ECG predictors of AF: A systematic review (predicting AF in ischaemic stroke-PrAFIS).

In 25% of patients presenting with embolic stroke, a cause is not determined. Atrial fibrillation (AF) is a commonly identified mechanism of stroke in this population, particularly in older patients. Conventional investigations are used to detect AF, but can we predict AF in this population and generally? We performed a systematic review to identify potential predictors of AF on 12-lead electrocardiogram (ECG). METHOD: We conducted a search of EMBASE and Medline databases for prospective and retrospective cohorts, meta-analyses or case-control studies of ECG abnormalities in sinus rhythm predicting subsequent atrial fibrillation. We assessed quality of studies based on the Newcastle-Ottawa scale and data were extracted according to PRISMA guidelines. RESULTS: We identified 44 studies based on our criteria. ECG patterns that predicted the risk of developing AF included interatrial block, P-wave terminal force lead V1, P-wave dispersion, abnormal P-wave-axis, abnormal P-wave amplitude, prolonged PR interval, left ventricular hypertrophy, QT prolongation, ST-T segment abnormalities and atrial premature beats. Furthermore, we identified that factors such as increased age, high CHADS-VASC, chronic renal disease further increase the positive-predictive value of some of these parameters. Several of these have been successfully incorporated into clinical scoring systems to predict AF. CONCLUSION: There are several ECG abnormalities that can predict AF both independently, and with improved predictive value when combined with clinical risk factors, and if incorporated into clinical risk scores. Improved and validated predictive models could streamline selection of patients for cardiac monitoring and initiation of oral anticoagulants.

Targeting the DNA repair defect in BRCA mutant cells as a therapeutic strategy.

BRCA1 and BRCA2 are important for DNA double-strand break repair by homologous recombination, and mutations in these genes predispose to breast and other cancers. Poly(ADP-ribose) polymerase (PARP) is an enzyme involved in base excision repair, a key pathway in the repair of DNA single-strand breaks. We show here that BRCA1 or BRCA2 dysfunction unexpectedly and profoundly sensitizes cells to the inhibition of PARP enzymatic activity, resulting in chromosomal instability, cell cycle arrest and subsequent apoptosis. This seems to be because the inhibition of PARP leads to the persistence of DNA lesions normally repaired by homologous recombination. These results illustrate how different pathways cooperate to repair damage, and suggest that the targeted inhibition of particular DNA repair pathways may allow the design of specific and less toxic therapies for cancer.

Safety and Efficacy of an On-Site Intensive Treatment Protocol for Mild and Moderate Sympathomimetic Toxicity at Australian Music Festivals.

INTRODUCTION: Serotonin and sympathomimetic toxicity (SST) after ingestion of amphetamine-based drugs can lead to severe morbidity and death. There have been evaluations of the safety and efficacy of on-site treatment protocols for SST at music festivals. PROBLEM: The study aimed to examine the safety and efficacy of treating patients with SST on-site at a music festival using a protocol adapted from hospital-based treatment of SST. METHODS: The study is an audit of presentations with SST over a one-year period. The primary outcome was need for ambulance transport to hospital. The threshold for safety was prospectively defined as less than 10% of patients requiring ambulance transport to hospital.The protocol suggested patients be treated with a combination of benzodiazepines; cold intravenous (IV) fluid; specific therapies (cyproheptadine, chlorpromazine, and clonidine); rapid sequence intubation; and cooling with ice, misted water, and convection techniques. RESULTS: One patient of 13 (7.7%) patients with mild or moderate SST required ambulance transport to hospital. Two of seven further patients with severe SST required transport to hospital. CONCLUSIONS: On-site treatment may be a safe, efficacious, and efficient alternative to urgent transport to hospital for patients with mild and moderate SST. The keys to success of the protocol tested included inclusive and clear education of staff at all levels of the organization, robust referral pathways to senior clinical staff, and the rapid delivery of therapies aimed at rapidly lowering body temperature. Further collaborative research is required to define the optimal approach to patients with SST at music festivals.

Patient satisfaction with procedural sedation in the emergency department.

OBJECTIVE: The aim of this study was to determine patient satisfaction with procedural sedation as a function of nature of the procedure and depth of sedation. METHOD: We undertook a prospective observational study of adult patients who received procedural sedation in two EDs (20 month period). The level of sedation was determined by an investigator, using the Observers Assessment of Anaesthesia/Sedation Scale (1 = awake to 6 = no response to noxious stimuli). Patient satisfaction was measured with the Iowa Satisfaction with Anaesthesia Scale after full recovery. This was self-administered, comprised 11 items (e.g. 'I felt pain') and has a score range of -3 (poor satisfaction) to +3 (very satisfied). RESULTS: A total of 163 patients were enrolled (51.2% men, mean age 50.7 years). The median (interquartile range) satisfaction score was 2.7 (0.7). Patient satisfaction was lower among patients who had orthopaedic procedures (median 2.6 vs 2.8, P < 0.01) and among patients who had a pre-sedation opioid (2.6 vs 2.8, P = 0.03). Satisfaction was positively correlated with deeper sedation (Spearman's correlation coefficient 0.49, P < 0.001). Satisfaction also differed significantly between the four most common sedation regimens (P < 0.001). It was greatest among those who were administered propofol with or without fentanyl and least among those who were administered nitrous oxide with or without opioid. Patients sedated with propofol with or without fentanyl had the greatest depths of sedation. There was no difference in satisfaction among patients who were and were not sedated by a consultant (median 2.6 and 2.7, respectively, P = 0.84). CONCLUSION: Generally, the level of patient satisfaction is high. Greater satisfaction is associated with deeper sedation, sedation with propofol and non-orthopaedic procedures.

Estimation of the potential eye and tissue donor pool in an Australian emergency department.

