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Previous analyses of fluids collected from chronic, nonhealing wounds found elevated levels of inflammatory cytokines, elevated levels of proteinases, and low levels of growth factor activity compared with fluids collected from acute, healing wounds. This led to the general hypothesis that chronic inflammation in acute wounds produces elevated levels of proteinases that destroy essential growth factors, receptors, and extracellular matrix proteins, which ultimately prevent wounds from healing. To test this hypothesis further, pro- and activated matrix metalloproteinases (MMP-2 and MMP-9), tissue inhibitors of metalloproteinases (TIMP-1 and TIMP-2), and the ratios of MMPs/TIMPs were assayed in fluids and biopsies collected from 56 patients with chronic pressure ulcers. Specimens included ulcers treated for 0, 10, and 36 days with conventional therapy or with exogenous cytokine therapies. Quantitative assay data were correlated with the amount of healing. The average MMP-9/TIMP-1 ratio in fluids from 56 ulcers decreased significantly as the chronic pressure ulcers healed. Furthermore, the average MMP-9/TIMP-1 ratio was significantly lower for fluids collected on day 0 from wounds that ultimately healed well (> or =85% reduction in initial wound volume) compared with wounds that healed poorly (< 50% wound volume reduction). These data show that the ratio of MMP-9/TIMP-1 levels is a predictor of healing in pressure ulcers and they provide additional support for the hypothesis that high levels of MMP activity and low levels of MMP inhibitor impair wound healing in chronic pressure ulcers. [ABSTRACT FROM AUTHOR]

Quantitatively mapping enzyme sequence-catalysis landscapes remains a critical challenge in understanding enzyme function, evolution, and design. Here, we expand an emerging microfluidic platform to measure catalytic constants- k cat and K M -for hundreds of diverse naturally occurring sequences and mutants of the model enzyme Adenylate Kinase (ADK). This enables us to dissect the sequence-catalysis landscape's topology, navigability, and mechanistic underpinnings, revealing distinct catalytic peaks organized by structural motifs. These results challenge long-standing hypotheses in enzyme adaptation, demonstrating that thermophilic enzymes are not slower than their mesophilic counterparts. Combining the rich representations of protein sequences provided by deep-learning models with our custom high-throughput kinetic data yields semi-supervised models that significantly outperform existing models at predicting catalytic parameters of naturally occurring ADK sequences. Our work demonstrates a promising strategy for dissecting sequence-catalysis landscapes across enzymatic evolution and building family-specific models capable of accurately predicting catalytic constants, opening new avenues for enzyme engineering and functional prediction.

Background and Aims: There is significant potential to streamline the clinical pathway for patients undergoing transcatheter aortic valve implantation (TAVI). The purpose of this study was to evaluate the effect of implementing BENCHMARK best practices on the efficiency and safety of TAVI in 28 sites in 7 European countries., Methods: This was a study of patients with severe symptomatic aortic stenosis (AS) undergoing TAVI with balloon-expandable valves before and after implementation of BENCHMARK best practices. Principal objectives were to reduce hospital length of stay (LoS) and duration of intensive care stay. Secondary objective was to document patient safety., Results: Between January 2020 and March 2023, 897 patients were documented prior to and 1491 patients after the implementation of BENCHMARK practices. Patient characteristics were consistent with a known older TAVI population and only minor differences. Mean LoS was reduced from 7.7 ± 7.0 to 5.8 ± 5.6 days (median 6 vs. 4 days; P < .001). Duration of intensive care was reduced from 1.8 to 1.3 days (median 1.1 vs. 0.9 days; P < .001). Adoption of peri-procedure best practices led to increased use of local anaesthesia (96.1% vs. 84.3%; P < .001) and decreased procedure (median 47 vs. 60 min; P < .001) and intervention times (85 vs. 95 min; P < .001). Thirty-day patient safety did not appear to be compromised with no differences in all-cause mortality (0.6% in both groups combined), stroke/transient ischaemic attack (1.4%), life-threatening bleeding (1.3%), stage 2/3 acute kidney injury (0.7%), and valve-related readmission (1.2%)., Conclusions: Broad implementation of BENCHMARK practices contributes to improving efficiency of TAVI pathway reducing LoS and costs without compromising patient safety., (© The Author(s) 2024. Published by Oxford University Press on behalf of the European Society of Cardiology.)

Importance: Transcatheter aortic valve implantation (TAVI) is a less invasive alternative to surgical aortic valve replacement and is the treatment of choice for patients at high operative risk. The role of TAVI in patients at lower risk is unclear., Objective: To determine whether TAVI is noninferior to surgery in patients at moderately increased operative risk., Design, Setting, and Participants: In this randomized clinical trial conducted at 34 UK centers, 913 patients aged 70 years or older with severe, symptomatic aortic stenosis and moderately increased operative risk due to age or comorbidity were enrolled between April 2014 and April 2018 and followed up through April 2019., Interventions: TAVI using any valve with a CE mark (indicating conformity of the valve with all legal and safety requirements for sale throughout the European Economic Area) and any access route (n = 458) or surgical aortic valve replacement (surgery; n = 455)., Main Outcomes and Measures: The primary outcome was all-cause mortality at 1 year. The primary hypothesis was that TAVI was noninferior to surgery, with a noninferiority margin of 5% for the upper limit of the 1-sided 97.5% CI for the absolute between-group difference in mortality. There were 36 secondary outcomes (30 reported herein), including duration of hospital stay, major bleeding events, vascular complications, conduction disturbance requiring pacemaker implantation, and aortic regurgitation., Results: Among 913 patients randomized (median age, 81 years [IQR, 78 to 84 years]; 424 [46%] were female; median Society of Thoracic Surgeons mortality risk score, 2.6% [IQR, 2.0% to 3.4%]), 912 (99.9%) completed follow-up and were included in the noninferiority analysis. At 1 year, there were 21 deaths (4.6%) in the TAVI group and 30 deaths (6.6%) in the surgery group, with an adjusted absolute risk difference of -2.0% (1-sided 97.5% CI, -∞ to 1.2%; P < .001 for noninferiority). Of 30 prespecified secondary outcomes reported herein, 24 showed no significant difference at 1 year. TAVI was associated with significantly shorter postprocedural hospitalization (median of 3 days [IQR, 2 to 5 days] vs 8 days [IQR, 6 to 13 days] in the surgery group). At 1 year, there were significantly fewer major bleeding events after TAVI compared with surgery (7.2% vs 20.2%, respectively; adjusted hazard ratio [HR], 0.33 [95% CI, 0.24 to 0.45]) but significantly more vascular complications (10.3% vs 2.4%; adjusted HR, 4.42 [95% CI, 2.54 to 7.71]), conduction disturbances requiring pacemaker implantation (14.2% vs 7.3%; adjusted HR, 2.05 [95% CI, 1.43 to 2.94]), and mild (38.3% vs 11.7%) or moderate (2.3% vs 0.6%) aortic regurgitation (adjusted odds ratio for mild, moderate, or severe [no instance of severe reported] aortic regurgitation combined vs none, 4.89 [95% CI, 3.08 to 7.75])., Conclusions and Relevance: Among patients aged 70 years or older with severe, symptomatic aortic stenosis and moderately increased operative risk, TAVI was noninferior to surgery with respect to all-cause mortality at 1 year., Trial Registration: isrctn.com Identifier: ISRCTN57819173.

