Clinical Performance Status and Technical Factors Affecting Outcomes from Percutaneous Transhepatic Biliary Interventions; A Multicentre, Prospective, Observational Cohort Study.

Funder: British Society of Interventional RadiologyPURPOSE: The purpose of this study was to evaluate the predictive value of a 'Modified Karnofsky Scoring System' on outcomes and provide real-world data regarding the UK practice of biliary interventions. MATERIALS AND METHODS: A prospective multi-centred cohort study was performed. The pre-procedure modified Karnofsky score, the incidence of sepsis, complications, biochemical improvement and mortality were recorded out to 30 days post procedure. RESULTS: A total of 292 patients (248 with malignant lesions) were suitable for inclusion in the study. The overall 7 and 30 day mortality was 3.1% and 16.1%, respectively. The 30 day sepsis rate was 10.3%. In the modified Karnofsky 'high risk' group the 7 day mortality was 9.7% versus 0% for the 'low risk' group (p = 0.002), whereas the 30 day mortality was 28.8% versus 13.3% (p = 0.003). The incidence of sepsis at 30 days was 19% in the high risk group versus 3.3% at the low risk group (p = 0.001) CONCLUSION: Percutaneous biliary interventions in the UK are safe and effective. Scoring systems such as the Karnofsky or the modified Karnofsky score hold promise in allowing us to identify high risk groups that will need more careful consideration and enhanced patient informed consent but further research with larger studies is warranted in order to identify their true impact on patient selection and outcomes post biliary interventions

The Role of Protein Kinase B and Mitochondrial Permeability Transition Pore in Ischaemic Preconditioning of Myocardium

Background: Protein kinase B (PKB) plays a critical role in cell survival, growth and proliferation. The investigation of its involvement has been limited by the lack of specific pharmacological agents. Similarly mitochondrial permeability transition pore (MPTP) plays a critical role in necrotic and apoptotic cell death. Opposed role of MPTP (transient versus sustained opening) in cardioprotection has been proposed. Therefore the primary aims of this thesis were to (i) to investigate the influence of PKB in the tolerance to ischaemia/reoxygenation (I/R), (ii) to define the relationship of PKB with the mitoKATP channel and with p38 MAPK in the signal transduction mechanism of cardioprotection by IP, (iii) to determine how two structurally different MPTP inhibitors (Cyclosporine A and Bongkrekic Acid) administered for varying time regimes influenced ischemia/reperfusion (I/R)-induced injury and (iv) to explore how pharmacologic MPTP opening at different time points during I/R modulated myocardial injury. Methods & Results: Myocardial slices from rat left ventricle and from the right atrial appendage of patients undergoing elective cardiac surgery were subjected to 90 min ischaemia/120 min reoxygenation at 37◦C. Tissue injury was assessed by creatine kinase (CK) released and determination of cell necrosis and apoptosis. Myocardial caspase 3 was also assessed. Muscles were randomized to receive various treatments. The results showed that blockade of PKB activity caused significant reduction of CK release and cell death, a benefit that was as potent as ischaemic preconditioning and could be reproduced by blockade of phosphatidylinositol 3-kinase (PI-3K) with wortmannin and LY 294002. The protection was time dependent with maximal benefit seen when PKB and PI-3K were inhibited before ischaemia or during both ischaemia and reoxygenation. PKB inhibition induced a similar degree of protection in the human and rat myocardium and, importantly, it reversed the unresponsiveness to protection of the diabetic myocardium. The status of MPTP can dramatically influence ischemic/reoxygenation-induced injury and protection of the rat left ventricular myocardium. Importantly, the status of the MPTP during first 10 min of reoxygenation is of critical importance with both opening and closing of the pore being as protective as ischemic preconditioning. Conclusion: Inhibition of PKB plays a critical role in protection of the mammalian myocardium and may represent a clinical target for the reduction of ischaemic injury. Both formation and inhibition of the MPTP can be exploited for therapeutic purposes and that there is a defined therapeutic window, with the first few minutes of reoxygenation being a crucial period to achieve cardioprotection

