Resuscitation for out-of-hospital cardiac arrest in Ireland 2012-2020: Modelling national temporal developments and survival predictors.

Aim: To explore potential predictors of national out-of-hospital cardiac arrest (OHCA) survival, including health system developments and the COVID pandemic in Ireland. Methods: National level OHCA registry data from 2012 through to 2020, relating to unwitnessed, and bystander witnessed OHCA were interrogated. Logistic regression models were built by including predictors through stepwise variable selection and enhancing the models by adding pairwise interactions that improved fit. Missing data sensitivity analyses were conducted using multiple imputation. Results: The data included 18,177 cases. The final model included seventeen variables. Of these nine variables were involved in pairwise interactions. The COVID-19 period was associated with reduced survival (OR 0.61, 95%CI 0.43, 0.87), as were increasing age in years (OR 0.96, 95% CI 0.96, 0.97) and call response interval in minutes (OR 0.97, 95% CI 0.96, 0.99). Amiodarone administration (OR 3.91, 95% CI 2.80, 5.48), urban location (OR 1.40, 95% CI 1.12, 1.77), and chronological year over time (OR 1.14, 95% CI 1.08, 1.20) were associated with increased survival. Conclusions: National survival from OHCA has significantly increased incrementally over time in Ireland. The COVID-19 pandemic was associated with decreased survival even after accounting for potential disruption to key elements of bystander and EMS care. Further research is needed to understand and address the discrepancy between urban and rural OHCA survival. Information concerning pre-event patient health status and inpatient care process may yield important additional insights in future.

Outcomes of out-of-hospital cardiac arrest in Ireland 2012-2020: Protocol for an observational study.

Background: Out-of-hospital cardiac arrest (OHCA) is a leading cause of preventable mortality that now affects almost 3,000 people each year in Ireland. Survival is low at 6-7%, compared to a European average of 8%. The Irish Out-of-Hospital Cardiac Registry (OHCAR) prospectively gathers data on all OHCA in Ireland where emergency medical services attempted resuscitation.The Irish health system has undergone several developments that are relevant to OHCA care in the period 2012-2020. OHCAR data provides a means of exploring temporal trends in OHCA incidence, care, and outcomes over time. It also provides a means of exploring whether system developments were associated with a change in key outcomes.This research aims to summarise key trends in available OHCAR data from the period 2012 - 2020, to explore and model predictors of bystander CPR, bystander defibrillation, and survival, and to explore the hypothesis that significant system level temporal developments were associated with improvements in these outcomes. Methods: The following protocol sets out the relevant background and research approach for an observational study that will address the above aims. Key trends in available OHCAR data (2012 - 2020) will be described and evaluated using descriptive summaries and graphical displays. Multivariable logistic regression will be used to model predictors of 'bystander CPR', 'bystander defibrillation' and 'survival to hospital discharge' and to explore the effects (if any) of system level developments in 2015/2016 and the COVID-19 pandemic (2020) on these outcomes. Discussion: The findings of this research will be used to understand temporal trends in the care processes and outcomes for OHCA in Ireland over the period 2012-2020. The results can further be used to optimise future health system developments for OHCA in both Ireland and internationally.

Three-year trends in out-of-hospital cardiac arrest across the world: Second report from the International Liaison Committee on Resuscitation (ILCOR).

