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This thesis seeks to examine the circumstances of the London mercantile community in the crisis of the 1690's and to relate the contrasting experience of groups within it to the attack on the Last India company. This latter issue is taken as a convenient focus towards which all investigations of the mercantile community contained here converge - either directly or indirectly. The results throw light on the paradox of how the great institutions of the eighteenth-century city -namely the Bank of England and the East India Company - were either founded, as in the former case, or much extended, as in the latter case, during a decade of crisis, Thus while focusing ultimately on the attack on the East India Company, no opportunity is missed to point out how crucial was the role played by the London mercantile community in enabling England to survive to the modest victory at Ryswick. In defining the circumstances of the London mercantile community during the 1690's, new statistical series have been constructed from fiscal sources, and from figures culled from port books, to present for the first time a quantitative measure of both the extent and the chronology of the crisis of the decade. To these figures are added the “Hallage' receipts of the London cloth markets which supply an invaluable indicator of activity in the country's largest single market. Continued in thesis ...

Despite needs for new therapies and improvements in existing approaches in cardiovascular, pulmonary, endocrine, and renal disease, investment in these areas is lagging relative to other specialties. This article summarizes a meeting of key stakeholders of U.S. Food and Drug Administration (FDA) officials, representatives from academia, national organizations, and patients and caregivers. The purpose was to identify and discuss high-priority issues, establish areas of common interest, and explore opportunities for collaboration. During the meeting (September 2016), the construct of a “multimorbidity continuum” emerged, in which chronic diseases are understood as their effects on the whole rather than individual organ systems. Cross-disciplinary priorities included: 1) the need to generate greater high-quality evidence at lower cost; 2) the imperative to develop and implement patient-centered approaches to clinical investigations; 3) the importance of trial participation in under-represented populations, particularly with comorbid conditions, and 4) the need for progress in tobacco regulation. Representatives from each therapeutic area reported on their consensus priorities, and FDA representatives discussed the agency’s role in facilitating broader approaches to therapeutic development and evaluation of disease as linked across organ systems rather than in isolation, and emphasized the importance of patient engagement, collaboration and communication across stakeholders.

Significant changes in the state of the Arctic ice cover are occurring. As the summertime extent of sea ice diminishes, the Arctic is increasingly characterized by first-year rather than multi-year ice. It is during the early stages of ice growth that most brine is injected into the oceans, contributing to the buoyancy flux that mediates the thermo-haline circulation. Current operational sea-ice components of climate models often treat brine rejection between sea ice and the ocean similarly to a thermodynamic segregation process, assigning a fixed salinity to the sea ice, typical of multi-year ice. However, brine rejection is a dynamical, buoyancy-driven process and the salinity of sea ice varies significantly during the first growth season. As a result, current operational models may over predict the early brine fluxes from newly formed sea ice, which may have consequences for coupled simulations of the polar oceans. Improvements both in computational power and our understanding of the processes involved have led to the emergence of a new class of sea-ice models that treat brine rejection dynamically and should enhance predictions of the buoyancy forcing of the oceans.

Simple goitre is highly prevalent in New Zealand, and there is considerable incidence of toxic goitre. The ætiology of simple goitre seems fairly well established, and an attempt is being made to apply the data from simple goitre to the problems of toxic goitre. Endemic goitre is of great antiquity among the Maoris, and has been described among Europeans for about fifty years. It occurs in both men and animals. At five years its incidence is similar in boys and girls, later it decreases in boys but increases greatly in girls. It is often hereditary, and many children are born goitrous. In children it is generally small, but may enlarge and cause pressure, myxœdema and toxicity. Its incidence varies greatly in different districts. The only cause found consistent with this variation in distribution is lack of iodine in the soil. An inverse ratio has been demonstrated between the iodine content of the soil and the incidence of goitre in school children in thirty-three districts. The iodine content of the soil is reflected in the food raised upon it. The daily iodine intake was estimated at 35 microgrammes in a non-goitrous, and at 20 microgrammes in a goitrous district. The amount of iodine involved is infinitesimal, and its intake can be ensured by the use of salt for ordinary consumption, which contains four parts per million of potassium iodide. Toxic goitre is also frequent: in this connexion, the influence of iodine on the thyroid has been investigated. If starved of iodine the thyroid adapts itself either by increasing its colloid or by a diffuse hyperplasia, both may occur in different parts of the same gland. Simple goitre is the response of the healthy thyroid to iodine deficiency, the responding areas may be diffuse or adenomatous, and degenerations may occur. Such goitres may be treated with iodine, in children re-adjustment to the increased intake is readily made, but in adults long accustomed to a low intake, excess often causes too great hormone production, with toxic symptoms, hence the minimal dose alone is permissible in iodized salt. Goitre stored with iodine at low pressures may become toxic under stress, and this may be precipitated by iodine. The prevalence of toxic goitre may be partly due to the prescription of iodides in therapeutic doses for common ailments. Diffuse colloid goitre may subside under physiological iodine, the adenomatous is more prone to toxic symptoms and may go on to secondary Graves' disease or to myxœdema. Diffuse hyperplasia is a possible manifestation of iodine deficiency as primary Graves' disease. Lugol's solution probably allows of a temporary storage in this condition. Iodine has certainly some bearing on the problems of toxic goitre.

