Assessment of CD8+ T-cell mediated immunity in an influenza A(H3N2) human challenge model in Belgium: a single centre, randomised, double-blind phase 2 study.

BACKGROUND: Protection afforded by inactivated influenza vaccines can theoretically be improved by inducing T-cell responses to conserved internal influenza A antigens. We assessed whether, in an influenza controlled human infection challenge, susceptible individuals receiving a vaccine boosting T-cell responses would exhibit lower viral load and decreased symptoms compared with placebo recipients. METHODS: In this single centre, randomised, double-blind phase 2 study, healthy adult (aged 18-55 years) volunteers with microneutralisation titres of less than 20 to the influenza A(H3N2) challenge strain were enrolled at an SGS quarantine facility in Antwerp, Belgium. Participants were randomly assigned double-blind using a permuted-block list with a 3:2 allocation ratio to receive 0·5 mL intramuscular injections of modified vaccinia Ankara (MVA) expressing H3N2 nucleoprotein (NP) and matrix protein 1 (M1) at 1·5 × 108 plaque forming units (4·3 × 108 50% tissue culture infectious dose [TCID50]; MVA-NP+M1 group) or saline placebo (placebo group). At least 6 weeks later, participants were challenged intranasally with 0·5 mL of a 1 × 106 TCID50/mL dose of influenza A/Belgium/4217/2015 (H3N2). Nasal swabs were collected twice daily from day 2 until day 11 for viral PCR, and symptoms of influenza were recorded from day 2 until day 11. The primary outcome was to determine the efficacy of MVA-NP+M1 vaccine to reduce the degree of nasopharyngeal viral shedding as measured by the cumulative viral area under the curve using a log-transformed quantitative PCR. This study is registered with ClinicalTrials.gov, NCT03883113. FINDINGS: Between May 2 and Oct 24, 2019, 145 volunteers were enrolled and randomly assigned to the MVA-NP+M1 group (n=87) or the placebo group (n=58). Of these, 118 volunteers entered the challenge period (71 in the MVA-NP+M1 group and 47 in the placebo group) and 117 participants completed the study (71 in the MVA-NP+M1 group and 46 in the placebo group). 78 (54%) of the 145 volunteers were female and 67 (46%) were male. The primary outcome, overall viral load as determined by quantitative PCR, did not show a statistically significant difference between the MVA-NP+M1 (mean 649·7 [95% CI 552·7-746·7) and placebo groups (mean 726·1 [604·0-848·2]; p=0·17). All reported treatment emergent adverse events (TEAEs; 11 in the vaccination phase and 51 in the challenge phase) were grade 1 and 2, except for two grade 3 TEAEs in the placebo group in the challenge phase. A grade 4 second trimester fetal death, considered possibly related to the MVA-NP+M1 vaccination, and an acute psychosis reported in a placebo participant during the challenge phase were reported. INTERPRETATION: The use of an MVA vaccine to expand CD4+ or CD8+ T cells to conserved influenza A antigens in peripheral blood did not affect nasopharyngeal viral load in an influenza H3N2 challenge model in seronegative, healthy adults. FUNDING: Department of Health and Human Services; Administration for Strategic Preparedness and Response; Biomedical Advanced Research and Development Authority; and Barinthus Biotherapeutics.

Effects of a Transoceanic Rowing Challenge on Cardiorespiratory Function and Muscle Fitness.

Ultra-endurance sports and exercise events are becoming increasingly popular for older age groups. We aimed to evaluate changes in cardiac function and physical fitness in males aged 50-60 years who completed a 50-day transoceanic rowing challenge. This case account of four self-selected males included electro- and echo-cardiography (ECG, echo), cardiorespiratory and muscular fitness measures recorded nine months prior to and three weeks after a transatlantic team-rowing challenge. No clinically significant changes to myocardial function were found over the course of the study. The training and race created expected functional changes to left ventricular and atrial function; the former associated with training, the latter likely due to dehydration, both resolving towards baseline within three weeks post-event. From race-start to finish all rowers lost 8.4-15.6 kg of body mass. Absolute cardiorespiratory power and muscular strength were lower three weeks post-race compared to pre-race, but cardiorespiratory exercise economy improved in this same period. A structured program of moderate-vigorous aerobic endurance and muscular training for>6 months, followed by 50-days of transoceanic rowing in older males proved not to cause any observable acute or potential long-term risks to cardiovascular health. Pre-event screening, fitness testing, and appropriate training is recommended, especially in older participants where age itself is an increasingly significant risk factor.

Thirty-Day Unplanned Readmissions Following Elective and Acute Percutaneous Coronary Intervention.