BACKGROUND: The International Liaison Committee on Resuscitation (ILCOR) Research and Registries Working Group previously reported data on systems of care and outcomes of out-of-hospital cardiac arrest (OHCA) in 2015 from 16 national and regional registries. To describe the temporal trends with updated data on OHCA, we report the characteristics of OHCA from 2015 through 2017. METHODS: We invited national and regional population-based OHCA registries for voluntary participation and included emergency medical services (EMS)-treated OHCA. We collected descriptive summary data of core elements of the latest Utstein style recommendation during 2016 and 2017 at each registry. For registries that participated in the previous 2015 report, we also extracted the 2015 data. RESULTS: Eleven national registries in North America, Europe, Asia, and Oceania, and 4 regional registries in Europe were included in this report. Across registries, the estimated annual incidence of EMS-treated OHCA was 30.0-97.1 individuals per 100,000 population in 2015, 36.4-97.3 in 2016, and 40.8-100.2 in 2017. The provision of bystander cardiopulmonary resuscitation (CPR) varied from 37.2% to 79.0% in 2015, from 2.9% to 78.4% in 2016, and from 4.1% to 80.3% in 2017. Survival to hospital discharge or 30-day survival for EMS-treated OHCA ranged from 5.2% to 15.7% in 2015, from 6.2% to 15.8% in 2016, and from 4.6% to 16.4% in 2017. CONCLUSION: We observed an upward temporal trend in provision of bystander CPR in most registries. Although some registries showed favourable temporal trends in survival, less than half of registries in our study demonstrated such a trend.

Care of patients with ST-elevation myocardial infarction: an international analysis of quality indicators in the acute coronary syndrome STEMI Registry of the EURObservational Research Programme and ACVC and EAPCI Associations of the European Society of Cardiology in 11 462 patients.

AIMS: To use quality indicators to study the management of ST-segment elevation myocardial infarction (STEMI) in different regions. METHODS AND RESULTS: Prospective cohort study of STEMI within 24 h of symptom onset (11 462 patients, 196 centres, 26 European Society of Cardiology members, and 3 affiliated countries). The median delay between arrival at a percutaneous cardiovascular intervention (PCI) centre and primary PCI was 40 min (interquartile range 20-74) with 65.8% receiving PCI within guideline recommendation of 60 min. A third of patients (33.2%) required transfer from their initial hospital to one that could perform emergency PCI for whom only 27.2% were treated within the quality indicator recommendation of 120 min. Radial access was used in 56.6% of all primary PCI, but with large geographic variation, from 76.4 to 9.1%. Statins were prescribed at discharge to 98.7% of patients, with little geographic variation. Of patients with a history of heart failure or a documented left ventricular ejection fraction ≤40%, 84.0% were discharged on an angiotensin-converting enzyme inhibitor/angiotensin receptor blocker and 88.7% were discharged on beta-blockers. CONCLUSION: Care for STEMI shows wide geographic variation in the receipt of timely primary PCI, and is in contrast with the more uniform delivery of guideline-recommended pharmacotherapies at time of hospital discharge.

Taming Electrowetting Using Highly Concentrated Aqueous Solutions.

Wetting of carbon surfaces is one of the most widespread, yet poorly understood, physical phenomena. Control over wetting properties underpins the operation of aqueous energy-storage devices and carbon-based filtration systems. Electrowetting, the variation in the contact angle with an applied potential, is the most straightforward way of introducing control over wetting. Here, we study electrowetting directly on graphitic surfaces with the use of aqueous electrolytes to show that reversible control of wetting can be achieved and quantitatively understood using models of the interfacial capacitance. We manifest that the use of highly concentrated aqueous electrolytes induces a fully symmetric and reversible wetting behavior without degradation of the substrate within the unprecedented potential window of 2.8 V. We demonstrate where the classical "Young-Lippmann" models apply, and break down, and discuss reasons for the latter, establishing relations among the applied bias, the electrolyte concentration, and the resultant contact angle. The approach is extended to electrowetting at the liquid|liquid interface, where a concentrated aqueous electrolyte drives reversibly the electrowetting response of an insulating organic phase with a significantly decreased potential threshold. In summary, this study highlights the beneficial effect of highly concentrated aqueous electrolytes on the electrowettability of carbon surfaces, being directly related to the performance of carbon-based aqueous energy-storage systems and electronic and microfluidic devices.

Downregulation of PDCD4 by deSUMOylation associates with the progression of gestational trophoblastic disease.

