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Aims The Global Registry of Acute Coronary Events (GRACE) score was developed to evaluate risk in patients with myocardial infarction. However, its performance in type 2 myocardial infarction is uncertain. Methods and results In two cohorts of consecutive patients with suspected acute coronary syndrome from 10 hospitals in Scotland (n = 48 282) and a tertiary care hospital in Sweden (n = 22 589), we calculated the GRACE 2.0 score to estimate death at 1 year. Discrimination was evaluated by the area under the receiver operating curve (AUC), and compared for those with an adjudicated diagnosis of type 1 and type 2 myocardial infarction using DeLong’s test. Type 1 myocardial infarction was diagnosed in 4981 (10%) and 1080 (5%) patients in Scotland and Sweden, respectively. At 1 year, 720 (15%) and 112 (10%) patients died with an AUC for the GRACE 2.0 score of 0.83 [95% confidence interval (CI) 0.82–0.85] and 0.85 (95% CI 0.81–0.89). Type 2 myocardial infarction occurred in 1121 (2%) and 247 (1%) patients in Scotland and Sweden, respectively, with 258 (23%) and 57 (23%) deaths at 1 year. The AUC was 0.73 (95% CI 0.70–0.77) and 0.73 (95% CI 0.66–0.81) in type 2 myocardial infarction, which was lower than for type 1 myocardial infarction in both cohorts (P Conclusion The GRACE 2.0 score provided good discrimination for all-cause death at 1 year in patients with type 1 myocardial infarction, and moderate discrimination for those with type 2 myocardial infarction. Trial registration ClinicalTrials.gov number, NCT01852123.

Background: We recently introduced the myocardial-ischemic-injury-index (MI3), a machine learning algorithm that predicts the likelihood of myocardial infarction in patients with suspected acute coronary syndrome. Whether this algorithm performs well in routine clinical practice or predicts subsequent events is unknown.Methods: MI3 was validated in a prespecified exploratory analysis from a multi-centre randomised trial that included consecutive patients with suspected acute coronary syndrome undergoing serial high-sensitivity cardiac troponin I measurement. Patients with ST-segment elevation myocardial infarction were excluded. MI3 incorporates age, sex, and two troponin measurements to compute a value (0-100) reflecting an individual’s likelihood of myocardial infarction during the index visit and estimates diagnostic performance metrics at the computed score. Model performance for an index diagnosis of myocardial infarction, and for subsequent myocardial infarction or cardiovascular death at one year was determined using previously defined low- and high-probability MI3 thresholds (1·6 and 49·7, respectively). Findings: In total, 20,761 patients (64±16 years, 46% women) were included of whom 3,272 (15·8%) had myocardial infarction. MI3 had an area under the receiver-operating-characteristic curve of 0·949 (95% confidence interval 0·946-0·952) identifying 12,983 (62·5%) patients as low-probability (sensitivity 99·3% [99·0-99·6%], negative predictive value 99·8% [99·8-99·9%]), and 2,961 (14·3%) as high-probability (specificity 95·0% [94·6-95·3%], positive predictive value 70·4% [68·7-72·0%]). At one year, subsequent myocardial infarction or cardiovascular death occurred more often in high-probability compared to low-probability patients (17·6% [520/2,961] versus 1·5% [197/12,983], PInterpretation: In consecutive patients undergoing serial cardiac troponin measurement for suspected acute coronary syndrome, the MI3 algorithm accurately estimates the likelihood of myocardial infarction and predicts subsequent adverse cardiovascular events.

Background: Type 2 myocardial infarction is caused by myocardial oxygen supply-demand imbalance, and its diagnosis is increasingly common with the advent of high-sensitivity cardiac troponin assays. Although this diagnosis is associated with poor outcomes, widespread uncertainty and confusion remain among clinicians as to how to investigate and manage this heterogeneous group of patients with type 2 myocardial infarction. Methods: In a prospective cohort study, 8064 consecutive patients with increased cardiac troponin concentrations were screened to identify patients with type 2 myocardial infarction. We excluded patients with frailty or renal or hepatic failure. All study participants underwent coronary (invasive or computed tomography angiography) and cardiac (magnetic resonance or echocardiography) imaging, and the underlying causes of infarction were independently adjudicated. The primary outcome was the prevalence of coronary artery disease. Results: In 100 patients with a provisional diagnosis of type 2 myocardial infarction (median age, 65 years [interquartile range, 55–74 years]; 43% women), coronary and cardiac imaging reclassified the diagnosis in 7 patients: type 1 or 4b myocardial infarction in 5 and acute myocardial injury in 2 patients. In those with type 2 myocardial infarction, median cardiac troponin I concentrations were 195 ng/L (interquartile range, 62–760 ng/L) at presentation and 1165 ng/L (interquartile range, 277–3782 ng/L) on repeat testing. The prevalence of coronary artery disease was 68% (63 of 93), which was obstructive in 30% (28 of 93). Infarct-pattern late gadolinium enhancement or regional wall motion abnormalities were observed in 42% (39 of 93), and left ventricular systolic dysfunction was seen in 34% (32 of 93). Only 10 patients had both normal coronary and normal cardiac imaging. Coronary artery disease and left ventricular systolic dysfunction were previously unrecognized in 60% (38 of 63) and 84% (27 of 32), respectively, with only 33% (21 of 63) and 19% (6 of 32) on evidence-based treatments. Conclusions: Systematic coronary and cardiac imaging of patients with type 2 myocardial infarction identified coronary artery disease in two-thirds and left ventricular systolic dysfunction in one-third of patients. Unrecognized and untreated coronary or cardiac disease is seen in most patients with type 2 myocardial infarction, presenting opportunities for initiation of evidence-based treatments with major potential to improve clinical outcomes. Registration: URL: https://www.clinicaltrials.gov ; Unique identifier: NCT03338504.