BACKGROUND: Prior studies have reported a high rate of unplanned readmissions following acute percutaneous coronary intervention (PCI). Data outside the USA comparing 30-day unplanned readmissions following elective PCI to those who undergo acute PCI remain limited. METHODS: Patients who underwent a PCI procedure in Australia and New Zealand between 2010 and 2015 were included. We determined the rates, causes and predictors of 30-day unplanned readmissions, as well as rates of repeat revascularisation procedures, for patients who underwent an elective or acute PCI. Predictors of readmissions were identified using logistic regression. RESULTS: A total of 199,686 PCI encounters were included, of which 74,890 (37.5%) were elective and 124,796 (62.5%) were acute procedures. Overall, 10.6% of patients had at least one unplanned readmission within 30 days of discharge with lower rates following elective PCI (7.0%) compared to acute PCI (12.7%) (p<0.01). Non-specific chest pain was the commonest cause of readmission after elective and acute PCI, accounting for 20.7% and 21.5% of readmission diagnoses, respectively. Readmissions for acute myocardial infarction (13.0% vs 4.6%, p<0.01) and heart failure (6.5% vs 3.3%, p<0.01) were higher following acute PCI compared to elective PCI. Among readmitted patients, 16.7% had a coronary catheterisation, 12.2% had a PCI and 0.7% had coronary artery bypass surgery. Multivariable predictors of 30-day unplanned readmission included female sex and comorbidities such as heart failure, metastatic disease, chronic lung disease and renal failure (p<0.0001 for all). CONCLUSIONS: Unplanned readmissions following elective or acute PCI are high. Clinical and quality-control measures are required to prevent avoidable readmissions in both settings.

Automated segmentation of normal and diseased coronary arteries - The ASOCA challenge.

Cardiovascular disease is a major cause of death worldwide. Computed Tomography Coronary Angiography (CTCA) is a non-invasive method used to evaluate coronary artery disease, as well as evaluating and reconstructing heart and coronary vessel structures. Reconstructed models have a wide array of for educational, training and research applications such as the study of diseased and non-diseased coronary anatomy, machine learning based disease risk prediction and in-silico and in-vitro testing of medical devices. However, coronary arteries are difficult to image due to their small size, location, and movement, causing poor resolution and artefacts. Segmentation of coronary arteries has traditionally focused on semi-automatic methods where a human expert guides the algorithm and corrects errors, which severely limits large-scale applications and integration within clinical systems. International challenges aiming to overcome this barrier have focussed on specific tasks such as centreline extraction, stenosis quantification, and segmentation of specific artery segments only. Here we present the results of the first challenge to develop fully automatic segmentation methods of full coronary artery trees and establish the first large standardized dataset of normal and diseased arteries. This forms a new automated segmentation benchmark allowing the automated processing of CTCAs directly relevant for large-scale and personalized clinical applications.

Efficacy and safety of a universal influenza A vaccine (MVA-NP+M1) in adults when given after seasonal quadrivalent influenza vaccine immunisation (FLU009): a phase 2b, randomised, double-blind trial.

BACKGROUND: In animal, epidemiological, and human challenge studies, a pre-existing T-cell response to internal proteins of influenza A has been associated with improved virological and disease outcomes. The aim of this study was to assess whether inducing additional responses to conserved CD4 and CD8 T-cell antigens provides added benefit to standard influenza vaccination. METHODS: We designed a phase 2b, randomised, placebo-controlled, double-blind trial of a recombinant viral-vectored vaccine (modified vaccinia Ankara expressing virus nucleoprotein and matrix protein 1; MVA-NP+M1), which has been shown to induce both CD4 and CD8 T cells, at eight outpatient clinical trial sites in Australia over two consecutive influenza seasons. We recruited non-immunosuppressed adults (≥18 years) who had received the 2019 quadrivalent influenza vaccine (QIV) vaccine within 28 days before study enrolment and randomisation (day 0). Participants were randomly assigned (1:1) according to a computer-generated random sequence to receive one dose of 1·5 × 108 plaque-forming units of MVA-NP+M1 or saline (placebo) intramuscularly. Randomisation was stratified by age (<65 years or ≥65 years). The patients and trial assessors were masked to treatment assignment. During the subsequent influenza seasons, participants with symptoms related to respiratory illness or influenza-like illness were to attend the clinic within 72 h of symptom onset for two nasal swabs for influenza testing by quantitative RT-PCR. The primary endpoint was the incidence rate of laboratory-confirmed influenza in the intention-to-treat (ITT) population. Safety (solicited adverse events within 7 days and unsolicited adverse events within 28 days after study vaccination, and serious adverse events for the study duration) was assessed in all randomly assigned participants who received at least one vaccination (according to the treatment received). The trial is registered with ClinicalTrials.gov, NCT03880474. FINDINGS: Between April 2 and June 14, 2019, 2152 adults were randomly allocated and received MVA-NP+M1 (n=1077) or placebo (n=1075), comprising the efficacy (ITT) analysis set. Participants were followed up throughout the 2019 Australia influenza season (May 1 to Oct 15, 2019). 419 (19·5%) of 2152 participants were aged 65 years or older. The incidence of laboratory-confirmed influenza did not differ between the MVA-NP+M1 group (35 of 1077 participants; 3·25% [95% CI 2·31-4·44]) and the placebo group (23 of 1075; 2·14% [1·39-3·14]; Fisher's exact p=0·14). 23 severe solicited local injection site reactions were reported in 13 (0·6%) of 2152 participants, 22 of which were reported in the MVA-NP + M1 group (in 12 [1·1%] participants). 100 severe systemic events were reported in 45 (4·2%) MVA-NP + M1 recipients, and 20 were reported in 14 (1·3%) placebo recipients. Three unsolicited grade 3 events in three participants (two headache and one nausea, all in the MVA-NP+M1 group) were deemed vaccine related. 21 serious adverse events were reported in 18 (1·7%) of 1077 participants in the MVA-NP+M1 group and 25 serious adverse events were reported in 22 (2·0%) of 1075 participants in the placebo group; none were considered vaccine related. The trial was stopped after one season for futility on the recommendation of the data monitoring committee. INTERPRETATION: MVA-NP+M1 was well tolerated with no vaccine-associated serious adverse events. A vaccine designed to induce moderate T-cell responses to the cross-reactive internal proteins of influenza A did not lead to improved incidence when given within 28 days after standard QIV immunisation. A greater magnitude of T-cell response with a different vaccine or regimen, or localisation in the lungs via alternative delivery, such as intranasal or aerosol, might be successful and require further investigation. FUNDING: Vaccitech.