INTRODUCTION: Gestational trophoblastic disease (GTD) encompasses a range of trophoblastic disorders from hydatidiform mole (HM), to malignant gestational trophoblastic neoplasia (GTN). The exact molecular mechanisms of GTN remain unknown. Dysregulation and dysfunction of programmed cell death 4 (PDCD4)have been observed in many cancers. The roles of PDCD4 in GTD have not been previously reported. METHODS: A total of 161 cases of formalin-fixed, paraffin-embedded trophoblast blocks, and 36 cases of fresh trophoblast tissues were collected, including normal first trimester placentas, HM, and invasive HM. Choriocarcinoma cells JAR and JEG-3 were employed. The expressions of PDCD4 and small ubiquitin-like modifier 2/3 (SUMO2/3) were examined by immunohistochemistry, quantitative reverse transcription PCR and Western blotting in trophoblastic tissues and cells. The relationship between SUMOylation and PDCD4 was investigated. The effects of PDCD4 on proliferation, invasion, and migration of choriocarcinoma cells were evaluated by Cell Counting Kit-8 and transwell assays post siRNA transfection. Extracellular Matrix & Adhesion Profiler PCR Array was used to screen the downstream molecules of PDCD4. RESULTS: PDCD4 was significantly repressed in HM tissues. Loss of PDCD4 expression was demonstrated in 90% invasive HMs. Choriocarcinoma cells also displayed with suppressed PDCD4 expression. The varied expression of PDCD4 was paralleled by SUMO2/3. Inhibition of SUMOylation reduced the expression of PDCD4. Silencing of PDCD4promoted proliferation/migration/invasion, upregulatedMMP3/MMP8/ITGB2, and downregulated TIMP1/TIMP2 in choriocarcinoma cells. DISCUSSION: Our results suggest that reduced SUMOylation is one reason for suppressed PDCD4 in GTD. Loss of PDCD4 likely determines the malignant phenotype of GTN by dysregulating some members of the MMPs/TIMPs/integrins complex.

The Automated External Defibrillator: Heterogeneity of Legislation, Mapping and Use across Europe. New Insights from the ENSURE Study.

INTRODUCTION: The rapid use of an automated external defibrillator (AED) is crucial for increased survival after an out-of-hospital cardiac arrest (OHCA). Many factors could play a role in limiting the chance of an AED use. We aimed to verify the situation regarding AED legislation, the AED mapping system and first responders (FRs) equipped with an AED across European countries. METHODS: We performed a survey across Europe entitled "European Study about AED Use by Lay Rescuers" (ENSURE), asking the national coordinators of the European Registry of Cardiac Arrest (EuReCa) program to complete it. RESULTS: Nineteen European countries replied to the survey request for a population covering 128,297,955 inhabitants. The results revealed that every citizen can use an AED in 15 countries whereas a training certificate was required in three countries. In one country, only EMS personnel were allowed to use an AED. An AED mapping system and FRs equipped with an AED were available in only 11 countries. The AED use rate was 12-59% where AED mapping and FR systems were implemented, which was considerably higher than in other countries (0-7.9%), reflecting the difference in OHCA survival. CONCLUSIONS: Our survey highlighted a heterogeneity in AED legislation, AED mapping systems and AED use in Europe, which was reflected in different AED use and survival.

Hypoxic effects on the mitochondrial content and functions of the placenta in fetal growth restriction.

INTRODUCTION: In this study we examined the hypothesis that a hypoxic intrauterine environment causes mitochondrial dysfunction of trophoblasts in fetal growth restriction (FGR). METHODS: The mtDNA content, mRNA levels of mitochondrial encoded genes (ND6, COX I), mitochondrial membrane proteins (COX I, COX IV and VDAC), HIF-1α and BINP3 (mitophagy receptor) protein levels were examined in FGR placentas and normal placentas. The mitochondrial function (ATP production and mitochondrial membrane potential-ΔΨm) and above related proteins were further examined in hypoxic HTR-8/SVneo cells induced by cobalt chloride (CoCl2). Mitophagy and its regulating mechanism under hypoxia in FGR was also investigated. RESULTS: Compared with normal controls, both FGR placentas and CoCl2-treated trophoblast cells demonstrated statistically lower mtDNA content, reduced mRNAs of mitochondrial encoding genes, and decreased mitochondrial membrane proteins, accompanied by increased HIF-1α. Mitochondrial functions were impaired as demonstrated by decreased ATP production, and, reduced ΔΨm in CoCl2-treated cells. Meanwhile, mitophagy was markedly enhanced as indicated by increased LC3 fluorescent puncta in mitochondria of hypoxic trophoblastic cells. The upregulated BINP3 expression was demonstrated in FGR placentas as well as in hypoxic trophoblastic cells. DISCUSSION: We demonstrated that hypoxic conditions lead to impaired mitochondrial function in trophoblasts in FGR. Reduced mtDNA may be associated with enhanced mitophagy via activating HIF-1α/BINP3 signalling pathway, that may, in turn, affect nutrition and energy transfer to the growth-restricted fetus.