Magmatism in subduction zones builds continental crust and causes most of Earth's subaerial volcanism. The production rate and composition of magmas are controlled by the thermal structure of subduction zones. A range of geochemical and heat flow evidence has recently converged to indicate that subduction zones are hotter at lithospheric depths beneath the arc than predicted by canonical thermomechanical models, which neglect magmatism. We show that this discrepancy can be resolved by consideration of the heat transported by magma. In our one- and two-dimensional numerical models and scaling analysis, magmatic transport of sensible and latent heat locally alters the thermal structure of canonical models by $\sim$300 K, increasing predicted surface heat flow and mid-lithospheric temperatures to observed values. We find the advection of sensible heat to be larger than the deposition of latent heat. Based on these results we conclude that thermal transport by magma migration affects the chemistry and the location of arc volcanoes.

Partial melting of asthenospheric mantle generates magma that supplies volcanic systems. The timescale of melt extraction from the mantle has been hotly debated. Microstructural measurements of permeability typically suggest relatively slow melt extraction (1 m/yr) whereas geochemical (Uranium-decay series) and geophysical observations suggest much faster melt extraction (100 m/yr). The deglaciation of Iceland triggered additional mantle melting and magma flux at the surface. The rapid response has been used to argue for relatively rapid melt extraction. However, this episode must, at least to some extent, be unrepresentative, because the rates of magma eruption at the surface increased about thirty-fold relative to the steady state. Our goal is to quantify this unrepresentativeness. We develop a one-dimensional, time-dependent and nonlinear (far from steady-state), model forced by the most recent, and best mapped, Icelandic deglaciation. We find that 30 m/yr is the best estimate of the steady-state maximum melt velocity. This is a factor of about 3 smaller than previously claimed, but still relatively fast. We translate these estimates to other mid-ocean ridges accounting for differences in passive and active upwelling and degree of melting. We find that fast melt extraction greater than about 10 m/yr prevails globally., Accepted for publication in Earth and Planetary Science Letters (2020). Total 17 pages and 5 figures (including Supplementary Material)

Evaluation of the success and impact of human papillomavirus (HPV) vaccine introduction \ud and collation of key lessons learnt in low and middle-income countries (LAMICs) is now \ud possible given the number of recent HPV vaccine pilots, or ‘demonstration projects’, and \ud national programmes. Results may be useful for countries that have not yet commenced \ud implementation of the HPV vaccine and may also be generalizable to future introductions of \ud other pre-adolescent and adolescent vaccines. \ud This PhD addresses four aspects of HPV vaccine introduction: 1) barriers to adherence to \ud multi-dose vaccine schedules, 2) the potential impact of the HPV vaccine on human \ud immunodeficiency virus (HIV) acquisition, 3) the potential impact of HPV vaccine introduction \ud on other health services, and 4) lessons learnt and recommendations for HPV vaccine \ud implementation in LAMICs. \ud A systematic review of the published literature on factors influencing multi-dose vaccine \ud adherence in adolescents was conducted. The paucity of published data from LAMICs \ud meant that no geographical restriction was set in the search terms. The majority of research \ud included in the synthesis originated in the United States of America (USA), where race, \ud insurance status and parental healthcare seeking behaviour were found to be predictors of \ud vaccine schedule completion. As vaccination programmes in older children become more \ud established in LAMICs, more research is needed on factors influencing adherence in these \ud settings. \ud The association between HPV infection and subsequent HIV acquisition was assessed in a \ud nested case-control study using stored cervical samples from previous study cohorts of \ud Tanzanian and Ugandan women. In contrast to previous observational studies that have \ud found an association between HPV infection and HIV acquisition in men and women, we \ud found no evidence of an association between HPV infection, clearance or persistence, and \ud subsequent HIV acquisition. This precluded the calculation of an estimate of the potential \ud population attributable fraction for the effect of HPV infection (and vaccination) on HIV \ud incidence. \ud Data from health facility register books and interviews with health workers in two regions of \ud Tanzania were analysed to examine the potential impact of HPV vaccination introduction \ud through a demonstration project in Northern Tanzania in 2014 on the provision of routine \ud primary health services. A controlled before-after analysis was carried out on count data of \ud consultations at facilities involved in HPV vaccine delivery in Kilimanjaro Region, and control \ud facilities in a neighbouring region. Interviews with health workers provided important \ud contextual information. There was no evidence that the number of consultations at the health \ud facilities fell during campaign weeks in intervention facilities compared to control facilities. \ud Utilisation of the health facilities was highly variable. Interviews indicated that the quality of \ud care provided at the facility during vaccination campaigns might be affected by staff \ud absence. \ud Lessons learnt from 37 LAMICs with at least one year of experience in HPV vaccine delivery \ud were collated from 41 published articles, 124 pieces of unpublished literature, and 27 key \ud informant interviews. Recommendations were formulated in 7 key themes: preparation, \ud communication, delivery, coverage achievements, sustainability, value of demonstration \ud projects and common pitfalls. Lessons were consistent across world regions and included \ud the importance of collaboration during planning between the ministries of health and \ud education, strategies to respond to rumours and challenges encountered during delivery. \ud Key findings were disseminated widely and stimulated on-going supplemental research. \ud There is now a large evidence base to support the rationale for HPV vaccine introduction \ud and its successful delivery in LAMICs, which currently suffer the heaviest burden of cervical \ud cancer disease in the world. To date, HPV vaccine delivery in low resource settings has \ud achieved high coverage and experienced fewer barriers than expected. It is clear that if \ud funding is available, LAMICs can effectively introduce the HPV vaccine nationally and \ud prevent a high burden of a major and serious disease in women.