Little is known about the needs these interventions are designed to address, the reasons that lead PLWD and their carers to participate in them, their effectiveness and the extent to which they could increase positive health outcomes if adopted and how. Methods and analysis: A complex intervention systematic review of SP for PLWD and/or their carers will be conducted using an iterative logic model approach. Six electronic (MEDLINE, EMBASE, PsycINFO, CINAHL, Scopus and Cochrane/CENTRAL) and two grey literature databases (EThOS and CORE) were searched for publications between 1 January 2003 and June 2023, supplemented by handsearching of reference lists of included studies. Study selection, data extraction and risk of bias assessment, using Gough’s Weight of Evidence Framework, will be independently performed by two reviewers. A narrative approach will be employed to synthesise and report quantitative and qualitative data. Reporting will be informed by the Preferred Reporting Items for Systematic Review and Meta-Analysis Complex Interventions extension statement and checklist. Ethics and dissemination: No ethical approval is required due to this systematic review operating only with secondary sources. Findings will be disseminated through peer-reviewed publications, conference presentations and meetings with key stakeholders including healthcare professionals, patient and carer groups, community organisations (eg, the Social Prescribing Network and the Evidence Collaborative at the National Academy for Social Prescribing), policymakers and funding bodies

Effects of antiplatelet therapy on stroke risk by brain imaging features of intracerebral haemorrhage and cerebral small vessel diseases: subgroup analyses of the RESTART randomised, open-label trial

Background Findings from the RESTART trial suggest that starting antiplatelet therapy might reduce the risk of recurrent symptomatic intracerebral haemorrhage compared with avoiding antiplatelet therapy. Brain imaging features of intracerebral haemorrhage and cerebral small vessel diseases (such as cerebral microbleeds) are associated with greater risks of recurrent intracerebral haemorrhage. We did subgroup analyses of the RESTART trial to explore whether these brain imaging features modify the effects of antiplatelet therapy

The Long-Baseline Neutrino Experiment: Exploring Fundamental Symmetries of the Universe

The preponderance of matter over antimatter in the early Universe, the dynamics of the supernova bursts that produced the heavy elements necessary for life and whether protons eventually decay --- these mysteries at the forefront of particle physics and astrophysics are key to understanding the early evolution of our Universe, its current state and its eventual fate. The Long-Baseline Neutrino Experiment (LBNE) represents an extensively developed plan for a world-class experiment dedicated to addressing these questions. LBNE is conceived around three central components: (1) a new, high-intensity neutrino source generated from a megawatt-class proton accelerator at Fermi National Accelerator Laboratory, (2) a near neutrino detector just downstream of the source, and (3) a massive liquid argon time-projection chamber deployed as a far detector deep underground at the Sanford Underground Research Facility. This facility, located at the site of the former Homestake Mine in Lead, South Dakota, is approximately 1,300 km from the neutrino source at Fermilab -- a distance (baseline) that delivers optimal sensitivity to neutrino charge-parity symmetry violation and mass ordering effects. This ambitious yet cost-effective design incorporates scalability and flexibility and can accommodate a variety of upgrades and contributions. With its exceptional combination of experimental configuration, technical capabilities, and potential for transformative discoveries, LBNE promises to be a vital facility for the field of particle physics worldwide, providing physicists from around the globe with opportunities to collaborate in a twenty to thirty year program of exciting science. In this document we provide a comprehensive overview of LBNE's scientific objectives, its place in the landscape of neutrino physics worldwide, the technologies it will incorporate and the capabilities it will possess.Comment: Major update of previous version. This is the reference document for LBNE science program and current status. Chapters 1, 3, and 9 provide a comprehensive overview of LBNE's scientific objectives, its place in the landscape of neutrino physics worldwide, the technologies it will incorporate and the capabilities it will possess. 288 pages, 116 figure

Seamount Observatory and SAMOC Overturning, Cruise No. MSM60, January 04 - February 01, 2017, Cape Town (South Africa) - Montevideo (Uruguay)

The scientific program of the MARIA S. MERIAN MSM60 expedition was the first basin-wide section across the South Atlantic following the SAMBA/SAMOC line at 34°30'S. The scientific program consisted of full water depth sampling (up to 5300m) using the CTD/O2/lADCP rosette system. The water samples have been analysed on board for oxygen, dissolved inorganic carbon, alkalinity, salinity, CFC12, and SF6. In addition samples have been taken for later analysis of nutrients, chlorophyll structure (HPLC), POC, and nitrogen isotope analysis. The sampling and measurements where performed against highest standards defined in the GO-SHIP cruise recommendations (http://www.go-ship.org/). An Underwater Vision Profiler (UVP) was mounted on the CTD for full depth particle photography. Underway measurements included hull mounted ADCPs (75kHz and 38kHz) and high resolution (11nm) XBT probes. The data will be analysed for multiple purposes including calculation of the meridional volume, heat, and freshwater transport across the SAMBA/SAMOC line. The biogeochemical data will be compared to historical data acquired at neighbouring sections, e.g. along the WOCE/GO-SHIP A10 section (30°S) occupied by RV Meteor in 1993 as part of the WOCE program. The MSM60 expedition is a contribution to the EU H-2020 AtlantOS project