Studies to date have failed to identify the most effective treatment regimes for patients with chronic genotype 3 HCV infection. There is controversy regarding the role of cirrhosis in modifying response and disagreement regarding the impact of ethnicity on treatment outcome. Given the importance of genotype 3 HCV in the global epidemic and the lack of high quality research into this genotype, the purpose of this work has been to address some of the deficiencies in our understanding of the optimal management of this strain of hepatitis C. Specifically we have examined the following hypotheses:- 1) Patients from the Indian sub-continent (South Asians) will respond differently to therapy with pegylated interferon and ribavirin when compared to Caucasians. 2) An analysis of viral and host factors underlying differences between treatment sensitive and treatment refractory cohorts will reveal new insights into the virology of Genotype 3 HCV infection. 3) Increasing the duration of therapy in ‘difficult to manage’ patients with Genotype 3 HCV will improve response rates. 4) Whether non-invasive methods of identifying liver fibrosis are valuable in identifying the stages of fibrosis in Genotype 3 HCV patients. Three different research methodologies were used to address these questions including a metaanalysis of factors associated with treatment failure in patients with genotype 3 HCV, virological and immunological studies on patients with genotype 3 HCV who had failed to respond to therapy and a clinical trial evaluating extended duration therapy in patients with Genotype 3 HCV infection and cirrhosis.

Background: This thesis is based on a randomised controlled trial comparing the effectiveness of intrauterine insemination (IUI) plus Controlled Ovarian Hyperstimulation (COH) versus in vitro fertilisation (IVF) as the first line treatment option for couples with unexplained subfertility. Subfertility of a couple is classed as unexplained when they fail to conceive after one year of regular unprotected intercourse and when all the standard investigations for ovulation, tubal patency and semen analysis have been found to be normal. It affects 30-40% of couples. The age-old methods of treating these couples have included the empirical use of clomiphene or gonadotrophins to correct any possible subtle defects in ovulation with or without IUI (to overcome any existing cervical barrier to natural conception) or IVF. However, the best treatment options for these couples have yet to be determined. The matter has been made even more controversial by the issue of NICE (National Institute for Health and Care Excellence) guidelines in the UK that suggest IUI be abandoned completely for these women in favour of IVF after 2 years of expectant management. A systematic review of the available literature comparing IUI + COH versus IVF for unexplained subfertility revealed limited numbers of available studies and high clinical and statistical heterogeneity among them. An online survey was also conducted among fertility specialists to establish the general consensus regarding management of such couples. The results revealed a lack of agreement among fertility specialists with regards to the first line treatment of couples with unexplained subfertility. The mixed 8 response to this survey demonstrated the ongoing dilemma among practitioners, much of which was due to the lack of robust evidence. A randomised controlled trial was then designed to examine the effectiveness of COH with gonadotrophins + IUI versus IVF as the first line approach to the treatment of unexplained subfertility (Figure 1). This was the first UK-based randomised controlled trial comparing these two first-line management options for unexplained subfertility.

Haemorrhage is a leading cause of trauma morbidity and mortality, with many deaths potentially preventable. Hyperfibrinolysis is a central characteristic of trauma-induced coagulopathy (TIC) which develops rapidly and is associated with poor outcomes. Tranexamic acid (TXA) improves survival in trauma haemorrhage but its uptake worldwide remains variable, in part because its effects on the coagulation system during trauma haemorrhage have not been described. Further uncertainty regarding patient selection for TXA therapy has emerged following the description of an early viscoelastic haemostatic assay (VHA) diagnosed hypofibrinolytic phenotype in whom TXA may potentiate thrombotic complications. The patient characteristics and mechanisms leading to this apparent hypofibrinolytic phenotype are poorly understood. Over 900 trauma patients prospectively recruited to a multicentre observational cohort study had blood drawn within 2-hours of injury for VHA and fibrinolysis plasma protein analysis. Patients were categorised according to VHA maximum lysis (ML) and D-dimer (DD) levels. Patients with MLLOW exhibited heterogeneity in clinical and injury characteristics and outcomes. Those who died were severely injured, with a high incidence of traumatic brain injury and a 7-fold higher D-dimer. Patients with MLLOW+DDHIGH had a hyperfibrinolytic biomarker profile, with the fibrinolytic mediator S100A10 identified as a potential driver of fibrinolysis, which can ex-vivo artificially reduce ML. Empiric TXA could benefit this occult hyperfibrinolytic phenotype. Over two subsequent observational studies, the effects of TXA on the coagulation system during trauma haemorrhage and the effect of TXA infusion and timing of treatment on thrombotic events were investigated. Early empiric TXA avoided VHA-hyperfibrinolysis and provided a degree of protection from TIC. Whilst univariate analysis suggested increased thromboses with later TXA treatment in patients receiving TXA bolus+infusion, neither the TXA infusion nor time to bolus were associated with thrombotic events after multivariate analysis. A single TXA bolus may provide a lower effective therapeutic dose with reduced complications.

Contents: Ferric Siderophore Transport via Outer Membrane Receptors of Escherichia coli: Structural Advancement and A Tribute to Dr. Dick van der Helm -- An 'Ironman' of Siderophore Biology -- The Tricky Ways Bacteria Cope with Iron Limitation -- Iron Transport Systems and Iron Homeostasis in Pseudomonas. Abstract: Iron is essential for the growth of most bacteria because it serves as a cofactor for vital enzymes and for the components of the electron transport chain. Moreover, Iron plays an important role in bacterial pathogenicity; in fact, the iron transport systems in bacteria works as target for designing novel antibiotics. Because iron is not soluble under aerobic conditions, bacteria have had to find ways to overcome iron deficiency. One of them is producing an iron-chelating small organic molecule called siderophore. Indeed, most bacteria and fungi produce structurally and chemically diverse siderophores which are transported back to the cytoplasm using complex energy dependent transport systems. / https://dc.etsu.edu/etsu_books/1036/thumbnail.jpg