Arterial calcification is an important hallmark of cardiovascular disease and shares many similarities with skeletal mineralisation. The bone-specific protein osteocalcin (OCN) is an established marker of vascular smooth muscle cell (VSMC) osteochondrogenic trans-differentiation and a known regulator of glucose metabolism. However, the role of OCN in controlling arterial calcification is unclear. We hypothesised that OCN regulates calcification in VSMCs and sought to identify the underpinning signalling pathways. Immunohistochemistry revealed OCN co-localisation with VSMC calcification in human calcified carotid artery plaques. Additionally, 3 mM phosphate treatment stimulated OCN mRNA expression in cultured VSMCs (1.72 fold; p

Purpose Endothelial dysfunction is central to the pathogenesis of acute coronary syndrome. The study of diseased endothelium is very challenging due to inherent difficulties in isolating endothelial cells from the coronary vascular bed. We sought to isolate and characterise coronary endothelial cells from patients undergoing thrombectomy for myocardial infarction to develop a patient-specific in vitro model of endothelial dysfunction. Methods In a prospective cohort study, 49 patients underwent percutaneous coronary intervention with thrombus aspiration. Specimens were cultured, and coronary endothelial outgrowth (CEO) cells were isolated. CEO cells, endothelial cells isolated from peripheral blood, explanted coronary arteries, and umbilical veins were phenotyped and assessed functionally in vitro and in vivo. Results CEO cells were obtained from 27/37 (73%) atherothrombotic specimens and gave rise to cells with cobblestone morphology expressing CD146 (94 ± 6%), CD31 (87 ± 14%), and von Willebrand factor (100 ± 1%). Proliferation of CEO cells was impaired compared to both coronary artery and umbilical vein endothelial cells (population doubling time, 2.5 ± 1.0 versus 1.6 ± 0.3 and 1.2 ± 0.3 days, respectively). Cell migration was also reduced compared to umbilical vein endothelial cells (29 ± 20% versus 85±19%). Importantly, unlike control endothelial cells, dysfunctional CEO cells did not incorporate into new vessels or promote angiogenesis in vivo. Conclusions CEO cells can be reliably isolated and cultured from thrombectomy specimens in patients with acute coronary syndrome. Compared to controls, patient-derived coronary endothelial cells had impaired capacity to proliferate, migrate, and contribute to angiogenesis. CEO cells could be used to identify novel therapeutic targets to enhance endothelial function and prevent acute coronary syndromes.

Background Type 2 myocardial infarction is common in clinical practice. However, despite these patients having a similar rate of major adverse cardiovascular events as those with atherothrombotic type 1 myocardial infarction, there is currently no consensus on how these patients should be evaluated or managed. Whether risk assessment for coronary artery disease can identify patients at increased risk of death is unclear. Methods The High-STEACS trial was a stepped wedge cluster randomised controlled trial in ten hospitals across Scotland, including 48,282 consecutive patients with suspected acute coronary syndrome. The index diagnosis was adjudicated in all patients and the likelihood of underlying coronary artery disease recorded as either low-probability, high-probability, or known based on the clinical history, risk factors and comorbidities. The adjudicators were blinded to the primary and secondary outcomes including all-cause mortality at one year. Results High-sensitivity cardiac troponin I concentrations were above the sex-specific 99th centile in 22% (10,360/48,282) of patients. The adjudicated diagnosis was type 1 and type 2 myocardial infarction in 55% (4,981/9,115) and 12% (1,121/9,115), respectively. Compared to patients with type 1 myocardial infarction, those with type 2 myocardial infarction were older and more likely to be women. In patients with type 2 myocardial infarction, 20% were low-probability, 55% were high-probability and 25% had known coronary artery disease. All-cause mortality was highest in patients with known or suspected coronary artery disease (22.5% and 23.3%, respectively). Those with a low-probability of coronary artery disease had the lowest event rate (8.8%), even compared to those with type 1 myocardial infarction (Figure). Discussion A simple clinical assessment of whether patients have a low- or high-probability of coronary artery disease is associated with future risk of death in patients with type 2 myocardial infarction. Whether incorporating this assessment into clinical practice to guide secondary prevention could improve outcomes requires prospective evaluation. Figure 1 Funding Acknowledgement Type of funding source: Foundation. Main funding source(s): British Heart Foundation

Introduction The Global Registry of Acute Coronary Events (GRACE) score was developed to evaluate risk in patients with myocardial infarction. However, its performance in type 2 myocardial infarction is uncertain. Methods In two cohorts of consecutive patients with suspected acute coronary syndrome from ten hospitals in Scotland (n=48,282) and a tertiary care hospital in Sweden (n=22,589), we calculated the GRACE 2.0 score to estimate death at one year. Discrimination was evaluated by the area under the receiver-operator-curve (AUC), and compared for those with an adjudicated diagnosis of type 1 and type 2 myocardial infarction using DeLong’s test. Results Type 1 myocardial infarction was diagnosed in 4,981 (10%) and 1,080 (5%) patients in Scotland and Sweden, respectively. At one year, 720 (15%) and 112 (10%) patients died with an AUC for the GRACE score of 0.83 (95% confidence interval [CI] 0.82 to 0.85) and 0.85 (95% CI 0.81 to 0.89). Type 2 myocardial infarction occurred in 1,121 (2%) and 247 (1%) patients in Scotland and Sweden respectively, with 258 (23%) and 57 (23%) deaths at one year. The AUC was 0.73 (95% CI 0.70 to 0.77) and 0.73 (95% CI 0.66 to 0.81) in type 2 myocardial infarction, which was lower than for type 1 myocardial infarction in both cohorts (P Conclusions The GRACE score provided good discrimination for all-cause death at one year in patients with type 1 myocardial infarction, and moderate discrimination for those with type 2 myocardial infarction. Conflict of Interest None