Reperfusion therapies and in-hospital outcomes for ST-elevation myocardial infarction in Europe: the ACVC-EAPCI EORP STEMI Registry of the European Society of Cardiology.

AIMS: The aim of this study was to determine the contemporary use of reperfusion therapy in the European Society of Cardiology (ESC) member and affiliated countries and adherence to ESC clinical practice guidelines in patients with ST-elevation myocardial infarction (STEMI). METHODS AND RESULTS: Prospective cohort (EURObservational Research Programme STEMI Registry) of hospitalized STEMI patients with symptom onset <24 h in 196 centres across 29 countries. A total of 11 462 patients were enrolled, for whom primary percutaneous coronary intervention (PCI) (total cohort frequency: 72.2%, country frequency range 0-100%), fibrinolysis (18.8%; 0-100%), and no reperfusion therapy (9.0%; 0-75%) were performed. Corresponding in-hospital mortality rates from any cause were 3.1%, 4.4%, and 14.1% and overall mortality was 4.4% (country range 2.5-5.9%). Achievement of quality indicators for reperfusion was reported for 92.7% (region range 84.8-97.5%) for the performance of reperfusion therapy of all patients with STEMI <12 h and 54.4% (region range 37.1-70.1%) for timely reperfusion. CONCLUSIONS: The use of reperfusion therapy for STEMI in the ESC member and affiliated countries was high. Primary PCI was the most frequently used treatment and associated total in-hospital mortality was below 5%. However, there was geographic variation in the use of primary PCI, which was associated with differences in in-hospital mortality.

General practice and cardiac arrest community first response in Ireland.

BACKGROUND: In Ireland, the MERIT 3 scheme enables doctors to volunteer as cardiac arrest community first responders and receive text message alerts from emergency medical services (EMS) to facilitate early care. AIM: To establish the sustainability, systems and clinical outcomes of a novel, general practice based, cardiac arrest first response initiative over a four-year period. METHODS: Data on alerts, responses, incidents and outcomes were gathered prospectively using EMS control data, incident data reported by responders and corroborative data from the national Out-of-Hospital Cardiac Arrest Registry. RESULTS: Over the period 2016-2019, 196 doctors joined MERIT 3 and 163 (83.2%) were alerted on one or more occasions; 61.3% of those alerted responded to at least one alert. Volunteer doctors attended 300 patients of which 184 (61.3%) had suffered OHCA and had a resuscitation attempt. Responders arrived to OHCA before EMS on 75 occasions (40.8%), initiated chest compressions on seven occasions (3.8%), and brought the first defibrillator on 42 occasions (22.8%). Information on the first monitored rhythm was available for 149/184 (81.0%) patients and was shockable in 30/149 (20.1%); in 9/30 cases, shocks were administered by responders. The overall survival rate was 11.0% (national survival rate 7.3%). Doctors also provided advanced life support and were closely involved in decision making on ceasing resuscitation. CONCLUSION: The MERIT 3 initiative in Ireland has been sustained over a four-year period and has demonstrated the ability of volunteer doctors to provide early care for OHCA patients as well as more complex interventions including end-of-life care. Further development of this strategy is warranted.

'All hands-on deck', working together to develop UK standards for public involvement in research.