The role of protein kinase B and mitochondrial permeability transition pore in ischaemic preconditioning of myocardium

Background: Protein kinase B (PKB) plays a critical role in cell survival, growth and proliferation. The investigation of its involvement has been limited by the lack of specific pharmacological agents. Similarly mitochondrial permeability transition pore (MPTP) plays a critical role in necrotic and apoptotic cell death. Opposed role of MPTP (transient versus sustained opening) in cardioprotection has been proposed. Therefore the primary aims of this thesis were to (i) to investigate the influence of PKB in the tolerance to ischaemia/reoxygenation (I/R), (ii) to define the relationship of PKB with the mitoKATP channel and with p38 MAPK in the signal transduction mechanism of cardioprotection by IP, (iii) to determine how two structurally different MPTP inhibitors (Cyclosporine A and Bongkrekic Acid) administered for varying time regimes influenced ischemia/reperfusion (I/R)-induced injury and (iv) to explore how pharmacologic MPTP opening at different time points during I/R modulated myocardial injury. Methods & Results: Myocardial slices from rat left ventricle and from the right atrial appendage of patients undergoing elective cardiac surgery were subjected to 90 min ischaemia/120 min reoxygenation at 37°C. Tissue injury was assessed by creatine kinase (CK) released and determination of cell necrosis and apoptosis. Myocardial caspase 3 was also assessed. Muscles were randomized to receive various treatments. The results showed that blockade of PKB activity caused significant reduction of CK release and cell death, a benefit that was as potent as ischaemic preconditioning and could be reproduced by blockade of phosphatidylinositol 3-kinase (PI-3K) with wortmannin and LY 294002. The protection was time dependent with maximal benefit seen when PKB and PI-3K were inhibited before ischaemia or during both ischaemia and reoxygenation. PKB inhibition induced a similar degree of protection in the human and rat myocardium and, importantly, it reversed the unresponsiveness to protection of the diabetic myocardium. The status of MPTP can dramatically influence ischemic/reoxygenation-induced injury and protection of the rat left ventricular myocardium. Importantly, the status of the MPTP during first 10 min of reoxygenation is of critical importance with both opening and closing of the pore being as protective as ischemic preconditioning. Conclusion: Inhibition of PKB plays a critical role in protection of the mammalian myocardium and may represent a clinical target for the reduction of ischaemic injury. Both formation and inhibition of the MPTP can be exploited for therapeutic purposes and that there is a defined therapeutic window, with the first few minutes of reoxygenation being a crucial period to achieve cardioprotection.EThOS - Electronic Theses Online ServiceGBUnited Kingdo

OUTBACK catheter for treatment of superficial femoral and iliac artery chronic total occlusion: Experience from two centers

Purpose: The OUTBACK® catheter is a reentry device that enables reentry into a vessel lumen from the subintimal space during subintimal angioplasty. It is reserved for cases where reentry has not been possible using conventional wire and catheter techniques. We report a two-center experience in recanalization of the chronic total occlusions of the common iliac (CIA) and the superficial femoral artery (SFA) using the OUTBACK® catheter in cases where other techniques were unsuccessful. Material and Methods: All cases where recanalization was performed using the OUTBACK® reentry catheter between January 2010 to January 2015 were retrospectively identified and included in this study. 21 patients were identified. The indication for intervention in these cases included claudication and critical leg ischemia. In all cases, conventional recanalization could not be successfully achieved. Results: The OUTBACK® catheter was used to recanalize 10 SFA occlusion and 9 CIA occlusions. In 19 patients (90%), reentry into true arterial lumen was successfully achieved. 17 patients had their recanalization through the transfemoral approach whereas 2 patients had a transpopliteal artery approach. In 2 patients, reentry into the true lumen could not be achieved using the OUTBACK® catheter due to patient's intolerability for the procedure and severe atherosclerotic calcified plaques. There was 100% patency of the vessel intervened on Duplex ultrasound at 24 months of follow up. 16 patients (84%) remained asymptomatic and 2 patients (10.5%) reported worsening of their symptoms due to the development of new lesions within the arterial system. Conclusion: The OUTBACK® catheter is an effective and safe technique for reentry into the vessel lumen when conventional techniques fail