Background Type 2 myocardial infarction is common in clinical practice. However, despite these patients having a similar rate of major adverse cardiovascular events as those with atherothrombotic type 1 myocardial infarction, there is currently no consensus on how these patients should be evaluated or managed. Whether risk assessment for coronary artery disease can identify patients at increased risk of death is unclear. Methods The High-STEACS trial was a stepped wedge cluster randomised controlled trial in ten hospitals across Scotland, including 48,282 consecutive patients with suspected acute coronary syndrome. The index diagnosis was adjudicated in all patients and the likelihood of underlying coronary artery disease recorded as either low probability, high-probability, or known based on the clinical history, risk factors and comorbidities. The adjudicators were blinded to the primary and secondary outcomes including all-cause mortality at one year. Results High-sensitivity cardiac troponin I concentrations were above the sex-specific 99th centile in 22% (10,360/48,282) of patients. The adjudicated diagnosis was type 1 and type 2 myocardial infarction in 55% (4,981/9,115) and 12% (1,121/9,115), respectively. Compared to patients with type 1 myocardial infarction, those with type 2 myocardial infarction were older and more likely to be women. In patients with type 2 myocardial infarction, 20% were low-probability, 55% were high-probability and 25% had known coronary artery disease. All-cause mortality was highest in patients with known or suspected coronary artery disease (22.5% and 23.3%, respectively). Those with a low-probability of coronary artery disease had the lowest event rate (8.8%), even compared to those with type 1 myocardial infarction (figure 1). Discussion A simple clinical assessment of whether patients have a low- or high-probability of coronary artery disease is associated with future risk of death in patients with type 2 myocardial infarction. Whether incorporating this assessment into clinical practice to guide secondary prevention could improve outcomes requires prospective evaluation. Conflict of Interest None

Introduction Heart failure (HF) affects approximately 1 million people in the UK, adversely affecting quality of life, functional capacity and cognitive health. This results in frequent hospitalisation and significant healthcare costs1, 2. Iron deficiency complicates heart failure in approximately 50% of patients3, and is increasingly recognised as a significant contributor to morbidity in this group. Intravenous ferric carboxymaltose (FCM) has been shown to improve quality of life (New York Heart Association [NYHA] class and Kansas City Cardiomyopathy Questionnaire [KCCQ]), performance in 6-minute walk test (6MWT), reduce hospitalisations, and is reflected in international guidelines4-7. We aimed to assess the feasibility, safety and cost implications of establishing an IV iron service for patients with HF in a large tertiary cardiology centre. Method Over a 6-month period (July-December 2019), outpatients with symptomatic heart failure (NYHA class ≥2) and severe left ventricular systolic dysfunction (LVEF ≤40%) were screened, and serum iron studies performed. Patients with iron deficiency (ferritin Results Fifty-two patients underwent IV iron replacement (69% male, mean age 66 years) with no significant adverse events or hospital admissions. The financial impact to the trust was a net income of £55 per patient (FCM treatment £290, remuneration £345). Ferritin increased significantly 83.3ug/L to 433ug/L (p Conclusion Utilisation of the existing iron infusion service facilitated the delivery of IV iron replacement for patients with heart failure with little need for additional training and resources. Delivery of the service did not incur additional cost to the trust and in fact there was a small net gain. In-keeping with published data we demonstrated comparable improvements in serum iron parameters and a trend towards improvement in NYHA class. IV iron replacement with FCM is safe and affordable and should be considered in all iron deficient patients with symptomatic heart failure. Conflict of Interest Yes - recieved honorarium from Vifor

Objective: Long noncoding RNAs (lncRNAs) are an emergent class of molecules with diverse functional roles, widely expressed in human physiology and disease. Although some lncRNAs have been identified in cardiovascular disease, their potential as novel targets in the prevention of atherosclerosis is unknown. We set out to discover important lncRNAs in unstable plaque and gain insight into their functional relevance. Approach and Results: Analysis of RNA sequencing previously performed on stable and unstable atherosclerotic plaque identified a panel of 47 differentially regulated lncRNAs. We focused on LINC01272, a lncRNA upregulated in unstable plaque previously detected in inflammatory bowel disease, which we termed PELATON (plaque enriched lncRNA in atherosclerotic and inflammatory bowel macrophage regulation). Here, we demonstrate that PELATON is highly monocyte- and macrophage-specific across vascular cell types, and almost entirely nuclear by cellular fractionation (90%–98%). In situ hybridization confirmed enrichment of PELATON in areas of plaque inflammation, colocalizing with macrophages around the shoulders and necrotic core of human plaque sections. Consistent with its nuclear localization, and despite containing a predicted open reading frame, PELATON did not demonstrate any protein-coding potential in vitro. Functionally, knockdown of PELATON significantly reduced phagocytosis, lipid uptake and reactive oxygen species production in high-content analysis, with a significant reduction in phagocytosis independently validated. Furthermore, CD36, a key mediator of phagocytic oxLDL (oxidized low-density lipoprotein) uptake was significantly reduced with PELATON knockdown. Conclusions: PELATON is a nuclear expressed, monocyte- and macrophage-specific lncRNA, upregulated in unstable atherosclerotic plaque. Knockdown of PELATON affects cellular functions associated with plaque progression.