Background: The use of transcatheter aortic valve implantation (TAVI) for treating aortic stenosis (AS) has increased exponentially in recent years. Despite the availability of clinical practice guidelines for the management of valvular heart disease, disparities in quality of care (QoC) for TAVI patients remain widespread across Europe. Tailored QoC measures will help to reduce resource utilization and improve patient outcomes without compromising patient safety. Using a clear set of QoC measures, the BENCHMARK registry aims to document the progress that can be achieved if such tailored QoC measures are implemented., Methods: The BENCHMARK registry (BENCHMARK) is a non-interventional, multicenter registry in patients with severe symptomatic AS undergoing TAVI with a 1- and 12-months follow-up. BENCHMARK will be conducted at 30 centers across Europe and will enroll a total of 2400 consecutive TAVI patients. Patients suffering from severe symptomatic AS who undergo TAVI with a balloon-expandable transcatheter aortic valve will be included. The registry will comprise four phases: (1) a retrospective baseline evaluation phase; (2) an education phase; (3) an implementation phase; and (4) a prospective effect documentation phase (prospective phase). The registry's primary objectives are to reduce the length of hospital stay and accelerate the post-procedural patient recovery pathway, but without compromising safety. The study started in April 2021 and has an estimated completion date of May 2023., Discussion: BENCHMARK will establish QoC measures to reduce resource utilization, intensive care unit bed occupancy, and overall length of hospitalization with uncompromised patient safety post-TAVI (ClinicalTrials.gov Identifier: NCT04579445)., (© 2021 The Authors. Clinical Cardiology published by Wiley Periodicals LLC.)

The proposed 2020 Core Curriculum for Percutaneous Cardiovascular Interventions aims to provide an updated European consensus that defines the level of experience and knowledge in the field of percutaneous cardiovascular intervention (PCI). It promotes homogenous education and training programmes among countries, and is the cornerstone of the new EAPCI certification, designed to support the recognition of competencies at the European level and the free movement of certified specialists in the European Community. It is based on a thorough review of the ESC guidelines and of the EAPCI textbook on percutaneous interventional cardiovascular medicine. The structure of the current core curriculum evolved from previous EAPCI core curricula and from the "2013 core curriculum of the general cardiologist" to follow the current ESC recommendations for core curricula. In most subject areas, there was a wide - if not unanimous - consensus among the task force members on the training required for the interventional cardiologist of the future. The document recommends that acquisition of competence in interventional cardiology requires at least two years of postgraduate training, in addition to four years devoted to cardiology. The first part of the curriculum covers general aspects of training and is followed by a comprehensive description of the specific components in 54 chapters. Each of the chapters includes statements of the objectives, and is further subdivided into the required knowledge, skills, behaviours, and attitudes.

Background Despite the availability of guidelines for the performance of transcatheter aortic valve implantation (TAVI), current treatment pathways vary between countries and institutions, which impact on the mean duration of postprocedure hospitalization. Methods and Results This was a prospective, multicenter registry of 502 patients to validate the appropriateness of discharge timing after transfemoral TAVI, using prespecified risk criteria from FAST-TAVI (Feasibility and Safety of Early Discharge After Transfemoral [TF] Transcatheter Aortic Valve Implantation), based on hospital events within 1-year after discharge. The end point-a composite of all-cause mortality, vascular access-related complications, permanent pacemaker implantation, stroke, cardiac rehospitalization, kidney failure, and major bleeding-was reached in 27.0% of patients (95% CI, 23.3-31.2) within 1 year after intervention; 7.5% (95% CI, 5.5-10.2) had in-hospital complications before discharge and 19.6% (95% CI, 16.3-23.4) within 1 year after discharge. Overall mortality within 1 year after discharge was 7.3% and rates of cardiac rehospitalization 13.5%, permanent pacemaker implantation 4.2%, any stroke 1.8%, vascular-access-related complications 0.7%, life-threatening bleeding 0.7%, and kidney failure 0.4%. Composite events within 1 year after discharge were observed in 18.8% and 24.3% of patients with low risk of complications/early (≤3 days) discharge and high risk and discharged late (>3 days) (concordant discharge), respectively. Event rate in patients with discordant discharge was 14.3% with low risk but discharged late and increased to 50.0% in patients with high risk but discharged in ≤3 days. Conclusions The FAST-TAVI risk assessment provides a tool for appropriate, risk-based discharge that was validated with the 1-year event rate after transfemoral TAVI. Registration URL: https://www.ClinicalTrials.gov; Unique identifier: NCT02404467.

Background: Surgical subclavian (SC) and direct aortic (DA) access are established alternatives to the default transfemoral route for transcatheter aortic valve implantation (TAVI). We sought to find differences in survival and procedure-related outcomes after SC- versus DA-TAVI., Methods: We performed an observational cohort analysis of cases prospectively uploaded to the UK TAVI registry. To ensure the most contemporaneous comparison, the analysis focused on SC and DA procedures performed from 2013 to 2015., Results: Between January 2013 and July 2015, 82 (37%) SC and 142 (63%) DA cases were performed that had validated 1-year life status. Multivariable regression analysis showed procedure duration was longer for SC cases (SC 193.5 ± 65.8 vs. DA 138.4 ± 57.7 min; p < .01) but length of hospital stay was shorter (SC 8.6 ± 9.5 vs. DA 11.9 ± 10.8 days; p = .03). Acute kidney injury was observed less frequently after SC cases (odds ratio [OR] 0.35, 95% confidence interval [CI 0.12-0.96]; p = .042) but vascular access site-related complications were more common (OR 9.75 [3.07-30.93]; p < .01). Procedure-related bleeding (OR 0.54 [0.24-1.25]; p = .15) and in-hospital stroke rate (SC 3.7% vs. DA 2.1%; p = .67) were similar. There were no significant differences in in-hospital (SC 2.4% vs. DA 4.9%; p = .49), 30-day (SC 2.4% vs. DA 4.2%; p = .71) or 1-year (SC 14.5% vs. DA 21.9%; p = .344) mortality., Conclusions: Surgical subclavian and direct aortic approaches can offer favourable outcomes in appropriate patients. Neither access modality conferred a survival advantage but there were significant differences in procedural metrics that might influence which approach is selected., Competing Interests: Declaration of competing interest Aung Myat, Olympia Papachristofi, Uday Trivedi, Adam de Belder, James Cockburn, Andreas Baumbach, Michael Mullen, Mark de Belder, Ian Cox, Iqbal S. Malik, Peter Ludman and Linda Sharples report no conflicts to declare pertaining to this manuscript. Adrian P. Banning reports institutional funding from Boston Scientific for a Fellowship. Daniel J. Blackman is a Consultant and Proctor for Medtronic and Boston Scientific. Philip MacCarthy declares consulting/proctorship contracts with Edwards Lifesciences and research support from Boston Scientific. Douglas Muir is a Proctor for Edwards Lifesciences and Abbott Vascular. Jan Kovac is a Proctor and Consultant for Edwards Lifesciences, Medtronic, Boston Scientific and Abbott. Stephen Brecker is a Clinical Advisor/Consultant for Medtronic, Boston Scientific and Abbott. Mark Turner is a proctor for Medtronic pulmonary valves currently, and has been a proctor for Edwards Lifesciences pulmonary valves in the past, but no longer holds a contract with them. He is also a Consultant and Advisory Board Member for St Jude (now Abbott), and has previously received educational meeting support from Edwards Lifesciences, Medtronic and Abbott. Saib Khogali is a Proctor for Boston Scientific and Medtronic. Simon Redwood declares Proctor and Lecture fees from Edwards Lifesciences. Bernard Prendergast declares unrestricted research grants and lecture fees from Edwards Lifesciences. David Hildick-Smith has advisory and proctoring contracts with Boston Scientific, Edwards and Medtronic., (Copyright © 2020. Published by Elsevier B.V.)

