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The prognostic significance of patients presenting with pulmonary embolism (PE) and elevated International Normalised Ratio (INR) not on anticoagulant therapy has not been described. We investigated whether these patients had higher mortality compared to patients with normal INR. A retrospective study of patients admitted to a tertiary hospital with acute PE from 2000 to 2012 was undertaken, with study outcomes tracked using a state-wide death registry. Patients were excluded if they were taking anticoagulants or had inadequate documentation of their INR and medication status. Of the 1,039 patients identified, 94 (9 %) had an elevated INR (> 1.2) in the absence of anticoagulant use. These patients had higher mortality at six months follow-up (26 % vs 6 %, p< 0.001) compared to controls (INR ≤ 1.2). An INR > 1.2 at diagnosis was an independent predictor of death at six months post-PE (hazard ratio [HR] 2.9, 95 % confidence interval [CI] 1.8–4.7, p< 0.001). The addition of INR to a multivariable model that included the simplified pulmonary embolism severity index (sPESI), chest pain, and serum sodium led to a significant net reclassification improvement estimated at 8.1 %. The final model’s C statistic increased significantly by 0.04 (95 % CI 0.01–0.08, p=0.03) to 0.83 compared to sPESI alone (0.79). In summary, patients presenting with acute PE and elevated INR while not on anticoagulant therapy appear to be at high risk of death. Future validation studies in independent cohorts will clarify if this novel finding can be usefully incorporated into clinical decision making in patients with acute PE.

© 2016 Bing et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. Background Acute pulmonary embolism (PE) carries an increased risk of death. Using transthoracic echocardiography (TTE) to assist diagnosis and risk stratification is recommended in current guidelines. However, its utilization in real-world clinical practice is unknown. We conducted a retrospective observational study to delineate the prevalence of inpatient TTE use following confirmed acute PE, identify predictors for its use and its impact on patient's outcome. Methods Clinical details of consecutive patients (2000 to 2012) from two tertiary-referral hospitals were retrieved from dedicated PE databases. All-cause and cause-specific mortality was tracked from a state-wide death registry. Results In total, 2306 patients were admitted with confirmed PE, of whom 687 (29.8%) had inpatient TTE (39.3% vs 14.4% between sites, P<0.001). Site to which patient presented, older age, cardiac failure, atrial fibrillation and diabetes were independent predictors for inpatient TTE use, while malignancy was a negative predictor. Overall mortality was 41.4% (mean followup 66.5±49.5months). Though inpatient TTE use was not an independent predictor for allcause or cardiovascular mortality in multivariable analysis, in the inpatient TTE subgroup, right ventricle-right atrial pressure gradient (hazard ratio [HR] 1.02 per-1mmHg increase, 95% confidence interval [CI] 1.01-1.03) and moderate/severe aortic stenosis (HR 2.26, 95% CI 1.20-4.27) independently predicted all-cause mortality. Conclusions Inpatient TTE is used infrequently in real-world clinical settings following acute PE despite its usefulness in risk stratification, prognostication and assessing comorbid cardiac pathologies. Identifying patients that will benefit most from a T

Background and objectives:We documented treatment and outcomes of Culturally and Linguistically Diverse (CALD) patients from the CONCORDANCE investigator initiated acute coronary syndromes (ACS) registry. Method(s): Of 1500 subjects from 17 sites, we analysed cardiovascular outcomes and usage of evidence-based therapies according to region of origin and whether the subject reported English as their second language (ESL). Result(s): Region of origin was 1033 from Australia/New Zealand, 99 Asian, 127 UK/USA, 144 European and 97 African/Other. Three hundred (20%) reported ESL. English speakers (ES) were older 63.3+/-13.2 versus 59.4+/-15.4 years (p < 0.001) and had less diabetes mellitus (24.4% vs. 41.2%, p < 0.001) and smoking (31.8% vs. 45.4%, p < 0.001), but similar previous MI and heart failure rates. At 479 days, all cause death (4.3% vs. 2.0%; p = 0.03) was higher among the ESL cohort. All cause death and MI were 7.3% (ESL) vs. 5.6% (ES; p = 0.281). After adjusting for GRACE score and diabetes, ESL had a hazard ratio of 1.88 (95% C.I. 0.95-3.74, p = 0.07) for increased mortality. Cardiac catheterisation (77% vs. 82%; p = 0.03) and percutaneous coronary intervention (37% vs. 49%; p = 0.001) rates were lower in the ESL group. At discharge, use of ACE inhibitors (62% vs. 64%, p = 0.54); clopidogrel (65% vs. 62%, p = 0.224); aspirin (86% vs. 88%; p = 0.23) and betablockers (80% vs. 76%; p = 0.132) were similar in ES and ESL groups but statin usage was less in the ESL group (88% vs. 93%; p = 0.01). Conclusion(s): Patients inwhompatients report ESL have a worse outcome after presenting with ACS.