OBJECTIVE: EDs have long been considered a potential source of eye and tissue donors, but no specific evidence to support this was identified in the Australian setting. The present study aims to bridge that knowledge gap, by analysing medical and social histories of those who have died over a 5 year period so as to determine donation eligibility in this population. METHODS: A retrospective audit was undertaken of all patients who died within the Royal Melbourne Hospital ED between 2010 and 2014. ED records, pharmacy records and electronic medical histories were audited for the presence of eye and tissue donation exclusion criteria and the distribution of these criteria within the target population. RESULTS: Over the 5 year period, of 326 deaths that occurred in the ED, one third was suitable for eye donation (n = 106) and one in seven (n = 45) for tissue donation. Of the age appropriate patients, five criteria were identified that excluded up to 85% of the population not eligible to donate. These were: haematological malignancies, neurodegenerative conditions, non-haematological malignancies, chronic renal failure and eye disease. CONCLUSION: The present study has identified a large pool of potential eye and tissue donors; a pool mostly unrecognised by emergency clinicians. An extensive list of exclusion criteria restricts donor potential. However, the present study has identified that only five fundamentally limit donation in the ED population. Utilisation of this knowledge will allow for the development of clinical triggers that will improve identification, and increase realisation, of potential donors.

An in vivo functional screen identifies ST6GalNAc2 sialyltransferase as a breast cancer metastasis suppressor.

To interrogate the complex mechanisms involved in the later stages of cancer metastasis, we designed a functional in vivo RNA interference (RNAi) screen combined with next-generation sequencing. Using this approach, we identified the sialyltransferase ST6GalNAc2 as a novel breast cancer metastasis suppressor. Mechanistically, ST6GalNAc2 silencing alters the profile of O-glycans on the tumor cell surface, facilitating binding of the soluble lectin galectin-3. This then enhances tumor cell retention and emboli formation at metastatic sites leading to increased metastatic burden, events that can be completely blocked by galectin-3 inhibition. Critically, elevated ST6GALNAC2, but not galectin-3, expression in estrogen receptor-negative breast cancers significantly correlates with reduced frequency of metastatic events and improved survival. These data demonstrate that the prometastatic role of galectin-3 is regulated by its ability to bind to the tumor cell surface and highlight the potential of monitoring ST6GalNAc2 expression to stratify patients with breast cancer for treatment with galectin-3 inhibitors.

FGFR signaling promotes the growth of triple-negative and basal-like breast cancer cell lines both in vitro and in vivo.

PURPOSE: The oncogenic drivers of triple-negative (TN) and basal-like breast cancers are largely unknown. Substantial evidence now links aberrant signaling by the fibroblast growth factor receptors (FGFR) to the development of multiple cancer types. Here, we examined the role of FGFR signaling in TN breast cancer. EXPERIMENTAL DESIGN: We examined the sensitivity of a panel of 31 breast cancer cell lines to the selective FGFR inhibitor PD173074 and investigated the potential mechanisms underlying sensitivity. RESULTS: TN breast cancer cell lines were more sensitive to PD173074 than comparator cell lines (P = 0.011), with 47% (7/15) of TN cell lines showing significantly reduced growth. The majority of TN cell lines showed only modest sensitivity to FGFR inhibition in two-dimensional growth but were highly sensitive in anchorage-independent conditions. PD173074 inhibited downstream mitogen-activated protein kinase and PI3K-AKT signaling and induced cell-cycle arrest and apoptosis. Basal-like breast cancer cell lines were found to express FGF2 ligand (11/21 positive) and, similarly, 62% of basal-like breast cancers expressed FGF2, as assessed by immunohistochemistry compared with 5% of nonbasal breast cancers (P < 0.0001). RNA interference targeting of FGF2 in basal-like cell lines significantly reduced growth in vitro and reduced down stream signaling, suggesting an autocrine FGF2 signaling loop. Treatment with PD173074 significantly reduced the growth of CAL51 basal-like breast cancer cell line xenografts in vivo. CONCLUSIONS: Basal-like breast cancer cell lines, and breast cancers, express autocrine FGF2 and show sensitivity to FGFR inhibitors, identifying a potential novel therapeutic approach for these cancers.

The collagen receptor Endo180 (CD280) Is expressed on basal-like breast tumor cells and promotes tumor growth in vivo.

Tumor cell invasion into the surrounding stroma requires increased cell motility and extensive remodeling of the extracellular matrix. Endo180 (CD280, MRC2, urokinase-type plasminogen activator receptor-associated protein) is a recycling endocytic receptor that functions in both these cellular activities by promoting cell migration and uptake of collagens for intracellular degradation. In the normal breast, Endo180 is predominantly expressed by stromal fibroblasts. The contrary observation that Endo180 is expressed on epithelial tumor cell lines that display a high invasive capacity suggested that up-regulation of this receptor may be an associated and functional component in the acquisition of a more aggressive phenotype by tumor cells in vivo. Here, we show that high levels of Endo180 are found in a subset of basal-like breast cancers and that this expression is an independent prognostic marker for shorter disease-free survival. Two potential mechanisms for Endo180 up-regulation were uncovered. First, it was shown that Endo180 can be transcriptionally up-regulated in vitro following transforming growth factor-beta treatment of breast cancer cells. Second, a proportion of Endo180(+) tumors were shown to have Endo180 gene copy number gains and amplifications. To investigate the functional consequence of Endo180 up-regulation, MCF7 cells transfected with Endo180 were inoculated into immunocompromised mice. Expression of wild-type Endo180, but not an internalization-defective Endo180 mutant, resulted in enhanced tumor growth together with a reduction in tumor collagen content. Together, these data argue that elevated expression of this receptor in tumor cells could have important consequences in subsets of basal-like carcinomas for which there is a current lack of effective treatment.