Accuracy of vascular tortuosity measures using computational modelling.

Severe coronary tortuosity has previously been linked to low shear stresses at the luminal surface, yet this relationship is not fully understood. Several previous studies considered different tortuosity metrics when exploring its impact of on the wall shear stress (WSS), which has likely contributed to the ambiguous findings in the literature. Here, we aim to analyze different tortuosity metrics to determine a benchmark for the highest correlating metric with low time-averaged WSS (TAWSS). Using Computed Tomography Coronary Angiogram (CTCA) data from 127 patients without coronary artery disease, we applied all previously used tortuosity metrics to the left main coronary artery bifurcation, and to its left anterior descending and left circumflex branches, before modelling their TAWSS using computational fluid dynamics (CFD). The tortuosity measures included tortuosity index, average absolute-curvature, root-mean-squared (RMS) curvature, and average squared-derivative-curvature. Each tortuosity measure was then correlated with the percentage of vessel area that showed a < 0.4 Pa TAWSS, a threshold associated with altered endothelial cell cytoarchitecture and potentially higher disease risk. Our results showed a stronger correlation between curvature-based versus non-curvature-based tortuosity measures and low TAWSS, with the average-absolute-curvature showing the highest coefficient of determination across all left main branches (p < 0.001), followed by the average-squared-derivative-curvature (p = 0.001), and RMS-curvature (p = 0.002). The tortuosity index, the most widely used measure in literature, showed no significant correlation to low TAWSS (p = 0.86). We thus recommend the use of average-absolute-curvature as a tortuosity measure for future studies.

Efficacy and Safety of a Modified Vaccinia Ankara-NP+M1 Vaccine Combined with QIV in People Aged 65 and Older: A Randomised Controlled Clinical Trial (INVICTUS).

BACKGROUND: Pre-existing T cell responses to influenza have been correlated with improved clinical outcomes in natural history and human challenge studies. We aimed to determine the efficacy, safety and immunogenicity of a T-cell directed vaccine in older people. METHODS: This was a multicentre, participant- and safety assessor-blinded, randomised, placebo-controlled trial of the co-administration of Modified Vaccinia Ankara encoding nucleoprotein and matrix protein 1 (MVA-NP+M1) and annual influenza vaccine in participants ≥ 65. The primary outcome was the number of days with moderate or severe influenza-like symptoms (ILS) during the influenza season. RESULTS: 846 of a planned 2030 participants were recruited in the UK prior to, and throughout, the 2017/18 flu season. There was no evidence of a difference in the reported rates of days of moderate or severe ILS during influenza-like illness episodes (unadjusted OR = 0.95, 95% CI: 0.54-1.69; adjusted OR = 0.91, 95% CI: 0.51-1.65). The trial was stopped after one season due to a change in the recommended annual flu vaccine, for which safety of the new combination had not been established. More participants in the MVA-NP+M1 group had transient moderate or severe pain, redness, and systemic responses in the first seven days. CONCLUSION: The MVA-NP+M1 vaccine is well tolerated in those aged 65 years and over. Larger trials would be needed to determine potential efficacy.

Vascular endothelial growth factor-A promoter polymorphisms, circulating VEGF-A and survival in acute coronary syndromes.