BACKGROUND: Public involvement in research is an established part of the research process in the UK, however there remain questions about what good public involvement in research looks and feels like. Until now public involvement practitioners, researchers and members of the public have looked for answers in examples shared across networks, published case studies, guidance and research articles. Pulling these strands together, the UK Standards for Public Involvement provides six statements (standards) about public involvement in research. They were produced by a partnership of organisations from Scotland, Northern Ireland, Wales and England with contributions from involvement practitioners, public partners, researchers and research funders. MAIN BODY: Each standard has reflective questions, which are designed to encourage standard users to use approaches and behaviours that improve involvement, over time. The standards are designed to be used as a practical tool, and reflect the agreed hallmarks of good public involvement in research for example, flexibility in approaches used, shared learning, and mutual respect.The standards development process is described from the initial idea and scoping, via the appraisal of existing standard sets and integration of values and principles in public involvement in research. The collaborative writing process of and consultation on the draft standard set is described, together with what changed as a result of feedback. The initiation of a year-long testing programme with forty participating research organisations, the experiential feedback and the resulting changes to the standards is summarised. CONCLUSION: This commentary paper describes, in some detail, a process to develop a set of six standards for public involvement in research in the UK. Producing a complex, national public involvement initiative is not without its challenges, and in supplementary material partnership members reflect on and share their experiences of standards development. The next phase of integration and implementation is explored with concluding comments from those that tested and helped improve the standards.

Inflammation-related downregulation of zonula Occludens-1 in fetal membrane contributes to development of prelabor rupture of membranes.

INTRODUCTION: The aim of this research was to study the alteration of three key tight junction proteins, to explore whether they were involved in the occurrence of prelabor rupture of the membrane (PROM) and to determine the correlation with intrauterine infection. METHODS: A total of 208 women were enrolled between January 2015 to December 2018, including those with preterm and term PROM (PROM group) and normal pregnancies with intact fetal membrane (control group). We investigated the expressions of three key TJ molecules (Zonula occludens-1, Occludin and Claudin-5) in fetal membranes. The localization and expression of Zonula occludens-1 (ZO-1) in the amnion and chorion were studied by immunohistochemistry assay. The associations between ZO-1 expression levels and extent of inflammatory reactions as well as other obstetric characteristics were further studied using Spearman's rank correlation test and Mann-Whitney U test. RESULTS: ZO-1 was significantly downregulated in PROM group compared with control group (P < 0.001), whereas no significant changes were found for Occludin and Claudin-5. ZO-1 expression was reduced in the chorion and amnion layers in PROM group compared with that in control group, which showed a significant difference (P < 0.01), but no significant differences were observed between the preterm PROM and term PROM groups (P > 0.05). The expression levels of ZO-1 in the chorion were negatively correlated with the stage/grade of acute chorioamnionitis (P < 0.05). DISCUSSION: Our study suggests that inflammation-related downregulation of ZO-1 might be a pivotal event in the occurrence of PROM, which helps to clarify the mechanism of membrane rupture caused by infection.

Transformation of Australian Community Pharmacies Into Good Clinical Practice Compliant Trial Pharmacies for HIV Pre-Exposure Prophylaxis.

Background: In Australia, clinical trial drugs are conventionally dispensed through clinical trial pharmacies only, while community pharmacies dispense drugs approved by Australia's regulatory body. A large HIV pre-exposure prophylaxis study aimed to deliver clinical trial drug through community pharmacies to improve convenience and mimic real world prescribing. This paper describes the process of making community trials compliant with good clinical practice and reports outcomes of delivering clinical trial drug through community pharmacies. Methods: Eight community and four clinical trial pharmacies across three Australian states were approached to participate. A good clinical practice checklist was generated and pharmacies underwent a number of changes to meet clinical trial pharmacy requirements prior to study opening. Changes were made to community pharmacies to make them compliant with good clinical trial practice including; staff training, structural changes, and implementing monitoring of study drug and prescribing practices. Study drug was ordered through standard clinical trial processes and dispensed from study pharmacies by accredited pharmacists. Throughout the trial, record logs for training, prescriber signature and delegation, temperature, participant, and drug accountability were maintained at each pharmacy. The study team monitored each log and delivered on-site training to correct protocol variations. Results: Each pharmacy that was approached agreed to participate. All community pharmacies achieved good clinical practice compliance prior to dispensing study drug. Over the course of the study, 20,152 dispensations of study drug occurred, 83% of these occurred at community pharmacies. Only 2.0% of dispensations had an error, and errors were predominantly minor. On five occasions a pharmacist who was not accredited dispensed study drug. Conclusions: Community based pharmacies can undergo training and modifications to achieve good clinical practice compliance and dispense clinical trial study drug. Community based pharmacies recorded few variations from study protocol. Community based pharmacies offer a useful alternative to clinical trial pharmacies to increase convenience for study participants and expanded use of these pharmacies should be considered for large clinical trials, including HIV prevention trials.