Aims: There are limited data on aspirin (ASA) desensitization for patients with coronary disease. We present our experience with a rapid nurse-led oral desensitization regimen in patients with aspirin sensitivity undergoing coronary angiography., Methods: This single-center retrospective observational study includes patients with a history of ASA sensitivity undergoing coronary angiography with intent to perform percutaneous coronary intervention (PCI)., Results: Between January 2012 and January 2017, 24 patients undergoing coronary angiography for stable coronary disease (7 cases) or acute coronary syndromes (non-ST-segment myocardial infarction [NSTEMI; 8 cases], STEMI [9 cases]) underwent aspirin desensitization having reported previous reactions to aspirin. At initial presentation, previous sensitivity reactions were reported as: mucocutaneous reactions in 17 patients (urticaria in 3 [13%], nonurticarial rash in 6 [25%], angio-oedema in 8 [33%]), respiratory sensitivity in 4 (17%), and systemic anaphylactoid reactions in 3 (13%). Seventeen (71%) patients underwent PCI. Desensitization was acutely successful in 22 (92%) patients and unsuccessful in 2 (8%) patients who both had a single short-lived episode of acute bronchospasm treated successfully with nebulized salbutamol. Fifteen successfully desensitized patients completed 12 months of aspirin; no patient had recurrent hypersensitivity reaction. Aspirin was stopped prior to 12 months in 7 patients (replaced by warfarin [1 case], no antiplatelet or single antiplatelet clinically indicated and clopidogrel chosen [4 cases], patient choice without evidence of recurrent hypersensitivity [1 case], and death due to cardiogenic shock following STEMI [1 case])., Conclusion: A rapid aspirin desensitization protocol is safe and effective across a broad spectrum of hypersensitivity reactions and clinical presentations.

Aims: Treatment pathway optimisation in TAVI should include timely patient discharge with a minimised risk for out-of-hospital adverse events. The aim of this study was to define a standardised set of risk criteria that allows a safe and timely discharge, to validate their appropriateness prospectively in different centres and multiple European countries, and to assess post-discharge outcomes., Methods and Results: We defined and validated the adequacy of a set of discharge criteria and its ability to predict timely and safe discharge properly after the intervention in a prospective, European, multicentre registry. A total of 502 unselected patients were enrolled at 10 sites in three countries. The primary endpoint, defined as a composite of all-cause mortality, vascular access-related complications, permanent pacemaker implantation, stroke, re-hospitalisation due to cardiac reasons, kidney failure and major bleeding at 30 days, was reached in 12.9% of patients (95% CI: 11.3-16.5). The overall 30-day mortality was 1.1% (95% CI: 0.2-2.0), and the rates of stroke/TIA 1.7% (95% CI: -0.6 to 4.0), PPI 7.3% (95% CI: 5.8-8.9), major vascular complications 1.9% (95% CI: 0.7-3.1), major/life-threatening bleeding 2.4% (95% CI: 1.0-3.8) and cardiac re-hospitalisation 3.7% (95% CI: 1.4-6.0). Patients appropriately discharged early had a significantly lower risk of the primary endpoint (7.0 vs. 26.4%; p<0.001) which was reflected in some of its relevant components: stroke (0.0 vs. 2.8%; p=0.015), PPI (4.3 vs. 15.9%; p<0.001), major vascular complications (0.3 vs. 4.7%; p=0.004) and major/life-threatening bleeding (0.3 vs. 6.5%; p<0.001)., Conclusions: We validated the appropriateness of a pre-specified set of risk criteria that allows a safe and timely discharge. The rate of 30-day complications did not reveal any risk increase with this strategy compared with the reported outcomes in major TAVI trials and registries. ClinicalTrials.gov Identifier: NCT02404467.

Background: Vascular complications from transfemoral (TF) secondary access during transcatheter aortic valve implantation (TAVI) are common. We compare our experience of transradial (TR) versus transfemoral secondary access during TAVI and describe techniques for performing iliofemoral arterial intervention from the transradial approach., Methods: All TAVI procedures with a single secondary access were included. Demographics, procedural details and 30-day outcomes were recorded. VARC-2 criteria were used for procedural complications. Procedures with TF primary access were stratified by the site of secondary arterial access., Results: Single secondary access was used in 199 cases, of which 20 were performed via non-TF access. Of the 179 TF primary access cases, 115 (64%) used TR secondary access and 64 (36%) used TF secondary access. In the TR cohort percutaneous vascular intervention was performed from the transradial approach in 19 cases (17%). Emergent TF secondary access was not required in any case. There were no differences in procedural time, radiation dose, contrast use, bleeding complications, stroke or mortality between the groups. There was one secondary access complication in the TF cohort and none in the TR cohort., Conclusions: Transradial (TR) secondary access during TAVI is safe and feasible and may reduce the secondary access site vascular complication rate. With appropriate equipment, most peripheral vascular complications can be managed entirely via TR access avoiding unplanned femoral arterial access. TR secondary access should be considered the default approach for non-TF TAVI cases and can be considered for all TF cases as long as dedicated equipment is available., (Copyright © 2018 Australian and New Zealand Society of Cardiac and Thoracic Surgeons (ANZSCTS) and the Cardiac Society of Australia and New Zealand (CSANZ). Published by Elsevier B.V. All rights reserved.)

