Declining Public Awareness of Heart Attack Warning Symptoms in the Years Following an Australian Public Awareness Campaign: A Cross-Sectional Study

Background: The National Heart Foundation of Australia's (NHFA) Warning Signs campaign ran between 2010 and 2013. This study examines trends in Australian adults’ ability to name heart attack symptoms during the campaign and in the years following. Methods: Using the NHFA's HeartWatch data (quarterly online surveys) for adults aged 30–59 years, we conducted an adjusted piecewise regression analysis comparing trends in the ability to name symptoms during the campaign period plus one year lag (2010–2014) to the post-campaign period (2015–2020) Results: Over the study period, there were 101,936 Australian adults surveyed. Symptom awareness was high or increased during the campaign period. However, there was a significant downward trend in each year following the campaign period for most symptoms (e.g., chest pain: adjusted odds ratio [AOR] =0.91, 95%CI: 0.56–0.80; arm pain: AOR=0.92, 95%CI: 0.90–0.94). Conversely, the inability to name any heart attack symptom increased in each year following the campaign (3.7% in 2010 to 19.9% in 2020; AOR=1.13, 95%CI: 1.10–1.15); these respondents were more likely to be younger, male, have less than 12 years of education, identify as Aboriginal and/or Torres Strait Islander Peoples, speak a language other than English at home and have no cardiovascular risk factors. Conclusion: Awareness of heart attack symptoms has decreased in the years since the Warning Signs campaign in Australia, with 1 in 5 adults currently unable to name a single heart attack symptom. New approaches are needed to promote and sustain this knowledge, and to ensure people act appropriately and promptly if symptoms occur

The development of a risk-adjustment strategy to benchmark emergency medical service (EMS) performance in relation to out-of-hospital cardiac arrest in Australia and New Zealand

Introduction: The aim of this study was to develop a risk adjustment strategy, including effect modifiers, for benchmarking emergency medical service (EMS) performance for out-of-hospital cardiac arrest (OHCA) in Australia and New Zealand. Method: Using 2017–2019 data from the Australasian Resuscitation Outcomes Consortium (Aus-ROC) OHCA Epistry, we included adults who received an EMS attempted resuscitation for a presumed medical OHCA. Logistic regression was applied to develop risk adjustment models for event survival (return of spontaneous circulation at hospital handover) and survival to hospital discharge/30 days. We examined potential effect modifiers, and assessed model discrimination and validity. Results: Both OHCA survival outcome models included EMS agency and the Utstein variables (age, sex, location of arrest, witnessed arrest, initial rhythm, bystander cardiopulmonary resuscitation, defibrillation prior to EMS arrival, and EMS response time). The model for event survival had good discrimination according to the concordance statistic (0.77) and explained 28% of the variation in survival. The corresponding figures for survival to hospital discharge/30 days were 0.87 and 49%. The addition of effect modifiers did little to improve the performance of either model. Conclusion: The development of risk adjustment models with good discrimination is an important step in benchmarking EMS performance for OHCA. The Utstein variables are important in risk-adjustment, but only explain a small proportion of the variation in survival. Further research is required to understand what factors contribute to the variation in survival between EMS

Regions of High Out-Of-Hospital Cardiac Arrest Incidence and Low Bystander CPR Rates in Victoria, Australia