Out-of-hospital cardiac arrest survival in international airports.

BACKGROUND: The highest achievable survival rate following out-of-hospital cardiac arrest is unknown. Data from airports serving international destinations (international airports) provide the opportunity to evaluate the success of pre-hospital resuscitation in a relatively controlled but real-life environment. METHODS: This retrospective cohort study included all cases of out-of-hospital cardiac arrest at international airports with resuscitation attempted between January 1st, 2013 and December 31st, 2015. Crude incidence, patient, event characteristics and survival to hospital discharge/survival to 30 days (survival) were calculated. Mixed effect logistic regression analyses were performed to identify predictors of survival. Variability in survival between airports/countries was quantified using the median odds ratio. RESULTS: There were 800 cases identified, with an average of 40 per airport. Incidence was 0.024/100,000 passengers per year. Percentage survival for all patients was 32%, and 58% for patients with an initial shockable heart rhythm. In adjusted analyses, initial shockable heart rhythm was the strongest predictor of survival (odds ratio, 36.7; 95% confidence interval [CI], 15.5-87.0). In the bystander-witnessed subgroup, delivery of a defibrillation shock by a bystander was a strong predictor of survival (odds ratio 4.8; 95% CI, 3.0-7.8). Grouping of cases was significant at country level and survival varied between countries. CONCLUSIONS: In international airports, 32% of patients survived an out-of-hospital cardiac arrest, substantially more than in the general population. Our analysis suggested similarity between airports within countries, but differences between countries. Systematic data collection and reporting are essential to ensure international airports continually maximise activities to increase survival.

Computed tomography versus invasive coronary angiography: design and methods of the pragmatic randomised multicentre DISCHARGE trial.

OBJECTIVES: More than 3.5 million invasive coronary angiographies (ICA) are performed in Europe annually. Approximately 2 million of these invasive procedures might be reduced by noninvasive tests because no coronary intervention is performed. Computed tomography (CT) is the most accurate noninvasive test for detection and exclusion of coronary artery disease (CAD). To investigate the comparative effectiveness of CT and ICA, we designed the European pragmatic multicentre DISCHARGE trial funded by the 7th Framework Programme of the European Union (EC-GA 603266). METHODS: In this trial, patients with a low-to-intermediate pretest probability (10-60 %) of suspected CAD and a clinical indication for ICA because of stable chest pain will be randomised in a 1-to-1 ratio to CT or ICA. CT and ICA findings guide subsequent management decisions by the local heart teams according to current evidence and European guidelines. RESULTS: Major adverse cardiovascular events (MACE) defined as cardiovascular death, myocardial infarction and stroke as a composite endpoint will be the primary outcome measure. Secondary and other outcomes include cost-effectiveness, radiation exposure, health-related quality of life (HRQoL), socioeconomic status, lifestyle, adverse events related to CT/ICA, and gender differences. CONCLUSIONS: The DISCHARGE trial will assess the comparative effectiveness of CT and ICA. KEY POINTS: • Coronary artery disease (CAD) is a major cause of morbidity and mortality. • Invasive coronary angiography (ICA) is the reference standard for detection of CAD. • Noninvasive computed tomography angiography excludes CAD with high sensitivity. • CT may effectively reduce the approximately 2 million negative ICAs in Europe. • DISCHARGE addresses this hypothesis in patients with low-to-intermediate pretest probability for CAD.