Supplemental Digital Content is available in the text., Background: The introduction of more sensitive cardiac troponin assays has led to increased recognition of myocardial injury in acute illnesses other than acute coronary syndrome. The Universal Definition of Myocardial Infarction recommends high-sensitivity cardiac troponin testing and classification of patients with myocardial injury based on pathogenesis, but the clinical implications of implementing this guideline are not well understood. Methods: In a stepped-wedge cluster randomized, controlled trial, we implemented a high-sensitivity cardiac troponin assay and the recommendations of the Universal Definition in 48 282 consecutive patients with suspected acute coronary syndrome. In a prespecified secondary analysis, we compared the primary outcome of myocardial infarction or cardiovascular death and secondary outcome of noncardiovascular death at 1 year across diagnostic categories. Results: Implementation increased the diagnosis of type 1 myocardial infarction by 11% (510/4471), type 2 myocardial infarction by 22% (205/916), and acute and chronic myocardial injury by 36% (443/1233) and 43% (389/898), respectively. Compared with those without myocardial injury, the rate of the primary outcome was highest in those with type 1 myocardial infarction (cause-specific hazard ratio [HR] 5.64 [95% CI, 5.12–6.22]), but was similar across diagnostic categories, whereas noncardiovascular deaths were highest in those with acute myocardial injury (cause specific HR 2.65 [95% CI, 2.33–3.01]). Despite modest increases in antiplatelet therapy and coronary revascularization after implementation in patients with type 1 myocardial infarction, the primary outcome was unchanged (cause specific HR 1.00 [95% CI, 0.82–1.21]). Increased recognition of type 2 myocardial infarction and myocardial injury did not lead to changes in investigation, treatment or outcomes. Conclusions: Implementation of high-sensitivity cardiac troponin assays and the recommendations of the Universal Definition of Myocardial Infarction identified patients at high-risk of cardiovascular and noncardiovascular events but was not associated with consistent increases in treatment or improved outcomes. Trials of secondary prevention are urgently required to determine whether this risk is modifiable in patients without type 1 myocardial infarction. Clinical Trial Registration: https://www.clinicaltrials.gov. Unique identifier: NCT01852123.

Background Major disparities between women and men in the diagnosis, management, and outcomes of acute coronary syndrome are well recognized. Objectives The aim of this study was to evaluate the impact of implementing a high-sensitivity cardiac troponin I assay with sex-specific diagnostic thresholds for myocardial infarction in women and men with suspected acute coronary syndrome. Methods Consecutive patients with suspected acute coronary syndrome were enrolled in a stepped-wedge, cluster-randomized controlled trial across 10 hospitals. Myocardial injury was defined as high-sensitivity cardiac troponin I concentration >99th centile of 16 ng/l in women and 34 ng/l in men. The primary outcome was recurrent myocardial infarction or cardiovascular death at 1 year. Results A total of 48,282 patients (47% women) were included. Use of the high-sensitivity cardiac troponin I assay with sex-specific thresholds increased myocardial injury in women by 42% and in men by 6%. Following implementation, women with myocardial injury remained less likely than men to undergo coronary revascularization (15% vs. 34%) and to receive dual antiplatelet (26% vs. 43%), statin (16% vs. 26%), or other preventive therapies (p, Central Illustration

Introduction The Global Registry of Acute Coronary Events (GRACE) score is a widely used risk stratification tool in the evaluation of patients with myocardial infarction. However, the performance of GRACE in patients with myocardial infarction secondary to oxygen supply-demand imbalance in the absence of atherothrombosis (type 2 myocardial infarction), is uncertain. Outcomes in patients with type 2 myocardial infarction are poor, and a risk stratification tool is urgently required. Methods We assessed the GRACE score in two cohorts of consecutive patients presenting to the Emergency Department with suspected acute coronary syndrome. One cohort was recruited as part of a stepped wedge cluster randomised controlled trial across ten hospitals in Scotland, and one cohort from a large tertiary centre in Sweden. All diagnoses were adjudicated according to the Fourth Universal Definition. We applied the GRACE 2.0 algorithm to estimate death at one year. We assessed model discrimination using the area under the receiver-operator-curve (AUC), and compared AUC between type 1 and type 2 myocardial infarction using the DeLong test. Calibration was assessed using the Hosmer-Lemeshow (HL) goodness of fit test. Results We identified 2,538 and 1,080 patients with type 1 myocardial infarction from the Scottish and Swedish cohorts, with death from any cause occurring in 378 (14.9%) and 112 (10.4%) patients, respectively. The AUC for the GRACE score was 0.843 (0.823–0.864) and 0.848 (0.810–0.886). There were 642 and 247 patients with type 2 myocardial infarction in the Scottish and Swedish cohorts, respectively, with death occurring in 144 (22.4%) and 57 (23.1%) patients. The AUC was 0.708 (0.662–0.754) and 0.733 (0.657–0.808), (P Evaluation of GRACE 2.0 algorithm Type 1 Myocardial Infarction Type 2 Myocardial Infarction Scotland (n=2,538) Sweden (n=1,080) Scotland (n=642) Sweden (n=247) Deaths 378 (14.9%) 112 (10.4%) 144 (22.4%) 57 (23.0%) AUC (C-statistic) 0.843 (0.823–0.864) 0.848 (0.810–0.886) 0.708 (0.662–0.754) 0.733 (0.657–0.808) P-value for HL Figure 1. ROC curves Conclusions The GRACE score provided excellent discrimination for all cause death at one year in two contemporary consecutive patient cohorts with tye 1 myocardial infarction. In patients with type 2 myocardial infarction, GRACE performed well, but recalibration or the development of novel risk scores has the potential to improve risk stratification.