BACKGROUND: Out-of-hospital cardiac arrest (OHCA) remains a major public health issue and research has shown that large regional variation in outcomes exists. Of the interventions associated with survival, the provision of bystander CPR is one of the most important modifiable factors. The aim of this study is to identify census areas with high incidence of OHCA and low rates of bystander CPR in Victoria, Australia. METHODS: We conducted an observational study using prospectively collected population-based OHCA data from the state of Victoria in Australia. Using ArcGIS (ArcMap 10.0), we linked the location of the arrest using the dispatch coordinates (longitude and latitude) to Victorian Local Government Areas (LGAs). We used Bayesian hierarchical models with random effects on each LGA to provide shrunken estimates of the rates of bystander CPR and the incidence rates. RESULTS: Over the study period there were 31,019 adult OHCA attended, of which 21,436 (69.1%) cases were of presumed cardiac etiology. Significant variation in the incidence of OHCA among LGAs was observed. There was a 3 fold difference in the incidence rate between the lowest and highest LGAs, ranging from 38.5 to 115.1 cases per 100,000 person-years. The overall rate of bystander CPR for bystander witnessed OHCAs was 62.4%, with the rate increasing from 56.4% in 2008-2010 to 68.6% in 2010-2013. There was a 25.1% absolute difference in bystander CPR rates between the highest and lowest LGAs. CONCLUSION: Significant regional variation in OHCA incidence and bystander CPR rates exists throughout Victoria. Regions with high incidence and low bystander CPR participation can be identified and would make suitable targets for interventions to improve CPR participation rates

Sex differences in prehospital delays in patients with st-segment-elevation myocardial infarction undergoing percutaneous coronary intervention

BACKGROUND: Women with ST-segment-elevation myocardial infarction experience delays in reperfusion compared with men with little data on each time component from symptom onset to reperfusion. This study analyzed sex discrepancies in patient delays, prehospital system delays, and hospital delays. METHODS AND RESULTS: Consecutive patients with ST-segment-elevation myocardial infarction treated with percutaneous coronary intervention across 30 hospitals in the Victorian Cardiac Outcomes Registry (2013-2018) were analyzed. Data from the Ambulance Victoria Data warehouse were used to perform linkage to the Victorian Cardiac Outcomes Registry for all patients transported via emergency medical services (EMS). The primary end point was EMS call-to-door time (prehospital system delay). Secondary end points included symptom-to-EMS call time (patient delay), door-to-device time (hospital delay), 30-day mortality, major adverse cardiovascular events, and major bleeding. End points were analyzed according to sex and adjusted for age, comorbidities, cardiogenic shock, cardiac arrest, and symptom onset time. A total of 6330 (21% women) patients with ST-segment-elevation myocardial infarction were transported by EMS. Compared with men, women had longer adjusted geometric mean symptom-to-EMS call times (47.0 versus 44.0 minutes; P<0.001), EMS call-to-door times (58.1 versus 55.7 minutes; P<0.001), and door-to-device times (58.5 versus 54.9 minutes; P=0.006). Compared with men, women had higher 30-day mortality (odds ratio [OR], 1.38; 95% CI, 1.06-1.79; P=0.02) and major bleeding (OR, 1.54; 95% CI, 1.08-2.20; P=0.02). CONCLUSIONS: Female patients with ST-segment-elevation myocardial infarction experienced excess delays in patient delays, prehospital system delays, and hospital delays, even after adjustment for confounders. Prehospital system and hospital delays resulted in an adjusted excess delay of 10 minutes compared with men

Induction of JNK and c-Abl signalling by cisplatin and oxaliplatin in mismatch repair-proficient and -deficient cells

Loss of DNA mismatch repair has been observed in a variety of human cancers. Recent studies have shown that loss of DNA mismatch repair results in resistance to cisplatin but not oxaliplatin, suggesting that the mismatch repair proteins serve as a detector for cisplatin but not oxaliplatin adducts. To identify the signal transduction pathways with which the detector communicates, we investigated the effect of loss of DNA mismatch repair on activation of known damage-responsive pathways, and recently reported that cisplatin differentially activates c-Jun NH2-terminal kinase (JNK) and c-Abl in repair-proficient vs.-deficient cells. In the current study, we directly compared differential activation of these pathways by cisplatin vs. oxaliplatin. The results confirm that cisplatin activates JNK kinase 5.7 ± 1.5 (s.d.)-fold more efficiently in DNA mismatch repair-proficient than repair-deficient cells, and that the c-Abl response to cisplatin is completely absent in DNA mismatch repair-deficient cells. In contrast, there was no detectable activation of the JNK or c-Abl kinases in DNA mismatch repair-proficient or -deficient cells exposed to oxaliplatin. The present study demonstrates that, despite the similarity of the adducts produced by cisplatin and oxaliplatin, they appear to be recognized by different detectors. The DNA mismatch repair system plays an important part in the recognition of cisplatin adducts, and activation of both the JNK and c-Abl kinases in response to cisplatin damage is dependent on the detector function of the DNA mismatch repair proteins. In contrast, this detector does not respond to oxaliplatin adducts. © 1999 Cancer Research Campaig