Importance: Microvascular obstruction commonly affects patients with acute ST-segment elevation myocardial infarction (STEMI) and is associated with adverse outcomes., Objective: To determine whether a therapeutic strategy involving low-dose intracoronary fibrinolytic therapy with alteplase infused early after coronary reperfusion will reduce microvascular obstruction., Design, Setting, and Participants: Between March 17, 2016, and December 21, 2017, 440 patients presenting at 11 hospitals in the United Kingdom within 6 hours of STEMI due to a proximal-mid-vessel occlusion of a major coronary artery were randomized in a 1:1:1 dose-ranging trial design. Patient follow-up to 3 months was completed on April 12, 2018., Interventions: Participants were randomly assigned to treatment with placebo (n = 151), alteplase 10 mg (n = 144), or alteplase 20 mg (n = 145) by manual infusion over 5 to 10 minutes. The intervention was scheduled to occur early during the primary PCI procedure, after reperfusion of the infarct-related coronary artery and before stent implant., Main Outcomes and Measures: The primary outcome was the amount of microvascular obstruction (% left ventricular mass) demonstrated by contrast-enhanced cardiac magnetic resonance imaging (MRI) conducted from days 2 through 7 after enrollment. The primary comparison was the alteplase 20-mg group vs the placebo group; if not significant, the alteplase 10-mg group vs the placebo group was considered a secondary analysis., Results: Recruitment stopped on December 21, 2017, because conditional power for the primary outcome based on a prespecified analysis of the first 267 randomized participants was less than 30% in both treatment groups (futility criterion). Among the 440 patients randomized (mean age, 60.5 years; 15% women), the primary end point was achieved in 396 patients (90%), 17 (3.9%) withdrew, and all others were followed up to 3 months. In the primary analysis, the mean microvascular obstruction did not differ between the 20-mg alteplase and placebo groups (3.5% vs 2.3%; estimated difference, 1.16%; 95% CI, -0.08% to 2.41%; P = .32) nor in the analysis of 10-mg alteplase vs placebo groups (2.6% vs 2.3%; estimated difference, 0.29%; 95% CI, -0.76% to 1.35%; P = .74). Major adverse cardiac events (cardiac death, nonfatal MI, unplanned hospitalization for heart failure) occurred in 15 patients (10.1%) in the placebo group, 18 (12.9%) in the 10-mg alteplase group, and 12 (8.2%) in the 20-mg alteplase group., Conclusions and Relevance: Among patients with acute STEMI presenting within 6 hours of symptoms, adjunctive low-dose intracoronary alteplase given during the primary percutaneous intervention did not reduce microvascular obstruction. The study findings do not support this treatment., Trial Registration: ClinicalTrials.gov Identifier: NCT02257294.

Background: The PRAMI and CvLPRIT trials support preventive percutaneous coronary intervention (PCI) for multivessel coronary disease found during ST-segment elevation myocardial infarction (STEMI). We assess our real-world experience of the management of multivessel disease identified during primary PCI (PPCI) in a large UK regional centre., Patients and Methods: All STEMI patients who underwent culprit-only PPCI during the study period (August 2011 to August 2013) were retrospectively assessed for eligibility to each trial. The two resulting groups were designated as the 'observational' cohorts. Primary outcomes were then determined and compared with the culprit-only revascularisation cohorts from the respective published randomized controlled trials (RCTs)., Results: A total of 1143 consecutive cases were presented during the study period. Of these, 343 would have been suitable for inclusion to PRAMI and were included in the 'observational PRAMI' cohort; 196 patients were included in the 'observational CvLPRIT' cohort.The 'observational PRAMI' cohort experienced fewer primary outcome events (13.1 vs. 22.9%), cardiac deaths (0.6 vs. 4.3%) and nonfatal myocardial infarctions (3.5 vs. 8.7%) than the culprit-only PCI PRAMI cohort (n=231); there were significantly more diabetics (P=0.022) and anterior STEMI initial presentations in the culprit-only PCI PRAMI cohort. Primary outcomes were comparable to those of the preventive PCI PRAMI cohort.The 'observational CvLPRIT' cohort showed no significant difference in primary outcomes over 12 months (16.8 vs. 21.2%), but significantly lower all-cause mortality (2 vs. 6.9%) than the culprit-only PCI CvPLRIT cohort (n=146). The 30-day event rates were similar to the preventive PCI arm; the 12-month events were better than the nonpreventive, but not as good as the preventive RCT cohorts., Conclusion: Outcomes from culprit-only primary PCI for multivessel disease in patients selected by the RCT criteria from an all-comers population representing real-life experience are better than those published in the two main RCTs. The RCTs may have selected a high-risk population for study exaggerating the benefits of preventive PCI.

Background: There is an increasing trend towards shorter hospital stays after transcatheter aortic valve implantation (TAVI), in particular for patients undergoing the procedure via transfemoral (TF) access. Preliminary data suggest that there exists a population of patients that can be discharged safely very early after TF-TAVI. However, current evidence is limited to few retrospective studies, encompassing relatively small sample sizes., Methods: The Feasibility And Safety of early discharge after Transfemoral TAVI (FAST-TAVI) registry is a prospective observational registry that will be conducted at 10 sites across Italy, the Netherlands and the UK. Patients will be included if they have been scheduled to undergo TF-TAVI with the balloon-expandable SAPIEN 3 transcatheter heart valve (THV; Edwards Lifesciences, Irvine, CA). The primary endpoint is a composite of all-cause mortality, vascular-access-related complications, permanent pacemaker implantation, stroke, re-hospitalisation due to cardiac reasons, kidney failure and major bleeding, occurring during the first 30 days after hospital discharge. Patients will be stratified according to whether they were high or low risk for early discharge (≤3 days) (following pre-specified criteria), and according to whether or not they were discharged early. Secondary endpoints will include time-to-event (Kaplan-Meier) analysis for the primary outcome and its individual components, analysis of the relative costs of early and late discharge, and changes in short- and long-term quality of life. Multivariate logistic regression will be used to identify factors that indicate that a patient may be suitable for early discharge., Discussion: The data gathered in the FAST-TAVI registry should help to clarify the safety of early discharge after TF-TAVI and to identify patient and procedural characteristics that make early discharge from hospital a safe and cost-effective strategy., Trial Registration: ClinicalTrials.gov Identifier: NCT02404467 (registration first received March 23rd 2015).

Aim: This new laser facilitated 'inside-out' technique was used for transvenous pacemaker insertion in a pacemaker-dependent patient with bilateral subclavian occlusion and a failed epicardial system who is not suitable for a transfemoral approach., Method and Results: Procedure was undertaken under general anaesthesia with venous access obtained from right femoral vein and left axillary vein. 7F multipurpose catheter was used to enter proximal edge of the occluded segment of subclavian vein via femoral approach, which then supported stiff angioplasty wires and microcatheters to tunnel into the body of occlusion. When encountered with impenetrable resistance, 1.4 mm Excimer laser helped delivery of a Pilot 200 wire, which then progressed towards the distal edge of occlusion. Serial balloon dilatations allowed wire tracked into subintimal plane, advanced towards left clavicle using knuckle wire technique, which was then externalized with blunt dissection from infraclavicular pocket area. It was later changed to Amplatz superstiff wire exiting from both ends to form a rail, which ultimately allowed passage of pacing leads after serial balloon dilatation from clavicular end., Conclusion: Our hybrid 'inside-out' technique permitted transvenous pacemaker insertion without complication and this is, to our knowledge, the first case using laser in this context., (Published on behalf of the European Society of Cardiology. All rights reserved. © The Author 2016. For permissions please email: journals.permissions@oup.com.)