Supplemental Digital Content is available in the text., Rationale: In response to blood vessel wall injury, aberrant proliferation of vascular smooth muscle cells (SMCs) causes pathological remodeling. However, the controlling mechanisms are not completely understood. Objective: We recently showed that the human long noncoding RNA, SMILR, promotes vascular SMCs proliferation by a hitherto unknown mechanism. Here, we assess the therapeutic potential of SMILR inhibition and detail the molecular mechanism of action. Methods and Results: We used deep RNA-sequencing of human saphenous vein SMCs stimulated with IL (interleukin)-1α and PDGF (platelet-derived growth factor)-BB with SMILR knockdown (siRNA) or overexpression (lentivirus), to identify SMILR-regulated genes. This revealed a SMILR-dependent network essential for cell cycle progression. In particular, we found using the fluorescent ubiquitination-based cell cycle indicator viral system that SMILR regulates the late mitotic phase of the cell cycle and cytokinesis with SMILR knockdown resulting in ≈10% increase in binucleated cells. SMILR pulldowns further revealed its potential molecular mechanism, which involves an interaction with the mRNA of the late mitotic protein CENPF (centromere protein F) and the regulatory Staufen1 RNA-binding protein. SMILR and this downstream axis were also found to be activated in the human ex vivo vein graft pathological model and in primary human coronary artery SMCs and atherosclerotic plaques obtained at carotid endarterectomy. Finally, to assess the therapeutic potential of SMILR, we used a novel siRNA approach in the ex vivo vein graft model (within the 30 minutes clinical time frame that would occur between harvest and implant) to assess the reduction of proliferation by EdU incorporation. SMILR knockdown led to a marked decrease in proliferation from ≈29% in controls to ≈5% with SMILR depletion. Conclusions: Collectively, we demonstrate that SMILR is a critical mediator of vascular SMC proliferation via direct regulation of mitotic progression. Our data further reveal a potential SMILR-targeting intervention to limit atherogenesis and adverse vascular remodeling.

BACKGROUND: High-sensitivity cardiac troponin assays permit use of lower thresholds for the diagnosis of myocardial infarction, but whether this improves clinical outcomes is unknown. We aimed to determine whether the introduction of a high-sensitivity cardiac troponin I (hs-cTnI) assay with a sex-specific 99th centile diagnostic threshold would reduce subsequent myocardial infarction or cardiovascular death in patients with suspected acute coronary syndrome. METHODS: In this stepped-wedge, cluster-randomised controlled trial across ten secondary or tertiary care hospitals in Scotland, we evaluated the implementation of an hs-cTnI assay in consecutive patients who had been admitted to the hospitals' emergency departments with suspected acute coronary syndrome. Patients were eligible for inclusion if they presented with suspected acute coronary syndrome and had paired cardiac troponin measurements from the standard care and trial assays. During a validation phase of 6-12 months, results from the hs-cTnI assay were concealed from the attending clinician, and a contemporary cardiac troponin I (cTnI) assay was used to guide care. Hospitals were randomly allocated to early (n=5 hospitals) or late (n=5 hospitals) implementation, in which the high-sensitivity assay and sex-specific 99th centile diagnostic threshold was introduced immediately after the 6-month validation phase or was deferred for a further 6 months. Patients reclassified by the high-sensitivity assay were defined as those with an increased hs-cTnI concentration in whom cTnI concentrations were below the diagnostic threshold on the contemporary assay. The primary outcome was subsequent myocardial infarction or death from cardiovascular causes at 1 year after initial presentation. Outcomes were compared in patients reclassified by the high-sensitivity assay before and after its implementation by use of an adjusted generalised linear mixed model. This trial is registered with ClinicalTrials.gov, number NCT01852123. FINDINGS: Between June 10, 2013, and March 3, 2016, we enrolled 48 282 consecutive patients (61 [SD 17] years, 47% women) of whom 10 360 (21%) patients had cTnI concentrations greater than those of the 99th centile of the normal range of values, who were identified by the contemporary assay or the high-sensitivity assay. The high-sensitivity assay reclassified 1771 (17%) of 10 360 patients with myocardial injury or infarction who were not identified by the contemporary assay. In those reclassified, subsequent myocardial infarction or cardiovascular death within 1 year occurred in 105 (15%) of 720 patients in the validation phase and 131 (12%) of 1051 patients in the implementation phase (adjusted odds ratio for implementation vs validation phase 1·10, 95% CI 0·75 to 1·61; p=0·620). INTERPRETATION: Use of a high-sensitivity assay prompted reclassification of 1771 (17%) of 10 360 patients with myocardial injury or infarction, but was not associated with a lower subsequent incidence of myocardial infarction or cardiovascular death at 1 year. Our findings question whether the diagnostic threshold for myocardial infarction should be based on the 99th centile derived from a normal reference population. FUNDING: The British Heart Foundation.

FinFET technology has become a mainstream technology solution for post-20nm CMOS technology [1], since it has superior short-channel effects, better sub-threshold slope and reduced random dopant fluctuation. Therefore, it is expected to achieve better performance with lower SRAM VDDMIN. However, the quantized sizing of the channel width and length has drawbacks for conventional 6T-SRAM bitcell scaling. To minimize the bitcell area of the high-density SRAM bitcell, the number of fins (setting the channel width, W) of the pull-up PMOS (PU), passgate NMOS (PG) and pull-down NMOS (PD) transistors must be selected as 1:1:1. Since PU, PG, and PD have the same channel length (L), the ratio in geometry between the PU transistor and the PG transistor is equal to one. With the process variations, the strength of PU transistor can be much stronger than the PG transistor. A stronger PU transistor increases read stability of the SRAM bitcell but it degrades the write margin significantly and results in worse write-VDDMIN issue. Figure 13.5.1(a) shows a contention condition between PU and PG transistors of a 6T-SRAM bitcell for the write operation. During the write operation, the PU transistor impedes the ability of the PG transistor to pull the storage node (S) from VDD to ground. The bitcell may suffer a write failure at the stronger PU with weaker PG condition caused by the device variations. Two techniques have been proposed to improve the high density SRAM bitcell write VDDMIN: 1) negative bit-line voltage (NBL) to increase the strength of PG transistor and 2) lower cell VDD (LCV) to weaken PU transistor strength [1-5]. Compared to the conventional techniques, this work develops a suppressed-coupling-signal negative bitline (SCS-NBL) scheme and a write-recovery-enhancement lower-cell-VDD (WRE-LCV) scheme for write assist without the concern of reliability at higher VDD operating region. A comparison of the effectiveness of the two design techniques is also performed. Figure 13.5.1(b) shows the layout view of the high-density 6T-SRAM bit-cell with 0.07μm2 area in a 16nm high-k metal-gate FinFET technology. To minimize area, we set the geometric ratio of PU, PG, and PD transistors all equal to one. With the two developed write-assist circuits, the overall VDDMIN improvement can be over 300mV in a 128Mb SRAM test-chip.