The 22q11.2 region regulates presynaptic gene-products linked to schizophrenia

How the 22q11.2 deletion predisposes to psychiatric disease is unclear. Here, the authors examine living human neuronal cells and show that 22q11.2 regulates the expression of genes linked to autism during early development, and genes linked to schizophrenia and synaptic biology in neurons. It is unclear how the 22q11.2 deletion predisposes to psychiatric disease. To study this, we generated induced pluripotent stem cells from deletion carriers and controls and utilized CRISPR/Cas9 to introduce the heterozygous deletion into a control cell line. Here, we show that upon differentiation into neural progenitor cells, the deletion acted in trans to alter the abundance of transcripts associated with risk for neurodevelopmental disorders including autism. In excitatory neurons, altered transcripts encoded presynaptic factors and were associated with genetic risk for schizophrenia, including common and rare variants. To understand how the deletion contributed to these changes, we defined the minimal protein-protein interaction network that best explains gene expression alterations. We found that many genes in 22q11.2 interact in presynaptic, proteasome, and JUN/FOS transcriptional pathways. Our findings suggest that the 22q11.2 deletion impacts genes that may converge with psychiatric risk loci to influence disease manifestation in each deletion carrier.Peer reviewe

Functional Rotation of the Transporter AcrB: Insights into Drug Extrusion from Simulations

The tripartite complex AcrAB-TolC is the major efflux system in Escherichia coli. It extrudes a wide spectrum of noxious compounds out of the bacterium, including many antibiotics. Its active part, the homotrimeric transporter AcrB, is responsible for the selective binding of substrates and energy transduction. Based on available crystal structures and biochemical data, the transport of substrates by AcrB has been proposed to take place via a functional rotation, in which each monomer assumes a particular conformation. However, there is no molecular-level description of the conformational changes associated with the rotation and their connection to drug extrusion. To obtain insights thereon, we have performed extensive targeted molecular dynamics simulations mimicking the functional rotation of AcrB containing doxorubicin, one of the two substrates that were co-crystallized so far. The simulations, including almost half a million atoms, have been used to test several hypotheses concerning the structure-dynamics-function relationship of this transporter. Our results indicate that, upon induction of conformational changes, the substrate detaches from the binding pocket and approaches the gate to the central funnel. Furthermore, we provide strong evidence for the proposed peristaltic transport involving a zipper-like closure of the binding pocket, responsible for the displacement of the drug. A concerted opening of the channel between the binding pocket and the gate further favors the displacement of the drug. This microscopically well-funded information allows one to identify the role of specific amino acids during the transitions and to shed light on the functioning of AcrB

Evaluating model outputs using integrated global speleothem records of climate change since the last glacial

