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Pulmonary arterial hypertension (PAH) is a common complication of systemic sclerosis (SSc) with high morbidity and mortality. There is potential benefit of early diagnosis and initiation of therapy, thus a strong rationale for active screening programs. Several screening algorithms have been suggested including the DETECT algorithm that was introduced in 2013. Regular risk assessment of PAH is necessary to reassure those at lower risk, to assess the efficacy of intervention and to identify those where escalation of therapy is required. Comprehensive prognostic evaluation and risk assessment is therefore recommended in the most recent ESC/ERS guidelines for PH. The REVEAL study group also proposed a renewed REVEAL 2.0 risk prediction calculation tool. Most validation work to date of these models has focused on the idiopathic pulmonary hypertension population or mixed populations including modest numbers with connective tissue disease related PAH. Microvesicles (MVs) are submicron vesicles that are released by different cell types into the circulation when they become activated or undergo apoptosis. The role of MVs as a potential biomarker in PH (for screening and risk assessment) has been previously proposed. The hypothesis of this work is that there remains a potential to improvise on the current screening and risk assessment models for PAH in SSc patients, and that there is a potential role of MVs in screening and risk assessment of PAH in patients with SSc. The first objective was to try to demonstrate the impact of the current screening program on the early detection of PAH in SSc patients. The second objective was to validate, examine the reproducibility and to compare the different current risk assessment models in patients with SSc-PAH. The final objective was to examine the role of MVs in screening and risk stratification of SSC PAH. We demonstrated that despite screening there has not been significant change in the demographics or the haemodynamic and risk profiles of patients diagnosed with SSc-PAH in the Royal Free pulmonary hypertension unit between 2006 and 2018. On comparison of different risk assessment tools driven from the ESC risk assessment and REVEAL models in the same group of patients, we found that all risk scores have clear discriminatory value at both baseline and on first follow up of SSc-PAH patients. The full REVEAL 2.0 risk score was the most accurate method in prognostication particularly at baseline as demonstrated by the highest AUC. Inclusion of non-modifiable factors does, however, appear to limit its value for serial risk assessments. The ESC based models not only provide a similar (albeit slightly less) discriminatory value, but also provide feedback on the impact of response to therapeutic intervention and may be the most useful in clinical practice. In the fourth chapter, we found that in the recruited 33 patients with SSc-PH and 26 patients without PH, MVs were not shown to be effective biomarkers for the early detection of SSc-PAH. Total MV and the characterised MV subpopulations from endothelial, smooth muscle or platelet origin failed to differentiate PH from non-PH in the studied population, irrespective of the site of sampling. The role of MVs in risk prediction was also limited in the studied population. However, the study maybe limited by the relatively more advanced SSc disease in comparison to the typical population in other screening studies. An interesting finding in this study was the significant gradient between the peripheral arterial and peripheral venous counts of some of the MVs (the total, PECAM1+/CD42- and ICAM1+/PECAM1-) in the SSc-PH patients. To our knowledge, this is the first report of such a finding.

This thesis describes a series of investigations into the mycological problems affecting the prothalli of Pteridiuni aquilinum Kuhn. This prothallus has been chosen because it consists of a plate of almost unspecialized cells, only one cell thick over a large part of its area. It can be grown easily under precisely controlled conditions and it appears to be an excellent "tool" for the study of certain host-parasite relationships. The investigation has, involved four, phases: (1) The establishment of satisfactory methods for bracken spore decontamination and the study of the germination and the growth prothalli in pure cultures Treatment with 0.1% mercuric chloride solution for one minute has been found to be a satisfactory method for decontamination. It has, been found that part of the falling, off of power of spore germination and prothallial growth in pure cultures is associated with ageing of the spores, The results show that a proportion of the prothalli are non autotrophic and that these require a factor or factors which can he .provided by some contaminant fungi, (2) A general survey of the effect of common pathogens on prothalii was carried out with two objectant (a) The isolation of pathogens producing disease in nature. Only two actively pathogenic species of fungi hare been found and a diagnosis and description are given of one of these as new species of Coniothyrium. (b) The study of the effect of common pathogens of higher plants on prothalli. The prothalli have been found to be susceptible to the attack of a wide range of rot, mould and damping off fungi but not by those causing wilt and certain other diseases. (3) Detailed study of the effect of Botrytis cinerea Pers. on prothalli, (a) preliminary study of the effect of temperature and media on growth and sporulation of Botrytis oinerea has been carried out.