Background: Cardiovascular observational registries characterise patients and describe the manner and use of therapeutic strategies. They facilitate analyses on the quality of care among participating institutions and document variations in clinical practice which can be benchmarked against best practice recommendations. The Cooperative National Registry of Acute Coronary care, Guideline Adherence and Clinical Events (CONCORDANCE) is an Australian observational registry that describes management and outcomes in patients with acute coronary syndromes (ACS) and feeds back both performance and outcome measures to participating hospitals. Method(s): The CONCORDANCE registry has been designed within a comparative effectiveness research (CER) framework to collect and report data from hospitals located in geographically diverse regions of Australia. Information including patient demographics, presenting characteristics, past medical history, in-hospital management and outcomes at six months and two years are entered into a web-based database using an electronic clinical record form (eCRF). Individual hospital information is returned to the sites in a real time confidential report detailing information on key performance indicator (KPI) process measures and outcomes benchmarked against the aggregated study cohort. Governance rules ensure data security and protect patient and clinician confidentiality. Consistent with a CER framework, additional characteristics of the registry include: (a) the capacity to evaluate associations between the inter and intra hospital systems and the provision of evidence based care and outcomes, (b) ongoing data collection from representative hospitals which allow spatial and temporal analysis of change in practice and the application of treatment modalities in the real world setting and (c) the provision of a data spine for quality improvement strategies and practical clinical trials. Conclusion(s): The CONCORDANCE registry is a clinician-drive

Genetic factors explain a majority of risk variance for age-related macular degeneration (AMD). While genome-wide association studies (GWAS) for late AMD implicate genes in complement, inflammatory and lipid pathways, the genetic architecture of early AMD has been relatively under studied. We conducted a GWAS meta-analysis of early AMD, including 4,089 individuals with prevalent signs of early AMD (soft drusen and/or retinal pigment epithelial changes) and 20,453 individuals without these signs. For various published late AMD risk loci, we also compared effect sizes between early and late AMD using an additional 484 individuals with prevalent late AMD. GWAS meta-analysis confirmed previously reported association of variants at the complement factor H (CFH) (peak P = 1.5×10(-31)) and age-related maculopathy susceptibility 2 (ARMS2) (P = 4.3×10(-24)) loci, and suggested Apolipoprotein E (ApoE) polymorphisms (rs2075650; P = 1.1×10(-6)) associated with early AMD. Other possible loci that did not reach GWAS significance included variants in the zinc finger protein gene GLI3 (rs2049622; P = 8.9×10(-6)) and upstream of GLI2 (rs6721654; P = 6.5×10(-6)), encoding retinal Sonic hedgehog signalling regulators, and in the tyrosinase (TYR) gene (rs621313; P = 3.5×10(-6)), involved in melanin biosynthesis. For a range of published, late AMD risk loci, estimated effect sizes were significantly lower for early than late AMD. This study confirms the involvement of multiple established AMD risk variants in early AMD, but suggests weaker genetic effects on the risk of early AMD relative to late AMD. Several biological processes were suggested to be potentially specific for early AMD, including pathways regulating RPE cell melanin content and signalling pathways potentially involved in retinal regeneration, generating hypotheses for further investigation.

Background: The Australian Cooperative National Registry of Acute Coronary care, Guideline Adherence and Clinical Events (CONCORDANCE) is an observational registry reporting temporal trends in the management of acute coronary syndromes (ACS). System level factors impacting this care are described with clinical and epidemiological sub-studies, including an Aboriginal and Torres Strait Islander initiative and a biomarker data bank. Method(s): Patient's with an ST elevation myocardial infarction (STEMI),non ST elevation myocardial infarction (NSTEMI) and those considered high risk for anACS event are eligible for inclusion. The 16 participating Australian centres are located in geographically different regions and represent services provided in these locations. Data are returned to the sites in a real-time confidential report including 20 Key Primary Indicator (KPI) process measures, patient demographics, in-hospital management and outcomes at six months and two years. Aggregated data for the entire cohort are presented for comparison with local site performance. Current results: 901patients are enrolled with a median age of 62 yrs+/-13.7 and a mean GRACE risk score of 129. 563 (62.5%) are males. Overall 633 (70.3%) of ACS patients undergo in-hospital cath, 56.5% of patients are discharged on appropriate medical therapy and 505 (56%) of this ACS cohort are referred to cardiac rehabilitation. Conclusion(s): The CONCORDANCE Registry provides clinicians with performance measures for management of ACS. The participating centres reflect the diversity in services around the country and are associated with important variations in clinical practice. Documenting and understanding these variations will provide opportunities to improve processes of care nationally. (Figure presented).

Previous results indicate that apoE (apolipoprotein E) may be associated with the nucleus in specific cell types, particularly under stress conditions such as serum starvation. In addition, nuclear apoE localization in ovarian cancer was recently shown to be correlated with patient survival. In order to better understand the factors associated with apoE nuclear localization, we examined intracellular apoE trafficking using live-cell imaging of CHO (Chinese-hamster ovary) cells that constitutively expressed apoE-GFP (green fluorescent protein). In addition, we used biotinylated apoE (in a lipid-free state and as a lipidated discoidal complex) to track the uptake and potential nuclear targeting of exogenous apoE. Our results indicate that a small proportion of apoE-GFP is detected in the nucleus of living apoE-GFP-expressing CHO cells and that the level of apoE-GFP in the nucleus is increased with serum starvation. Exposure of control CHO cells to exogenous apoE-GFP did not result in nuclear apoE-GFP localization in the recipient cells. Similarly, biotinylated apoE did not reach the nucleus of control CHO cells or SK-N-SH neurons. In contrast, when biotinylated apoE was delivered to recipient cells as a lipidated apoE disc, apoE was detected in the nucleus, suggesting that the lipoprotein complex alters the intracellular degradation or trafficking of apoE. Biotinylated apoE discs containing each of the three common human apoE isoforms (E2, E3 and E4) were also tested for nuclear trafficking. All three apoE isoforms were equally detected in the nucleus. These studies provide new evidence that apoE may be targeted to the nucleus and shed light on factors that regulate this process. © The Authors Journal compilation.