Although quantitative isotope data from speleothems has been used to evaluate isotope-enabled model simulations, currently no consensus exists regarding the most appropriate methodology through which to achieve this. A number of modelling groups will be running isotope-enabled palaeoclimate simulations in the framework of the Coupled Model Intercomparison Project Phase 6, so it is timely to evaluate different approaches to using the speleothem data for data–model comparisons. Here, we illustrate this using 456 globally distributed speleothem δ18O records from an updated version of the Speleothem Isotopes Synthesis and Analysis (SISAL) database and palaeoclimate simulations generated using the ECHAM5-wiso isotope-enabled atmospheric circulation model. We show that the SISAL records reproduce the first-order spatial patterns of isotopic variability in the modern day, strongly supporting the application of this dataset for evaluating model-derived isotope variability into the past. However, the discontinuous nature of many speleothem records complicates the process of procuring large numbers of records if data–model comparisons are made using the traditional approach of comparing anomalies between a control period and a given palaeoclimate experiment. To circumvent this issue, we illustrate techniques through which the absolute isotope values during any time period could be used for model evaluation. Specifically, we show that speleothem isotope records allow an assessment of a model's ability to simulate spatial isotopic trends. Our analyses provide a protocol for using speleothem isotope data for model evaluation, including screening the observations to take into account the impact of speleothem mineralogy on δ18O values, the optimum period for the modern observational baseline and the selection of an appropriate time window for creating means of the isotope data for palaeo-time-slices

Using Polarized Spectroscopy to Investigate Order in Thin-Films of Ionic Self-Assembled Materials Based on Azo-Dyes

Three series of ionic self-assembled materials based on anionic azo-dyes and cationic benzalkonium surfactants were synthesized and thin films were prepared by spin-casting. These thin films appear isotropic when investigated with polarized optical microscopy, although they are highly anisotropic. Here, three series of homologous materials were studied to rationalize this observation. Investigating thin films of ordered molecular materials relies to a large extent on advanced experimental methods and large research infrastructure. A statement that in particular is true for thin films with nanoscopic order, where X-ray reflectometry, X-ray and neutron scattering, electron microscopy and atom force microscopy (AFM) has to be used to elucidate film morphology and the underlying molecular structure. Here, the thin films were investigated using AFM, optical microscopy and polarized absorption spectroscopy. It was shown that by using numerical method for treating the polarized absorption spectroscopy data, the molecular structure can be elucidated. Further, it was shown that polarized optical spectroscopy is a general tool that allows determination of the molecular order in thin films. Finally, it was found that full control of thermal history and rigorous control of the ionic self-assembly conditions are required to reproducibly make these materials of high nanoscopic order. Similarly, the conditions for spin-casting are shown to be determining for the overall thin film morphology, while molecular order is maintained

Innate Immune Responses of Drosophila melanogaster Are Altered by Spaceflight

Alterations and impairment of immune responses in humans present a health risk for space exploration missions. The molecular mechanisms underpinning innate immune defense can be confounded by the complexity of the acquired immune system of humans. Drosophila (fruit fly) innate immunity is simpler, and shares many similarities with human innate immunity at the level of molecular and genetic pathways. The goals of this study were to elucidate fundamental immune processes in Drosophila affected by spaceflight and to measure host-pathogen responses post-flight. Five containers, each containing ten female and five male fruit flies, were housed and bred on the space shuttle (average orbit altitude of 330.35 km) for 12 days and 18.5 hours. A new generation of flies was reared in microgravity. In larvae, the immune system was examined by analyzing plasmatocyte number and activity in culture. In adults, the induced immune responses were analyzed by bacterial clearance and quantitative real-time polymerase chain reaction (qPCR) of selected genes following infection with E. coli. The RNA levels of relevant immune pathway genes were determined in both larvae and adults by microarray analysis. The ability of larval plasmatocytes to phagocytose E. coli in culture was attenuated following spaceflight, and in parallel, the expression of genes involved in cell maturation was downregulated. In addition, the level of constitutive expression of pattern recognition receptors and opsonins that specifically recognize bacteria, and of lysozymes, antimicrobial peptide (AMP) pathway and immune stress genes, hallmarks of humoral immunity, were also reduced in larvae. In adults, the efficiency of bacterial clearance measured in vivo following a systemic infection with E. coli post-flight, remained robust. We show that spaceflight altered both cellular and humoral immune responses in Drosophila and that the disruption occurs at multiple interacting pathways