BACKGROUND: Development of a competent collateral circulation in established coronary artery disease is cardio-protective. The vascular endothelial growth factor (VEGF) system plays a key role in this process. We investigated the prognostic performance of circulating VEGF-A and three genetic variants in the VEGFA gene in a clinical coronary cohort. METHODS AND RESULTS: The Coronary Disease Cohort Study (CDCS) recruited 2,140 patients, with a diagnosis of acute coronary syndrome (ACS), after admission to Christchurch or Auckland City Hospitals between July 2002 and January 2009. We present data for 1927 patients from the cohort genotyped for three SNPs in the VEGF-A gene, rs699947 (C-2578A), rs2010963 (C405G) and rs3025039 (C936T). Plasma VEGF-A concentrations were assayed in a subgroup (n = 550) of CDCS patients (geometric mean 36.6 [34.7-38.5] pg/ml). VEGF-A levels correlated with patient heart rate at baseline (p = 0.034). None of rs699947, rs3025039, nor rs2010963 genotypes were significantly associated with VEGF-A levels, but rs3025039 genotype was positively associated with collateral vessels perfusion according to the Rentrop classification (p = 0.01) and baseline natriuretic peptide levels (p<0.05). Survival in the CDCS cohort was independently associated with baseline VEGF-A levels and (in males) with rs699947 genotype. CONCLUSIONS: This study is strongly suggestive that VEGF-A levels have value as a prognostic biomarker in coronary heart disease patients and SNPs in VEGF-A deserve further investigation as prognostic markers and indicators of angiogenic potential influencing the formation of collateral circulation.

Long term survival after acute myocardial infarction in Australia and New Zealand, 2009-2015: a population cohort study.

OBJECTIVE: To assess long term survival and patient characteristics associated with survival following acute myocardial infarction (AMI) in Australia and New Zealand. DESIGN: Cohort study. SETTING, PARTICIPANTS: All patients admitted with AMI (ICD-10-AM codes I21.0-I21.4) to all public and most private hospitals in Australia and New Zealand during 2009-2015. MAIN OUTCOME MEASURE: All-cause mortality up to seven years after an AMI. RESULTS: 239 402 initial admissions with AMI were identified; the mean age of the patients was 69.3 years (SD, 14.3 years), 154 287 were men (64.5%), and 64 335 had ST-elevation myocardial infarction (STEMI; 26.9%). 7-year survival after AMI was 62.3% (STEMI, 70.8%; non-ST-elevation myocardial infarction [NSTEMI], 59.2%); survival exceeded 85% for people under 65 years of age, but was 17.4% for those aged 85 years or more. 120 155 patients (50.2%) underwent revascularisation (STEMI, 72.2%; NSTEMI, 42.1%); 7-year survival exceeded 80% for patients in each group who underwent revascularisation, and was lower than 45% for those who did not. Being older (85 years or older v 18-54 years: adjusted hazard ratio [aHR], 10.6; 95% CI, 10.1-11.1) or a woman (aHR, 1.15; 95% CI, 1.13-1.17) were each associated with greater long term mortality during the study period, as was prior heart failure (aHR, 1.79; 95% CI, 1.76-1.83). Several non-cardiac conditions and geriatric syndromes common in these patients were independently associated with lower long term survival, including major and metastatic cancer, cirrhosis and end-stage liver disease, and dementia. CONCLUSION: AMI care in Australia and New Zealand is associated with high rates of long term survival; 7-year rates exceed 80% for patients under 65 years of age and for those who undergo revascularisation. Efforts to further improve survival should target patients with NSTEMI, who are often older and have several comorbid conditions, for whom revascularisation rates are low and survival after AMI poor.

Convalescent troponin and cardiovascular death following acute coronary syndrome.

OBJECTIVES: High-sensitivity cardiac troponin testing is used in the diagnosis of acute coronary syndromes but its role during convalescence is unknown. We investigated the long-term prognostic significance of serial convalescent high-sensitivity cardiac troponin concentrations following acute coronary syndrome. METHODS: In a prospective multicentre observational cohort study of 2140 patients with acute coronary syndrome, cardiac troponin I concentrations were measured in 1776 patients at 4 and 12 months following the index event. Patients were stratified into three groups according to the troponin concentration at 4 months using the 99th centile (women>16 ng/L, men>34 ng/L) and median concentration of those within the reference range. The primary outcome was cardiovascular death. RESULTS: Troponin concentrations at 4 months were measurable in 99.0% (1759/1776) of patients (67±12 years, 72% male), and were ≤5 ng/L (median) and >99th centile in 44.8% (795) and 9.3% (166), respectively. There were 202 (11.4%) cardiovascular deaths after a median of 4.8 years. After adjusting for the Global Registry of Acute Coronary Events score, troponin remained an independent predictor of cardiovascular death (HR 1.4, 95% CI 1.3 to 1.5 per doubling) with the highest risk observed in those with increasing concentrations at 12 months. Patients with 4-month troponin concentrations >99th centile were at increased risk of cardiovascular death compared with those ≤5 ng/L (29.5% (49/166) vs 4.3% (34/795); adjusted HR 4.9, 95% CI 3.8 to 23.7). CONCLUSIONS: Convalescent cardiac troponin concentrations predict long-term cardiovascular death following acute coronary syndrome. Recognising this risk by monitoring troponin may improve targeting of therapeutic interventions. TRIAL REGISTRATION NUMBER: ACTRN12605000431628;Results.