Objectives: The aim of this study was to describe the incidence and clinical impact of left atrial appendage thrombus (LAAT) in a population referred for transcatheter aortic valve replacement (TAVR) and to examine the role of cardiac computed tomography (CCT) in the diagnosis of LAAT., Background: Atrial fibrillation is common in patients undergoing TAVR. Embolization of LAAT is a potential mechanism of periprocedural stroke. The incidence and clinical impact of LAAT in a TAVR cohort have not been reported, and the optimal method for diagnosing LAAT remains unclear., Methods: Dual-phase cardiac computed tomographic scans were examined for the presence of LAAT in 198 consecutive patients referred for consideration of TAVR. Findings on CCT were compared with those on transesophageal echocardiography (TEE) when both modalities were available., Results: The incidence of LAAT on CCT was 11% in the overall cohort and 32% in patients with atrial fibrillation. Two patients (1.6%) had LAAT on CCT but were not known to have histories of atrial fibrillation. Ninety-eight patients also underwent TEE. Compared with TEE, CCT had sensitivity and specificity of 100% and 98%, respectively, and a negative predictive value of 100%. In the 124 patients who underwent TAVR, the in-hospital stroke rate was 4.8%. The risk for stroke appeared higher in patients with LAAT (20% [2 of 10]) compared with patients without LAAT (3.8% [4 of 105])., Conclusions: The incidence of LAAT in patients considered for TAVR is high, and LAAT embolization may represent a clinically relevant cause of periprocedural stroke. Dual-phase CCT is an accurate modality for the diagnosis of LAAT. It may obviate the need for pre-procedural TEE. The presence of LAAT should be examined in all patients undergoing TAVR and strategies developed for those patients in whom LAAT is identified., (Copyright © 2017 American College of Cardiology Foundation. Published by Elsevier Inc. All rights reserved.)

Objectives: To evaluate the feasibility and safety of direct transcatheter aortic valve implantation (TAVI) by the transfemoral approach without balloon pre-dilatation using the Edwards SapienXT valve., Background: TAVI is established in selected high-risk patients with severe aortic stenosis. Balloon aortic valvuloplasty (BAV) is recommended prior to valve implantation, but may contribute to procedural risk. It is unknown whether this is necessary for successful passage and deployment of the device., Methods: 81 patients (mean age 84 [95%CI:82-85.8], 62% male, median EuroScore 22.8% [95%CI:20.5-27]) undergoing transfemoral TAVI (35 by direct implantation [direct group]; 46 with balloon pre-dilatation [balloon group]) between 2010 and 2013 were analyzed for efficacy and safety endpoints., Results: Procedural success was 100%. Pre and post-procedural peak gradients in the direct group were 66mmHg (95%CI:59-72.8) and 14mmHg (95%CI:12-17.8)(P < 0.0001) compared to 76.5mmHg (95%CI:73.7-94.0) and 17mmHg (95%CI:16-19)(P < 0.0001) in the balloon group. Post-dilatation was performed in 4/35(11.4%) of the direct group and 3/46(6.5%) of the balloon group (P = 0.83). Post procedure moderate AR was present in 1/35(2.9%) in the direct group and none in the balloon group. In-hospital mortality (2.9% direct vs. 0% balloon group), stroke (2.9% vs. 4.4%), tamponade (2.9% vs. 2.2%), major vascular complications (2.9% vs. 8.7%) and new permanent pacing (2.2% vs. 0) were similar. Pacing time, inflations, radiation dose and contrast use were all significantly lower in the direct group., Conclusions: Direct implantation of the Edwards SapienXT valve during TAVI by the transfemoral route appears safe, efficacious and feasible in those without extreme calcification. © 2016 Wiley Periodicals, Inc., (© 2016 Wiley Periodicals, Inc.)

Neurofibromas, which are benign Schwann cell tumors, are the hallmark feature in the autosomal dominant condition neurofibromatosis 1 (NF1) and are associated with biallelic loss of NF1 gene function. There is a need for effective therapies for neurofibromas, particularly the larger, plexiform neurofibromas. Tissue culture is an important tool for research. However, it is difficult to derive enriched human Schwann cell cultures, and most enter replicative senescence after 6-10 passages, impeding cell-based research in NF1. Through exogenous expression of human telomerase reverse transcriptase and murine cyclin-dependent kinase (mCdk4), normal (NF1 wild-type), neurofibroma-derived Schwann cells heterozygous for NF1 mutation, and neurofibroma-derived Schwann cells homozygous for NF1 mutation were immortalized, including some matched samples from the same NF1 patient. Initial experiments employed retroviral vectors, while subsequent work utilized lentiviral vectors carrying these genes because of improved efficiency. Expression of both transgenes was required for immortalization. Molecular and immunohistochemical analysis indicated that these cell lines are of Schwann cell lineage and have a range of phenotypes, many of which are consistent with their primary cultures. This is the first report of immortalization and detailed characterization of multiple human NF1 normal nerve and neurofibroma-derived Schwann cell lines, which will be highly useful research tools to study NF1 and other Schwann tumor biology and conditions.

Background: Stent design and technological modifications to allow for anti-proliferative drug elution influence restenosis rates following percutaneous coronary intervention (PCI). We aimed to investigate whether peri-procedural administration of corticosteroids or the use of thinner strut cobalt alloy stents would reduce rates of binary angiographic restenosis (BAR) after PCI., Methods: This was a two centre, mixed single and double blinded, randomised controlled trial using a factorial design. We compared (a) the use of prednisolone to placebo, starting at least six hours pre-PCI and continued for 28days post-PCI, and (b) cobalt chromium (CoCr) to stainless steel (SS) alloy stents, in patients admitted for PCI. The primary end-point was BAR at six months., Results: 315 patients (359 lesions) were randomly assigned to either placebo (n=145) or prednisolone (n=170) and SS (n=160) or CoCr (n=160). The majority (58%) presented with an ACS, 11% had diabetes and 287 (91%) completed angiographic follow up. BAR occurred in 26 cases in the placebo group (19.7%) versus 31 cases in the prednisolone group (20.0%) respectively, p=1.00. For the comparison between SS and CoCr stents, BAR occurred in 32 patients (21.6%) versus 25 patients (18.0%) respectively, p=0.46., Conclusion: Our study showed that treating patients with a moderately high dose of prednisolone for 28days following PCI with BMS did not reduce the incidence of BAR. In addition, we showed no significant reduction in 6month restenosis rates with stents composed of CoCr alloy compared to SS (http://www.isrctn.com/ISRCTN05886349)., (Copyright © 2016 Elsevier Ireland Ltd. All rights reserved.)

Techniques to overcome challenging venous anatomy have become an increasingly important part of modern day cardiac device implantation. Complete superior vena cava (SVC) obstruction, however, is a rare and serious clinical entity, and consequently there is limited clinical experience in addressing this pathology in the context of transvenous pacemaker implantation. We present the case of a 48-year-old renal transplant patient with sick sinus syndrome and recurrent syncope, who had an upper SVC occlusion and a failed epicardial pacing system. The SVC was re-canalized and stented using techniques derived from chronic total occlusion coronary angioplasty, thus allowing successful implantation of a transvenous pacemaker lead. This case highlights the increased risk of developing central venous occlusion that exists in renal dialysis patients, and demonstrates the benefits of utilizing transferable interventional coronary and radiology techniques to overcome this pathology and facilitate pacemaker implantation. < Learning objective: Renal dialysis patients with implantable cardiac devices are at an increased risk of developing complications that include central venous obstruction. Advanced angioplasty techniques can be used to overcome complete venous obstruction and facilitate endovascular lead implantation.>.