Objective To identify the effects of preprocedural significant mitral regurgitation (MR) and change in MR severity upon mortality after transcatheter aortic valve implantation (TAVI) using the Edwards SAPIEN system. Methods A retrospective analysis of 316 consecutive patients undergoing TAVI for aortic stenosis at a single centre in the UK between March 2008 and January 2013. Patients were stratified into two groups according to severity of MR: ≥grade 3 were classed as significant and ≤grade 2 were non-significant. Change in MR severity was assessed by comparison of baseline and 30-day echocardiograms. Results 60 patients had significant MR prior to TAVI (19.0%). These patients were of higher perioperative risk (logistic EuroScore 28.7±16.6% vs 20.3±10.7%, p=0.004) and were more dyspnoeic (New York Heart Association class IV 20.0% vs 7.4%, p=0.014). Patients with significant preprocedural MR displayed greater 12-month and cumulative mortality (28.3% vs 20.2%, log-rank p=0.024). Significant MR was independently associated with mortality (HR 4.94 (95% CI 2.07 to 11.8), p

Vascular Ultrasound for AFA Introduction The most frequent complications of AF ablation (AFA) are related to vascular access, but there is little evidence as to how these can be minimized. Methods Consecutive patients undergoing AFA at a high-volume center received either standard care (Group S) or routine ultrasound-guided vascular access (Group U). Vascular complications were assessed before hospital discharge and by means of postal questionnaire 1 month later. Outcome measures were BARC 2+ bleeding complications, postprocedural pain, and prolonged bruising. Results Patients in Group S (n = 146) and U (n = 163) were well matched at baseline. Follow-up questionnaires were received from 92.6%. Patients in Group U were significantly less likely to have a BARC 2+ bleed, 10.4% versus 19.9% P = 0.02, were less likely to suffer groin pain after discharge (27.1% vs. 42.8%; P = 0.006) and were less likely to experience prolonged local bruising (21.5% vs. 40.4%; P = 0.001). Multivariable logistic regression analysis revealed a significant association of vascular complications with nonultrasound guided access (OR 3.12 95%CI 1.54–5.34; P = 0.003) and increasing age (OR 1.05 95%CI 1.01–1.09; P = 0.02). Conclusion Routine use of ultrasound-guided vascular access for AFA is associated with a significant reduction in bleeding complications, postprocedural pain, and prolonged bruising when compared to standard care.

A 27-year-old elite-level professional cyclist presented to the emergency department with a 6-hour history of chest pain and vomiting after prematurely aborting a competitive event. ECG demonstrated anterior ST segment elevation myocardial infarction, and blood tests revealed a grossly elevated high-sensitivity troponin T. Emergent coronary angiography confirmed the presence of a thrombus in the mid-left anterior descending artery with possible spontaneous coronary artery dissection. The patient recovered well following balloon angioplasty and thrombus aspiration, despite delayed recognition, invasive investigation and intervention.

Background: The knee's passive movement is insufficient to determine function in patients following ACL reconstruction. Hypothesis: We hypothesize that there are kinematic differences in the lower extremities (LE) during stair climbing and ground level walking following ACL surgery between the intact and reconstructed sides. Study Design: This was a retrospective cohort study. Eleven patients with an average age of 15.3 years at the time of their ACL reconstructive surgery (BPTB autograft) participated in the study. Methods: Patients were followed for at least 2 years post surgery. The subjects underwent a non-weight bearing ability test to reproduce predetermined knee joint positions. Their LE's velocity and joint kinematics were then measured during level ground walking and on a set of custom designed stairs as they ascended and descended. Results: During level ground walking the maximum internal rotation at the ankle during the swing phase on the reconstructed side increased significantly from 2.3o to 19.9 o compared to the unreconstructed limb (P=0.04). The leading reconstructed knee during stair ascent exhibited less knee flexion as compared to the unreconstructed knee for each step (1 st step: 74.2o vs 81.5o; 2 nd step:93.6o vs 97.6o; 3 rd step: 48o vs 53.5o; 4 th step: 72.5o vs 78.1o; p

The term jing-shen-fen-lie-zheng (mind-split-disease) has been used to denote schizophrenia in Chinese societies. Many Asian countries, where the Chinese writing system is used, adopt a similar translation. This study examined whether a less pejorative name si-jue-shi-diao (dys-regulation of thought and perception) as a diagnostic label for symptoms of schizophrenia could reduce stigma. Secondary school students (n = 313) were randomly assigned to read a vignette with one of four labels: si-jue-shi-diao, jing-shen-fen-lie-zheng, jing-shen-bin (mental illness), and no label. Students expressed their social distance, stereotypes held, and attributions toward a young adult who met the Diagnostic and Statistical Manual-IV of Mental Health Disorders criteria for schizophrenia. It was found that psychiatric labeling did not have a statistically significant main effect on attitude measures. However, students with religious beliefs were more accepting toward the target individual associated with diagnostic label than one with no labeling. The results cast doubts that less pejorative labels can reduce the social stigma of schizophrenia. Some potential drawbacks in using politically correct terms to describe schizophrenia are highlighted.