Safety and Immunogenicity of the Heterosubtypic Influenza A Vaccine MVA-NP+M1 Manufactured on the AGE1.CR.pIX Avian Cell Line.

Seasonal influenza infections have a significant global impact leading to increased health and economic burden. The efficacy of currently available seasonal influenza vaccines targeting polymorphic surface antigens has historically been suboptimal. Cellular immune responses against highly conserved Influenza A virus antigens, such as nucleoprotein (NP) and matrix protein-1 (M1), have previously been shown to be associated with protection from disease, whilst viral-vectored vaccines are an effective strategy to boost cell-mediated immunity. We have previously demonstrated that MVA encoding NP and M1 can induce potent and persistent T cell responses against influenza. In this Phase I study, we evaluated the safety and immunogenicity of MVA-NP+M1, which was newly manufactured on an immortalized cell line, in six healthy adult participants. The vaccine was well-tolerated with only mild to moderate adverse events that resolved spontaneously and were comparable to previous studies with the same vaccine manufactured in chick embryo fibroblasts. A significant increase in vaccine-specific T cell responses was detected seven days after immunization and was directed against both antigens in the vector insert. This small Phase I study supports progression of this vaccine to a Phase IIb study to assess immunogenicity and additional protective efficacy in older adults receiving licensed seasonal influenza vaccines.

All-Cause Mortality Following an Acute Coronary Syndrome: 12-Year Follow-Up of the Comprehensive 2002 New Zealand Acute Coronary Syndrome Audit.

BACKGROUND: To describe the long-term mortality of a complete national cohort of acute coronary syndrome (ACS) patients enrolled in 2002, to compare this with a national age, sex and Maori ethnicity matched population, and to assess the influence of baseline factors on the 12-year mortality. METHODS: We reviewed 721 patients with a discharge diagnosis of an ACS who were enrolled in the first New Zealand ACS audit group cohort over 14days in May 2002. We matched the cohort to the national mortality database using each patient's unique national identity number. RESULTS: Over a median follow-up of 12.7 years of 721 patients discharged with an ACS, overall mortality was 52%: ST-elevation myocardial infarction (STEMI) (58%), non-ST-elevation myocardial infarction (NSTEMI) (61%) and unstable angina pectoris (UAP) (42%) patients, p<0.0001. In an age-adjusted survival model, males had a 29% increased mortality rate compared to females with a hazard ratio of 1.29 (95% CI 1.04, 1.61, p=0.019). Over 12 years there were 339 (47%) deaths, compared to 284 (39%) deaths observed in the matched population. The standardised mortality ratio for patients admitted with an ACS in New Zealand is 1.3 (95% CI 1.2, 1.5) with eight patients per 100 not surviving to 12 years compared to this matched population. CONCLUSIONS: The high mortality rate in this ACS cohort is a stark reminder of the prognostic implications of a presentation with an ACS. It emphasises the on-going need for optimal management of these patients throughout every stage of their initial treatment and subsequent on-going care.

A phase IIb study to determine the safety and efficacy of candidate INfluenza Vaccine MVA-NP+M1 in combination with licensed Ina CTivated infl Uenza vaccine in adult S aged 65 years and above (INVICTUS): a study protocol.

Seasonal influenza has a significant annual global impact. Current influenza vaccines work by inducing strain-specific antibodies against the highly polymorphic surface proteins of the influenza virus and need to be redesigned every year, increasing their cost and limiting availability. There is a demand for a more efficacious vaccine, particularly in older adults in which the current vaccines show poor efficacy. The aim is to investigate a novel vaccine, MVA-NP+M1, which targets T cell responses to the nucleoprotein and matrix 1 core proteins of the influenza virus A, which are highly conserved,  and therefore may provide long protection against a broad range of influenza strains. INVICTUS is a phase IIb study to determine the safety and efficacy of candidate INfluenza Vaccine MVA-NP+M1 in combination with licensed Ina CTivated infl Uenza vaccine in adult S aged 65 years and above is a randomised, participant-blinded, placebo-controlled, multi-centre phase IIb efficacy study planned for 2030 volunteers aged 65 and over, in primary care. The primary objective is to assess the efficacy of MVA-NP+M1 co-administered with licensed inactivated quadrivalent influenza vaccine in adults ≥65 years. Participants complete daily diaries to record solicited and unsolicited events in the first four weeks post vaccination, and influenza-like illness (ILI) symptoms and severity throughout the influenza season. We hypothesise an improvement in the primary outcome, a reduction in the average number of days spent with moderate or severe influenza-like illness during periods of influenza circulation, in the group administered with MVA-NP+M1, compared to those in the control group. Registration: ClinicalTrials.gov identifier NCT03300362. Protocol version: INVICTUS Protocol v3.0, 08 June06 2018.