Background: Strategies to reduce DTB (door-to-balloon) time have been previously described. However, there is no well-established data-monitoring system that can be used for prompt feedback. The aims of this study were to use statistical process control (SPC) methodology to measure current processes, to provide real-time feedback on the impact of a change in service delivery and to identify individual outliers for specific investigation., Methods: A prospective study was conducted in a tertiary centre in North England. Data were collected for 841 consecutive STEMI patients from the local district undergoing PPCI. The impact on median DTB time after changes in protocols were prospectively determined., Results: Median DTB times fell significantly as a result of changes in protocol. The upper control limit (UCL) decreased from 209 to 86 min and narrower control limits indicated improved performance. The main outliers included patients presenting to the Accident and Emergency department and patients who developed STEMI while being treated in non-cardiology wards for other reasons (18.3% of the study population)., Conclusions: SPC provides a statistically robust mechanism for assessing the effect of process redesign interventions, and in this context provides a clear visual representation of DTB times for individual patients. Identification of significant outliers allows investigation of any variation with a special cause. It allows a unit to identify when a system of service delivery, albeit stable, is inadequate and needs redesign and can monitor the impact of changes in protocol.

Objective: To examine the safety and efficacy of emergency transradial primary percutaneous coronary intervention for ST-elevation myocardial infarction., Design: Single-centre observational study with prospective data collection., Setting: A regional cardiac centre, United Kingdom., Patients: 1051 consecutive patients admitted with ST-elevation myocardial infarction, without cardiogenic shock, between November 2004 and October 2008., Interventions: Percutaneous coronary interventions by radial and femoral access, Main Outcome Measures: The primary outcome measures were procedural success, major vascular complication and failed initial access strategy. Secondary outcomes were in-hospital mortality and major adverse cardiac and cerebrovascular events, needle-to-balloon times, contrast volume used, radiation dose absorbed and time to discharge. Multiple regression analysis was used to adjust for potential differences between the groups., Results: 571 patients underwent radial access and 480 femoral. A variable preference for radial access was observed among the lead operators (between 21% and 90%). Procedural success was similar between the radial and femoral groups, but major vascular complications were more frequent at the site of femoral access (0% radial versus 1.9% femoral, p = 0.001). Failure of the initial access strategy was more frequent in the radial group (7.7% versus 0.6%, p<0.001). Adjustment for other procedural and clinical predictors did not alter these findings. Needle-to-balloon time, as a measure of procedural efficiency, was equal for radial and femoral groups., Conclusions: In the setting of acute ST-elevation myocardial infarction without cardiogenic shock, transradial primary angioplasty is safe, with comparable outcomes to a femoral approach and a lower risk of vascular complications.

Background: Workable risk models for patients undergoing percutaneous coronary intervention (PCI) are needed urgently., Objective: To validate two proposed risk adjustment models (Mayo Clinic Risk Score (MC), USA and North West Quality Improvement Programme (NWQIP), UK models) for in-hospital PCI complications on an independent dataset of relatively high risk patients undergoing PCI., Setting: Tertiary centre in northern England., Methods: Between September 2002 and August 2006, 5034 consecutive PCI procedures (validation set) were performed on a patient group characterised by a high incidence of acute myocardial infarction (MI; 16.1%) and cardiogenic shock (1.7%). Two external models-the NWQIP model and the MC model-were externally validated., Main Outcome Measure: Major adverse cardiovascular and cerebrovascular events: in-hospital mortality, Q-wave MI, emergency coronary artery bypass grafting and cerebrovascular accidents., Results: An overall in-hospital complication rate of 2% was observed. Multivariate regression analysis identified risk factors for in-hospital complications that were similar to the risk factors identified by the two external models. When fitted to the dataset, both external models had an area under the receiver operating characteristic curve >or=0.85 (c index (95% CI), NWQIP 0.86 (0.82 to 0.9); MC 0.87(0.84 to 0.9)), indicating overall excellent model discrimination and calibration (Hosmer-Lemeshow test, p>0.05). The NWQIP model was accurate in predicting in-hospital complications in different patient subgroups., Conclusions: Both models were externally validated. Both predictive models yield comparable results that provide excellent model discrimination and calibration when applied to patient groups in a different geographic population other than that in which the original model was developed.

Objective: To use funnel plots and cumulative funnel plots to compare in-hospital outcome data for operators undertaking percutaneous coronary interventions with predicted results derived from a validated risk score to allow for early detection of variation in performance., Design: Analysis of prospectively collected data., Setting: Tertiary centre NHS hospital in the north east of England., Participants: Five cardiologists carrying out percutaneous coronary interventions between January 2003 and December 2006., Main Outcome Measures: In-hospital major adverse cardiovascular and cerebrovascular events (in-hospital death, Q wave myocardial infarction, emergency coronary artery bypass graft surgery, and cerebrovascular accident) analysed against the logistic north west quality improvement programme predicted risk, for each operator. Results are displayed as funnel plots summarising overall performance for each operator and cumulative funnel plots for an individual operator's performance on a case series basis., Results: The funnel plots for 5198 patients undergoing percutaneous coronary interventions showed an average observed rate for major adverse cardiovascular and cerebrovascular events of 1.96% overall. This was below the predicted risk of 2.06% by the logistic north west quality improvement programme risk score. Rates of in-hospital major adverse cardiovascular and cerebrovascular events for all operators were within the 3sigma upper control limit of 2.75% and 2sigma upper warning limit of 2.49%., Conclusion: The overall in-hospital major adverse cardiovascular and cerebrovascular events rates were under the predicted event rate. In-hospital rates after percutaneous coronary intervention procedure can be monitored successfully using funnel and cumulative funnel plots with 3sigma control limits to display and publish each operator's outcomes. The upper warning limit (2sigma control limit) could be used for internal monitoring. The main advantage of these charts is their transparency, as they show observed and predicted events separately. By this approach individual operators can monitor their own performance, using the predicted risk for their patients but in a way that is compatible with benchmarking to colleagues, encapsulated by the funnel plot. This methodology is applicable regardless of variations in individual operator case volume and case mix.

Background: Rescue angioplasty (rPCI) for failed fibrinolysis is associated with a low mortality if successful, but a high mortality if it fails. The latter may reflect a high-risk group or harm in some patients. Predictors of success or failure of rPCI may aid selection of patients to be treated., Methods: Unselected patients referred for rPCI from March 1994 to March 2005 were studied to determine the predictors of a failed procedure and 1-year mortality., Results: Of 440 patients undergoing emergency coronary angiography for failed fibrinolysis (1-year mortality 18%), 101 had thrombolysis in myocardial infarction flow grade (TFG) 3 in the infarct-related vessel. rPCI was attempted in 318 of 339 patients with 75 years, shock, and final TFG < 3 were independent predictors of 1-year mortality., Conclusions: Cardiogenic shock is an independent predictor of a failed rPCI. Age group >75 years and shock were the only independent clinical predictors of 1-year mortality. These clinical variables may help in selecting patients for either a strategy of rescue angioplasty after failed fibrinolysis, or in selecting specific patients who might do better with a policy of primary angioplasty., (Copyright 2008 Wiley-Liss, Inc.)