This pilot project employed a case study design consistent with that of Rice to describe the impact of violence on individuals who incurred a work related assault in 1992. Ten randomly selected subjects were interviewed from a population of 429 individuals reporting a work related assault that resulted in a wage loss claim. Half of the subjects had received permanency ratings, thought to be a measure of injury severity. The study hypothesis, stating the impact of the assault (e.g., pain and suffering, decrease in functioning) years after a work related assault was associated with the severity of the injury (i.e., permanency rating), was not supported by the data. However, individuals' health and quality of life 4 years after the assault were affected significantly and resulted in job changes, chronic pain, changes in functional status, and depression. The new hypothesis resulting from this study is employer support and mental health intervention immediately after an assault may prevent employee job changes and decrease mental health sequelae.

The most frequent complications of AF ablation (AFA) are related to vascular access, but there is little evidence as to how these can be minimized.Consecutive patients undergoing AFA at a high-volume center received either standard care (Group S) or routine ultrasound-guided vascular access (Group U). Vascular complications were assessed before hospital discharge and by means of postal questionnaire 1 month later. Outcome measures were BARC 2+ bleeding complications, postprocedural pain, and prolonged bruising.Patients in Group S (n = 146) and U (n = 163) were well matched at baseline. Follow-up questionnaires were received from 92.6%. Patients in Group U were significantly less likely to have a BARC 2+ bleed, 10.4% versus 19.9% P = 0.02, were less likely to suffer groin pain after discharge (27.1% vs. 42.8%; P = 0.006) and were less likely to experience prolonged local bruising (21.5% vs. 40.4%; P = 0.001). Multivariable logistic regression analysis revealed a significant association of vascular complications with nonultrasound guided access (OR 3.12 95%CI 1.54-5.34; P = 0.003) and increasing age (OR 1.05 95%CI 1.01-1.09; P = 0.02).Routine use of ultrasound-guided vascular access for AFA is associated with a significant reduction in bleeding complications, postprocedural pain, and prolonged bruising when compared to standard care.

Introduction The most frequent complications of AF Ablation (AFA) are related to vascular access but there is little published evidence as to how these can be minimised. In 2012 the European Society of Cardiology clearly stated in their updated guidelines that “improving safety of catheter ablation should be a primary goal in the further development of this therapy”. Methods In this prospective study, consecutive patients undergoing AFA received either standard femoral vascular access, guided by a landmark technique (Group S), or routine ultrasound-guided vascular access (Group U). Vascular complications were assessed before hospital discharge, and by means of bespoke postal questionnaire one month later. Outcome measures were actionable (BARC2+) bleeding complications, groin pain that required analgesics, and prolonged bruising lasting >2 weeks. Results Patients in Groups S (n = 146) and U (n = 163) were well matched at baseline. Follow up questionnaires were received from 92.6% of patients. Uninterrupted warfarin therapy was used in 65% of cases. There was no difference between the groups in mean INR levels, peak ACT levels or in the use of protamine post-procedure. Procedures in Group U were significantly shorter than those in Group S (184 ± 53 min v. 167 ± 4 min, p = 0.04). Inadvertent femoral arterial puncture, as recognised by the operator, was less common in Group U (10, 6.1%) than in Group S (19,13.0%), p = 0.04. Patients in Group U were significantly less likely to have a BARC 2+ bleed (10.4% v. 19.9% p = 0.02), were less likely to suffer groin pain after discharge (27.1% v. 42.8%, p = 0.006) and were less likely to experience prolonged local bruising (21.5% v. 40.4% p = 0.001). 2 patients in Group S and 1 patient in Group U had major (BARC 3) bleeding requiring blood transfusion (p = NS). Multivariable logistic regression analysis revealed a significant association of vascular complications with non-ultrasound guided access (OR 3.12 95% CI 1.54–5.34, p = 0.003) and increasing age (OR 1.05 95% CI 1.01–1.09 p = 0.02). The number needed to treat with ultrasound to prevent one bleeding complication was 11. Discussion Previous work has shown that physician-reported complication rates following AFA miss the majority of vascular events considered important to patients. For this reason we assessed patient reported outcome measures post-discharge, and chose a broad definition of bleeding complications rather than restricting ourselves to life-threatening complications. Accordingly our complication rates seem high at first glance, but we believe they better represent the true patient experience. To our knowledge, this is the first study to show the benefit of adopting a policy of using vascular ultrasound for AFA. Conclusion Routine use of ultrasound guided vascular access for AFA is associated with a significant reduction in bleeding complications, post procedural groin pain and prolonged local bruising when compared to standard vascular access.

Background Stress echocardiography (SE) is a versatile and safe imaging modality used in the evaluation of coronary artery disease. The sensitivity of stress echocardiography for detection of significant coronary disease ranges from 80–90%. The risk of serious adverse events is extremely low with no reported deaths. 1 A change in NICE recommendations 2 led to a large increase in demand for stress echocardiography. Despite this, SE is still an underutilised modality, due to limited resource and operator availability. 3 Contrast echocardiography improves the image quality and diagnostic yield for assessing left ventricular systolic function. It require intravenous administration of the contrast and it can be time consuming, requiring a medical doctor to insert cannula and administer the contrast. Method After the implementation of NICE guidelines (CG95) in 2010, we observed a 40% rise in requests for stress testing. A specialist nurse-led imaging service was introduced in April 2013. The imaging nurse was initially trained to perform the exercise stress echocardiography. After 3 months of further training with direct supervision of an imaging consultant (27 sessions), the nurse was able to perform Dobutamine stress echocardiography (DSE) with indirect supervision (total of 22 sessions). All referrals were screened, and suitability for nurse-led DSE was assessed by a consultant cardiologist. The imaging nurse was also trained to deliver contrast echocardiography; bubble echocardiography and myocardial perfusion scan. We present the data from 1st April to 1st November 2013. All the tests performed by the nurse were reported by a consultant. Results With the introduction of an imaging nurse specialist, we are able to perform 410 imaging tests which would have otherwise been delivered by a consultant or registrar (Table 1). Conclusion Introduction of a cardiac imaging nurse specialist is a safe and cost effective way of expanding the imaging service in a district general hospital. It helps with the freeing up of valuable consultants’ and registrars’ time for reporting images.