Deep immune phenotyping and single-cell transcriptomics allow identification of circulating TRM-like cells which correlate with liver-stage immunity and vaccine-induced protection from malaria

Protection from liver-stage malaria requires high numbers of CD8+ T cells to find and kill Plasmodium-infected cells. A new malaria vaccine strategy, prime-target vaccination, involves sequential viral-vectored vaccination by intramuscular and intravenous routes to target cellular immunity to the liver. Liver tissue-resident memory (TRM) CD8+ T cells have been shown to be necessary and sufficient for protection against rodent malaria by this vaccine regimen. Ultimately, to most faithfully assess immunotherapeutic responses by these local, specialised, hepatic T cells, periodic liver sampling is necessary, however this is not feasible at large scales in human trials. Here, as part of a phase I/II P. falciparum challenge study of prime-target vaccination, we performed deep immune phenotyping, single-cell RNA-sequencing and kinetics of hepatic fine needle aspirates and peripheral blood samples to study liver CD8+ TRM cells and circulating counterparts. We found that while these peripheral ‘TRM-like’ cells differed to TRM cells in terms of previously described characteristics, they are similar phenotypically and indistinguishable in terms of key T cell residency transcriptional signatures. By exploring the heterogeneity among liver CD8+ TRM cells at single cell resolution we found two main subpopulations that each share expression profiles with blood T cells. Lastly, our work points towards the potential for using TRM like cells as a correlate of protection by liver-stage malaria vaccines and, in particular, those adopting a prime-target approach. A simple and reproducible correlate of protection would be particularly valuable in trials of liver-stage malaria vaccines as they progress to phase III, large-scale testing in African infants. We provide a blueprint for understanding and monitoring liver TRM cells induced by a prime-target malaria vaccine approach

Deep immune phenotyping and single-cell transcriptomics allow identification of circulating TRM-like cells which correlate with liver-stage immunity and vaccine-induced protection from malaria

Protection from liver-stage malaria requires high numbers of CD8+ T cells to find and kill Plasmodium-infected cells. A new malaria vaccine strategy, prime-target vaccination, involves sequential viral-vectored vaccination by intramuscular and intravenous routes to target cellular immunity to the liver. Liver tissue-resident memory (TRM) CD8+ T cells have been shown to be necessary and sufficient for protection against rodent malaria by this vaccine regimen. Ultimately, to most faithfully assess immunotherapeutic responses by these local, specialised, hepatic T cells, periodic liver sampling is necessary, however this is not feasible at large scales in human trials. Here, as part of a phase I/II P. falciparum challenge study of prime-target vaccination, we performed deep immune phenotyping, single-cell RNA-sequencing and kinetics of hepatic fine needle aspirates and peripheral blood samples to study liver CD8+ TRM cells and circulating counterparts. We found that while these peripheral ‘TRM-like’ cells differed to TRM cells in terms of previously described characteristics, they are similar phenotypically and indistinguishable in terms of key T cell residency transcriptional signatures. By exploring the heterogeneity among liver CD8+ TRM cells at single cell resolution we found two main subpopulations that each share expression profiles with blood T cells. Lastly, our work points towards the potential for using TRM like cells as a correlate of protection by liver-stage malaria vaccines and, in particular, those adopting a prime-target approach. A simple and reproducible correlate of protection would be particularly valuable in trials of liver-stage malaria vaccines as they progress to phase III, large-scale testing in African infants. We provide a blueprint for understanding and monitoring liver TRM cells induced by a prime-target malaria vaccine approach