We present the case of a 65-year-old man who had undergone coronary artery bypass surgery 12 years previously. He presented with recurrent cardiac chest pain. Repeat coronary angiography showed anastomosis of the left internal mammary artery to the anterior cardiac vein. There was no evidence of a fistula formation. In conclusion, incorrect anastomosis of conduits is rare in cardiac surgery but should be considered, especially in the presence of symptoms or sign of fistula formation.

Background: Trials of rescue angioplasty (rPCI) following failed fibrinolysis have excluded patients with cardiogenic shock and the benefit of rPCI in this setting is unknown. We compared the clinical, angiographic characteristics, 30-day and 1-year outcomes of cardiogenic shock patients undergoing rPCI with those undergoing primary percutaneous coronary intervention (PPCI)., Methods: Of the 171 patients undergoing PCI for cardiogenic shock between 1994 and 2005 at our institution, the indication was for PPCI in 65 and rPCI in 59 patients. Clinical, procedural, 30- day and 1-year mortality data were compared., Results: There were no differences between the cohorts with regard to clinical and pre-PCI angiographic variables, except that patients who underwent rPCI were more likely to be interhospital transfers (64% vs. 43%; p = 0.02) and had a longer door-to-balloon time (median 298 [IQR 395 to 180] minutes in the rPCI group vs. 131 [IQR 215 to 90] minutes in the PPCI group; p <0.01). Glycoprotein IIb/IIIa inhibitors were used less often (20% vs. 42%; p = 0.01), but use of stents was similar in both groups. Patients undergoing rPCI had a lower rate of final TIMI 3 flow grade (56% vs. 74%; p = 0.04) and a higher 1-year mortality (71% vs. 49%; p = 0.01). In the patients with final TIMI flow 3, 1-year mortality was higher in the rPCI group (61% vs. 37%; p = 0.04). In patients with successful procedures (survived procedure, no emergency CABG, TIMI 3 flow), 1-year mortality was higher in the rPCI group (59% vs. 33%; p = 0.02). One-year mortality was 85% in both groups if the procedure was unsuccessful. One-year mortality in patients >70 years old with cardiogenic shock undergoing rPCI was 100% (n = 15) and 70% (n = 14) with PPCI. Rescue angioplasty, anterior myocardial infarction, multivessel disease and postprocedure TIMI flow grade <3 were found to be independent predictors of mortality at 30 days., Conclusions: In the setting of cardiogenic shock, rPCI patients were treated later than those undergoing PPCI. They had a lower final TIMI 3 flow and higher 1-year mortality. Even patients with a successful rPCI procedure had a higher 1-year mortality than those with a successful PPCI. Rescue angioplasty in the setting of cardiogenic shock was found be an independent predictor of mortality. Rescue angioplasty in elderly patients in cardiogenic shock (>75 years) may be a futile treatment. Efforts should be made to improve reperfusion and survival in these patients, possibly by either adopting PPCI for all patients presenting with ST-elevation acute myocardial infarction or, if this is not logistically possible, adopting PPCI for selected high-risk patients or early referral for rPCI in high-risk groups receiving fibrinolysis.

5-Hydroxytryptamine (5-HT; serotonin) has been implicated in the perception of exercise-induced fatigue. Sumatriptan is a selective 5-HT(1B/D) receptor agonist which does not cross the blood-brain barrier. The aim of the present study was to determine the effect of sumatriptan on exercise capacity. Ten healthy male subjects (mean age 28.4+/-10.8 years) performed a maximal treadmill exercise test according to the Bruce protocol with expired gas analysis on two occasions. Either 6 mg of sumatriptan or placebo was administered subcutaneously in a randomized, double-blind, placebo-controlled, cross-over design. Exercise time was greater after placebo compared with sumatriptan [914 and 879 s respectively; 95% confidence interval (CI) of difference 12.1 s, 59.1 s; P = 0.008]. There was no significant effect on peak oxygen consumption (placebo, 50.6+/-6.3 ml.min(-1).kg(-1); sumatriptan, 51.7+/-7.6 ml.min(-1).kg(-1)). Sumatriptan administration resulted in decreases in both heart rate (sumatriptan, 188+/-14 beats/min, placebo, 196+/-12 beats/min; 95% CI of difference 12.6, 2.6; P = 0.008) and respiratory exchange ratio (sumatriptan, 1.23+/-0.06; placebo, 1.26+/-0.07; 95% CI of difference 0.05, 0.01; P = 0.01) at peak exercise. There were no significant differences in blood pressure, heart rate or submaximal oxygen consumption between sumatriptan and placebo treatments at any stage of exercise. Thus sumatriptan reduces maximal exercise capacity in normal males. The failure to demonstrate any haemodynamic or cardiorespiratory effect suggests that sumatriptan enhances perception of fatigue by a peripheral mechanism affecting 5-HT modulation.

Background: We evaluated the prevalence of left ventricular hypertrophy in elite footballers compared with sedentary controls. A total of 141 elite male professional footballers and 32 healthy sedentary controls were studied. Echocardiographic and demographic variables were compared between groups by unpaired t-test., Results: The prevalence of left ventricular hypertrophy with maximal wall thickness values out with the normal range (>12 mm) was noted. Footballers were significantly younger than controls (20.9 vs. 24.3 years, P<0.005: 95% CI (-5.2, -1.73)) but there were no significant differences in height, weight or body surface area between the groups. Each of inter-ventricular septum (10.4 vs. 9.1 mm, P<0.0001; 95% CI (0.88, 1.72)), posterior wall (9.2 vs. 8.5 mm, P<0.01; 95% CI (0.22, 1.21)), left ventricular cavity (systolic and diastolic) (34.5 vs. 28.4 mm, P<0.0001; 95% CI (4.31, 7.76) in systole; 50.1 vs. 48.2 mm, P<0.05; 95% CI (0.15, 3.74) in diastole), aortic root size (29.1 vs. 27.8 mm, P<0.05; 95% CI (0.03,2.49)) and left ventricular mass index (112 vs. 89 g/m2, P<0.0001; 95% CI (14.4, 32.1)) were significantly greater in footballers than in controls. Absolute left ventricular wall thickness >12 mm was present in 17 footballers (12%) (range 13-15 mm) and in no controls., Conclusions: Elite professional footballers have increased cardiac dimensions compared with healthy controls. The prevalence of absolute wall thicknesses out with the normal range is relatively high.

A randomized prospective trial was undertaken to compare the hemodynamic performance and left ventricular regression after aortic valve replacement with the Toronto SPV stentless bioprosthesis and the Carpentier Edwards SAV (CE) bioprosthesis. Forty patients were randomized after the annular and sinotubular diameters had been measured. Early hemodynamic measurements were made with a thermodilution cardiac output catheter, and echocardiography was used thereafter. Left ventricular mass was assessed using magnetic resonance imaging (MRI) at 1 week, 6 months, and 32 months. The mean annular size was 25.3+/-2.2 mm (CE) and 25.5+/-1.5 mm (Toronto), although it was possible to implant valves with a mean diameter 3 mm larger in the stentless group (26.0+/-1.7 mm cf. 23.0+/-1.7 mm). Hemodynamic performance in the first 24 hours showed no significant difference between the groups, but there was a trend for shorter ventilation time and shorter stays in the intensive therapy unit in the stentless group. Echocardiography showed superior transvalvular gradients in the stentless group at 1 week (mean 5.5+/-3.1 mm Hg cf. 8.9+/-2.5 mm Hg), and this difference was maintained at a mean follow-up time of 32 months (3.5+/-0.6 mm Hg cf. 6.3+/-0.6 mm Hg). Similar regression of left ventricular mass was seen in both groups at 6 months, but at 32 months, measurement in diastole showed a reduction of 38% (P<.01) in the stentless group compared with 20% (P = ns) in the stented group, and measurements in systole showed a 23% (P<.01) and 13% (P = ns) reduction, respectively. This study confirms that a larger stentless valve can be implanted into a given size of aortic annulus with superior residual aortic valve gradients. These lower gradients seem to result in improved long-term regression of left ventricular mass as measured by MRI.