A patient-centred model to quality assure outputs from an echocardiography department: consensus guidance from the British Society of Echocardiography.

Background Quality assurance (QA) of echocardiographic studies is vital to ensure that clinicians can act on findings of high quality to deliver excellent patient care. To date, there is a paucity of published guidance on how to perform this QA. The British Society of Echocardiography (BSE) has previously produced an Echocardiography Quality Framework (EQF) to assist departments with their QA processes. This article expands on the EQF with a structured yet versatile approach on how to analyse echocardiographic departments to ensure high-quality standards are met. In addition, a process is detailed for departments that are seeking to demonstrate to external bodies adherence to a robust QA process. Methods The EQF consists of four domains. These include assessment of Echo Quality (including study acquisition and report generation); Reproducibility & Consistency (including analysis of individual variability when compared to the group and focused clinical audit), Education & Training (for all providers and service users) and Customer & Staff Satisfaction (of both service users and patients/their carers). Examples of what could be done in each of these areas are presented. Furthermore, evidence of participation in each domain is categorised against a red, amber or green rating: with an amber or green rating signifying that a quantifiable level of engagement in that aspect of QA has been achieved. Conclusion The proposed EQF is a powerful tool that focuses the limited time available for departmental QA on areas of practice where a change in patient experience or outcome is most likely to occur.

Plasma levels of soluble VEGF receptor isoforms, circulating pterins and VEGF system SNPs as prognostic biomarkers in patients with acute coronary syndromes.

BACKGROUND: Development of collateral circulation in coronary artery disease is cardio-protective. A key process in forming new blood vessels is attraction to occluded arteries of monocytes with their subsequent activation as macrophages. In patients from a prospectively recruited post-acute coronary syndromes cohort we investigated the prognostic performance of three products of activated macrophages, soluble vascular endothelial growth factor (VEGF) receptors (sFlt-1 and sKDR) and pterins, alongside genetic variants in VEGF receptor genes, VEGFR-1 and VEGFR-2. METHODS: Baseline levels of sFlt-1 (VEGFR1), sKDR (VEGFR2) and pterins were measured in plasma samples from subgroups (n = 513; 211; 144, respectively) of the Coronary Disease Cohort Study (CDCS, n = 2067). DNA samples from the cohort were genotyped for polymorphisms from the VEGFR-1 gene SNPs (rs748252 n = 2027, rs9513070 n = 2048) and VEGFR-2 gene SNPs (rs2071559 n = 2050, rs2305948 n = 2066, rs1870377 n = 2042). RESULTS: At baseline, levels of sFlt-1 were significantly correlated with age, alcohol consumption, NTproBNP, BNP and other covariates relevant to cardiovascular pathophysiology. Total neopterin levels were associated with alcohol consumption at baseline. 7,8 dihydroneopterin was associated with BMI. The A allele of VEGFR-2 variant rs1870377 was associated with higher plasma sFlt-1 and lower levels of sKDR at baseline. Baseline plasma sFlt-1 was univariately associated with all cause mortality with (p < 0.001) and in a Cox's proportional hazards regression model sFlt-1 and pterins were both associated with mortality independent of established predictors (p < 0.027). CONCLUSIONS: sFlt-1 and pterins may have potential as prognostic biomarkers in acute coronary syndromes patients. Genetic markers from VEGF system genes warrant further investigation as markers of levels of VEGF system components in these patients. TRIAL REGISTRATION: Australian New Zealand Clinical Trials Registry. ACTRN12605000431628 . 16 September 2005, Retrospectively registered.

Computational Assessment of Blood Flow Heterogeneity in Peritoneal Dialysis Patients' Cardiac Ventricles.

Dialysis prolongs life but augments cardiovascular mortality. Imaging data suggests that dialysis increases myocardial blood flow (BF) heterogeneity, but its causes remain poorly understood. A biophysical model of human coronary vasculature was used to explain the imaging observations, and highlight causes of coronary BF heterogeneity. Post-dialysis CT images from patients under control, pharmacological stress (adenosine), therapy (cooled dialysate), and adenosine and cooled dialysate conditions were obtained. The data presented disparate phenotypes. To dissect vascular mechanisms, a 3D human vasculature model based on known experimental coronary morphometry and a space filling algorithm was implemented. Steady state simulations were performed to investigate the effects of altered aortic pressure and blood vessel diameters on myocardial BF heterogeneity. Imaging showed that stress and therapy potentially increased mean and total BF, while reducing heterogeneity. BF histograms of one patient showed multi-modality. Using the model, it was found that total coronary BF increased as coronary perfusion pressure was increased. BF heterogeneity was differentially affected by large or small vessel blocking. BF heterogeneity was found to be inversely related to small blood vessel diameters. Simulation of large artery stenosis indicates that BF became heterogeneous (increase relative dispersion) and gave multi-modal histograms. The total transmural BF as well as transmural BF heterogeneity reduced due to large artery stenosis, generating large patches of very low BF regions downstream. Blocking of arteries at various orders showed that blocking larger arteries results in multi-modal BF histograms and large patches of low BF, whereas smaller artery blocking results in augmented relative dispersion and fractal dimension. Transmural heterogeneity was also affected. Finally, the effects of augmented aortic pressure in the presence of blood vessel blocking shows differential effects on BF heterogeneity as well as transmural BF. Improved aortic blood pressure may improve total BF. Stress and therapy may be effective if they dilate small vessels. A potential cause for the observed complex BF distributions (multi-modal BF histograms) may indicate existing large vessel stenosis. The intuitive BF heterogeneity methods used can be readily used in clinical studies. Further development of the model and methods will permit personalized assessment of patient BF status.