Background Atrial fibrillation (AF) is the most common arrhythmias managed by emergency physician. In 2005, a chapter setting out best practice for arrhythmia care and sudden cardiac death (SCD) was added to the National Service Framework for Coronary Heart Disease. This highlighted the need for early diagnosis and expert patient support. Methods A nurse led arrhythmia service was set up in 2011. The aim of this service was to develop and improve care pathways, avoid hospital admissions and reduce the length of stay (LOS) as well as providing continuity and support for patients diagnosed with an arrhythmia. Malignant ventricular arrhythmias were excluded. The nurses also managed a caseload of cardio version patients, undertaking pre and post procedure clinics, patient assessment and titration of anticoagulation therapy prior to performing the direct current cardio version (DCCV) itself. The service received referrals for the monitoring of anti-arrhythmic drugs and family screening for SCD. All patients are assessed by the nurse in the emergency room(ER). Depending on the severity of symptoms, the patient would either be discharged home or admitted. All patients would be seen within 24–48 hrs of being discharged. We also compared admission rates and LOS before and after the establishment of the service. All treatment regimes were as per the standardised AF management pathways. Results A total of 1169 patients were seen in arrhythmia service from 2011–2013.Eighty seven percent (1020 patients) were referred from the ER (Table 1). The most common referrals were for atrial fibrillation (77%), atrial Flutter (12%) and palpitations (10%). Thirty three percent of patients with acute AF were discharged from ER on the same day (n = 343). Of those who required admission (n = 677), 36% were discharged within the first 48 h (n = 246). The average LOS for AF was significantly improved compared to the pre Arrhythmia service era (2.6vs 7.3 days). The majority of patients with acute presentation were considered for a rate control strategy and one third of patients were referred for DCCV (n = 249). Majority of patients were discharged back to GP after treatment optimisation (87%), the rest were referred to cardiologist for further management (40% were referred for consideration of radiofrequency ablation, n = 93). There were no reported deaths or major adverse cardiac events (MACE) and the readmission rate was 1%. Conclusion The presence of an integrated Arrhythmia Service in the Emergency Room reduces hospital admissions as well as improving access and delivery of patient care. Nurse-led rapid access clinics provides close monitoring of the patients in an ambulatory setting resulting in less admissions and shorter LOS. A pre and post procedure clinics have led to freeing up valuable clinician’s time.

Introduction: Atrial fibrillation (AF) is the commonest cardiac arrhythmia managed by emergency and acute physicians, with a wide variation in management practices. Early specialist input in the management of AF improves patient outcomes. Objectives: The AF service was set up with 3 arrhythmia specialist nurses (ASNs) in 2011. The aim of the service was to improve quality of care by standardising treatment, streamlining patient care, and reducing hospital admissions for acute symptomatic AF. Decisions regarding rate vs rhythm control and anticoagulation are undertaken on discussion with a cardiologist, and subsequent treatment regimes are as per the standardised AF management pathways. All patients are reviewed by the ASNs within 48 hours of being discharged from hospital, who oversee the entire patient journey. Methods: Data was recorded for all patients referred to the AF service from 2011 to 2013. Patients were followed up until the point of discharge. Results: A total of 1020 patients aged 28 – 92 years old were referred to the service between 2011 and 2013. Thirty three percent of patients were seen and discharged on the same day (n1⁄4343). Of those who required admission (n1⁄4677), 36% were discharged within the first 48 hours (n1⁄4246). The majority of patients were considered for a rate control strategy and one third of patients were referred for direct current cardioversion (DCCV). (See figure 1) The DCCV was performed by the same nurses. There were no reported deaths or major adverse cardiac events (MACE). There were a total of 12 patients (1%) readmitted within 2 weeks of discharge with unsettled, symptomatic AF.

The benefit and utility of high-sensitivity cardiac troponin (hs-cTn) in the diagnosis of myocardial infarction in patients with kidney impairment is unclear. Here, we describe implementation of hs-cTnI testing on the diagnosis, management, and outcomes of myocardial infarction in patients with and without kidney impairment. Consecutive patients with suspected acute coronary syndrome enrolled in a stepped-wedge, cluster-randomized controlled trial were included in this pre-specified secondary analysis. Kidney impairment was defined as an eGFR under 60mL/min/1.73m2. The index diagnosis and primary outcome of type 1 and type 4b myocardial infarction or cardiovascular death at one year were compared in patients with and without kidney impairment following implementation of hs-cTnI assay with 99th centile sex-specific diagnostic thresholds. Serum creatinine concentrations were available in 46,927 patients (mean age 61 years; 47% women), of whom 9,080 (19%) had kidney impairment. hs-cTnIs were over 99th centile in 46% and 16% of patients with and without kidney impairment. Implementation increased the diagnosis of type 1 infarction from 12.4% to 17.8%, and from 7.5% to 9.4% in patients with and without kidney impairment (both significant). Patients with kidney impairment and type 1 myocardial infarction were less likely to undergo coronary revascularization (26% versus 53%) or receive dual anti-platelets (40% versus 68%) than those without kidney impairment, and this did not change post-implementation. In patients with hs-cTnI above the 99th centile, the primary outcome occurred twice as often in those with kidney impairment compared to those without (24% versus 12%, hazard ratio 1.53, 95% confidence interval 1.31 to 1.78). Thus, hs-cTnI testing increased the identification of myocardial injury and infarction but failed to address disparities in management and outcomes between those with and without kidney impairment.