Objective: To investigate the systemic, pulmonary, and coronary artery effects of eletriptan, a new 5HT1B/1D-agonist in patients undergoing cardiac catheterization., Methods: Ten patients (two men and eight women) without significant obstructive coronary artery disease were administered 3.33 microg/kg/min intravenous eletriptan after they were given a placebo infusion of 0.9% saline solution. Serial measurements of right heart and systemic pressures were taken at 5-minute intervals during placebo infusion, eletriptan infusion, and a 30-minute postinfusion period. Cardiac output by the thermodilution technique and coronary angiography were performed every 15 minutes. Quantitative coronary angiography was carried out to measure coronary artery dimensions., Results: A small but statistically significant increase in occluded wedge pressure (7.4 versus 8.8 mm Hg; 95% confidence interval [CI], 0.74, 2.51; P < .01), right atrial pressure (5.3 versus 6.1 mm Hg; 95% CI, 0.0, 1.4; P < .05), and mean pulmonary artery pressure (13.2 versus 14.6 mm Hg; 95% CI, 0.0, 2.7; P = .05) was observed during the eletriptan infusion compared with placebo. A statistically significant increase in systemic vascular resistance (1256 versus 1519 dyne/sec/cm(-5); 95% CI, 126, 398; P < .01) and pulmonary vascular resistance (76.4 versus 100.8 dyne/sec/cm(-5); 95% CI, 1.9, 46.9; P < .05) was observed in the period after drug infusion. No overall effect was observed on the coronary arteries, although a segmental right coronary artery constriction developed in one patient, possibly as a result of catheter-induced spasm., Conclusions: Eletriptan, a 5HT1B/1D-agonist effective in migraine, causes no significant coronary artery constriction in patients without significant obstructive coronary artery disease. This finding may reflect a relative selectivity for the 5HT1D-receptor subtype.

Aims: To investigate the effects of an intravenous infusion of BMS-180048, a novel 5HT1-like agonist, on the systemic, pulmonary and coronary circulations in patients undergoing diagnostic cardiac catheterisation., Methods: Ten patients (mean age 55 years (range 41-65)) were studied during diagnostic cardiac catheterisation. The haemodynamic response to an intravenous (i.v.) infusion for 30 min of BMS-180048 (0.56 mg kg(-1) h(-1) for 10 min and 0.39 mg kg(-1) h(-1) for 20 min) was assessed via a 7F Swan Ganz catheter and thermodilution cardiac output system. Quantitative coronary angiography was performed at 10 min intervals., Results: BMS-180048 caused a significant increase in systemic arterial systolic blood pressure (rise of 32.5 mmHg, 95% CI 24,44.5) P=0.009), pulmonary artery systolic (12.2 mmHg, 95% CI 6.8,18.5; P=0.009) and diastolic pressures (8.5 mmHg, 95% CI 5.0,13.8; P=0.009), right atrial pressure (4 mmHg, 95% CI 1.5,5.2; P=0.013) and pulmonary capillary wedge pressure (9.5 mmHg 95% CI 5.2,14.0; P=0.09). There was no significant change in cardiac output (0.1 l min(-1), 95% CI -0.17,0.57, P>0.05). Mean coronary artery diameter in the proximal coronary segments decreased by 0.73 mm (95% CI -1.22,-0.15; P=0.03) at 35 min. The corresponding reduction in middle segments was 0.26 mm (95% CI -0.395,-0.08; P=0.02). There was a non-significant trend to constriction in the most distal segments of 0.28 mm (95% CI -0.68,0.015); P=0.06). One patient experienced chest pain with ECG changes suggestive of ischaemia., Conclusions: BMS-180048 displayed a cardiovascular profile similar to that previously reported for sumatriptan. These changes appear to reflect a class effect of these agents.

Tumor development and progression in the nervous system are poorly understood. Consequently, even though there seems to be little possibility of major advances in existing clinical modalities used to treat malignant brain tumors, no targeted molecular therapies have risen to take their place. The variability and plasticity of brain neoplasms make them an illusive target for study and therapeutic intervention. Further complicated by infiltration of vital nervous tissue, clinical studies have serious practical limitations and the ability to assess tumor progression in vivo is still a developing technology. Evaluation of potential new therapies for brain tumors is heavily dependent on the development of more informative and cognate experimental models. To develop and validate new models, it is particularly important to integrate clinical, pathological, and cell biological characterizations of malignant brain tumors. This discussion provides an overview of developments in tumor cell culture and the impact of animal models on brain tumor research. Studies of malignant glial neoplasms associated with a dismal prognosis in patients receive particular attention.

Scanty irregular opacities are not uncommonly observed on the chest roentgenogram in the absence of interstitial fibrosis of the lungs. In such circumstances the irregular opacities, when present, tend to be relatively scanty and seldom, if ever, exceed an ILO category of 1/1. They are found in association with cigarette smoking, especially when emphysema is also present. The development of irregular opacities is also related to exposure to various mineral and other dusts, and although their prevalence increases with cumulative dust exposure, in general the type of dust, whether fibrogenic or relatively inert, seems to be of little moment. The presence of irregular opacities remains a troublesome confounding factor in epidemiologic studies of both dust-exposed and nonexposed populations. The morbid anatomic changes that occur in the lungs of nondust-exposed workers and which are responsible for the development of irregular opacities in the chest roentgenogram remain unknown.

1. In a retrospective study, we stratified 79 patients with paracetamol hepatotoxicity into two groups according to weekly alcohol consumption below (n = 49) or above (n = 30) Royal College of Physicians' guidelines of 21 units week-1 for males and 14 for females. 2. Survival was lower (33%) and serum creatinine on admission higher (median 207 mumol) in patients whose alcohol consumption was above recommended guidelines than in those whose drank less than this (65.9% and 138 mumol, P less than 0.01 and P = 0.027, respectively). An arterial blood pH less than 7.30 on admission was also more common in those patients with a higher alcohol consumption (30% v 12.2%, P = 0.05). 3. In all patients whose alcohol consumption exceeded the guidelines, paracetamol overdose was fatal if associated with a serum creatinine greater than 300 mumol in conjunction with a prothrombin time over 100 s and grade 3 or 4 encephalopathy or a peak prothrombin time over 180 s. 4. Chronic alcohol intake above suggested limits is an adverse prognostic feature in cases of severe paracetamol overdose. This effect is partly related to increased nephrotoxicity.