Management of suspected acute coronary syndrome patients admitted to cardiology or non-cardiology services at Auckland City Hospital: implications for future national data collection.

AIMS: To review the number, characteristics and clinical management of suspected ACS patients admitted to cardiology and non-cardiology services at Auckland City Hospital, to assess differences between these services and to assess the number who would potentially be enrolled in the All New Zealand Acute Coronary Syndrome (ACS) Quality Improvement Programme (ANZACS-QI) database. METHODS: Auckland City Hospital patient data was extracted from the Australia and New Zealand ACS 'SNAPSHOT' audit, performed over 14 days in May 2012. RESULTS: There were 121 suspected ACS admissions to Auckland City hospital during the audit period, with 45 (37%) patients directly managed by the cardiology service, and 76 (63%) patients cared for by non-cardiology services. Based on the subsequent discharge diagnosis, the cardiology service had more patients with definite ACS than the non-cardiology services; 27/45 (60%) compared to 16/76 (21%), difference (95%CI) 39% (22-56), P<0.0001). Cardiology ACS patients were more likely to undergo echocardiography; 15/27 (56%) compared to 2/16 (13%), difference 42% (18-68), P=0.0089), coronary angiography; 21/27 (78%) compared to 3/16 (19%), difference (95%CI) 59% (34-84), P=0.0003), coronary revascularisation; 18/27 (67%) compared to 3/16 (19%), difference (95%CI) 48% (22-74), P=0.004, and be discharged on two antiplatelet agents; 18/26 (69%) compared to 3/15 (20%), difference (95%CI) 49% (22-76), P=0.0036, or an ACEI/ARB; 20/26 (77%) compared to 5/15 (33%), difference (95%CI) 44% (15-72), P=0.0088. CONCLUSIONS: In patients with a discharge diagnosis of definite ACS, those managed by non-cardiology services were less likely to receive guideline-recommended investigations, and management, in this relatively small cohort study. About one-third of all ACS patients are managed by non-cardiology services and would not be recorded by the ANZACS-QI database.

Expertise and infrastructure capacity impacts acute coronary syndrome outcomes.

Objective Effective translation of evidence to practice may depend on systems of care characteristics within the health service. The present study evaluated associations between hospital expertise and infrastructure capacity and acute coronary syndrome (ACS) care as part of the SNAPSHOT ACS registry. Methods A survey collected hospital systems and process data and our analysis developed a score to assess hospital infrastructure and expertise capacity. Patient-level data from a registry of 4387 suspected ACS patients enrolled over a 2-week period were used and associations with guideline care and in-hospital and 6-, 12- and 18-month outcomes were measured. Results Of 375 participating hospitals, 348 (92.8%) were included in the analysis. Higher expertise was associated with increased coronary angiograms (440/1329; 33.1%), 580/1656 (35.0%) and 609/1402 (43.4%) for low, intermediate and high expertise capacity respectively; P<0.001) and the prescription of guideline therapies observed a tendency for an association with (531/1329 (40.0%), 733/1656 (44.3%) and 603/1402 (43.0%) for low, intermediate and high expertise capacity respectively; P=0.056), but not rehabilitation (474/1329 (35.7%), 603/1656 (36.4%) and 535/1402 (38.2%) for low, intermediate and high expertise capacity respectively; P=0.377). Higher expertise capacity was associated with a lower incidence of major adverse events (152/1329 (11.4%), 142/1656 (8.6%) and 149/149 (10.6%) for low, intermediate and high expertise capacity respectively; P=0.026), as well as adjusted mortality within 18 months (low vs intermediate expertise capacity: odds ratio (OR) 0.79, 95% confidence interval (CI) 0.58-1.08, P=0.153; intermediate vs high expertise capacity: OR 0.64, 95% CI 0.48-0.86, P=0.003). Conclusions Both higher-level expertise in decision making and infrastructure capacity are associated with improved evidence translation and survival over 18 months of an ACS event and have clear healthcare design and policy implications. What is known about the topic? There are comprehensive guidelines for treating ACS patients, but Australia and New Zealand registry data reveal substantial gaps in delivery of best practice care across metropolitan, regional, rural and remote health services, raising questions of equity of access and outcome. Greater mortality and morbidity gains can be achieved by increasing the application of current evidence-based therapies than by developing new therapy innovations. Health service system characteristics may be barriers or enablers to the delivery of best practice care and need to be identified and evaluated for correlations with performance indicators and outcomes in order to improve health service design. What does this paper add? This study measures two system characteristics, namely expertise and infrastructure, evaluating the relationship with ACS guideline application and clinical outcomes in a large and diverse cohort of Australian and New Zealand hospitals. The study identifies decision-making expertise and infrastructure capacity, to a lesser degree, as enabling characteristics to help improve patient outcomes. What are the implications for practitioners? In the design of health services to improve access and equity, expertise must be preserved. However, it is difficult to have experienced personnel at the bedside no matter where the health service, and engineering innovative systems and processes of care to facilitate delivery of expertise should be considered.

A decade of improvement in the management of New Zealand ST-elevation myocardial infarction (STEMI) patients: results from the New Zealand Acute Coronary Syndrome (ACS) Audit Group national audits of 2002, 2007 and 2012.

AIMS: To audit the management of ST-segment elevation myocardial infarction (STEMI) patients admitted to a New Zealand Hospital over three 14-day periods to review their number, characteristics, management and outcome changes over a decade. METHODS: The acute coronary syndrome (ACS) audits were conducted over 14 days in May of 2002, 2007 and 2012 at New Zealand Hospitals admitting patients with a suspected or definite ACS. Longitudinal analyses of the STEMI subgroup are reported. RESULTS: From 2002 to 2012, the largest change in management was the proportion of patients undergoing reperfusion by primary PCI from 3% to 15% and 41%; P<0.001, and the rates of second antiplatelet agent use in addition to aspirin from 14% to 62% and 98%; P<0.001. The use of proven secondary prevention medications at discharge also increased during the decade. There were also significant increases in cardiac investigations for patients, especially echocardiograms (35%, 62% and 70%, P<0.001) and invasive coronary angiograms (31%, 58% and 87%, P<0.001). Notably even in 2012, one in four patients presenting with STEMI did not receive any reperfusion therapy. CONCLUSIONS: Substantial improvements have been seen in the management of STEMI patients in New Zealand over the last decade, in accordance with evidenced-based guideline recommendations. However, there appears to be considerable room to optimise management, particularly with the use of timely reperfusion therapy for more patients.

Suspected ACS Patients Presenting With Myocardial Damage or a Type 2 Myocardial Infarction Have a Similar Late Mortality to Patients With a Type 1 Myocardial Infarction: A Report From the Australian and New Zealand 2012 SNAPSHOT ACS Study.

BACKGROUND: Cardiac troponin (T and I) are considered the standard markers for detection of myocardial damage and the diagnosis of acute coronary syndrome (ACS) among patients who present to an emergency department with chest pain. However, these markers can be released in other situations and may be associated with short- and long-term clinical outcomes. In this study, we examine late mortality rates among patients presenting with a suspected ACS due to an unstable coronary plaque and those patients having a non-ACS. METHODS: 4388 patients were hospitalised with suspected ACS, between 14 and 27 May 2012 in the Australia and New Zealand SNAPSHOT ACS study. Those patients were categorised in five diagnostic groups: 1) ST elevation MI (n=419); 2) non-ST elevation MI (n=1012); 3) unstable angina (n=925); 4) non-ACS diagnoses (n=837); and 5) chest pain considered unlikely ischaemic (not otherwise specified, n=1195). RESULT: The respective mortality rates at 18 months in these groups were 16.2%, 16.3%, 6.8%, 12.8%, and 4.8%; Pearson χ2=110 p<0.001. Among non-ACS diagnoses patients (group 4) those with the highest mortality rates (cardiac (14.4%), respiratory (18.2%), sepsis (15.4%) and neoplastic (67%) diagnoses) had the highest rates of elevated troponin levels (48%, 31%, 38% and 67% respectively). By contrast, those with the lowest mortality rates (musculoskeletal (2.9%), gastrointestinal disorders (3.9%) and non-specific chest pain (7.4%)) had the lowest rate of elevated troponin levels (9%, 18% and 15.8% respectively). However, after adjusting for baseline clinical and demographic characteristics, the mortality rate at 18 months for patients with elevated troponin was similar for ACS or non-ACS diagnoses (Hazard Ratio, 95% C.I.0.98-1.07, p=0.333). CONCLUSIONS: Among patients in the 2012 SNAPSHOT ACS study, non-ACS diagnoses characterised by high rates of elevated troponin levels had high mortality rates similar to those diagnosed with ACS. Therapies known to be effective in ACS patients, including early invasive management, should be examined in these non-ACS patients with troponin elevations within adequately powered randomised trials.