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After reviewing situational and demographic factors that have been argued to affect speakers' disfluency rates, we examined disfluency rates in a corpus of task-oriented conversations (Schober & Carstensen, 2001 ) with variables that might affect fluency rates. These factors included: speakers' ages (young, middle-aged, and older), task roles (director vs. matcher in a referential communication task), difficulty of topic domain (abstract geometric figures vs. photographs of children), relationships between speakers (married vs. strangers), and gender (each pair consisted of a man and a woman). Older speakers produced only slightly higher disfluency rates than young and middle-aged speakers. Overall, disfluency rates were higher both when speakers acted as directors and when they discussed abstract figures, confirming that disfluencies are associated with an increase in planning difficulty. However, fillers (such as uh) were distributed somewhat differently than repeats or restarts, supporting the idea that fillers may be a resource for or a consequence of interpersonal coordination. [ABSTRACT FROM AUTHOR]

Abstract Background An important question is whether evolution favors properties such as mutational robustness or evolvability that do not directly benefit any individual, but can influence the course of future evolution. Functionally similar proteins can differ substantially in their robustness to mutations and capacity to evolve new functions, but it has remained unclear whether any of these differences might be due to evolutionary selection for these properties. Results Here we use laboratory experiments to demonstrate that evolution favors protein mutational robustness if the evolving population is sufficiently large. We neutrally evolve cytochrome P450 proteins under identical selection pressures and mutation rates in populations of different sizes, and show that proteins from the larger and thus more polymorphic population tend towards higher mutational robustness. Proteins from the larger population also evolve greater stability, a biophysical property that is known to enhance both mutational robustness and evolvability. The excess mutational robustness and stability is well described by mathematical theory, and can be quantitatively related to the way that the proteins occupy their neutral network. Conclusion Our work is the first experimental demonstration of the general tendency of evolution to favor mutational robustness and protein stability in highly polymorphic populations. We suggest that this phenomenon could contribute to the mutational robustness and evolvability of viruses and bacteria that exist in large populations.

Abstract Background Many of the mutations accumulated by naturally evolving proteins are neutral in the sense that they do not significantly alter a protein's ability to perform its primary biological function. However, new protein functions evolve when selection begins to favor other, "promiscuous" functions that are incidental to a protein's original biological role. If mutations that are neutral with respect to a protein's primary biological function cause substantial changes in promiscuous functions, these mutations could enable future functional evolution. Results Here we investigate this possibility experimentally by examining how cytochrome P450 enzymes that have evolved neutrally with respect to activity on a single substrate have changed in their abilities to catalyze reactions on five other substrates. We find that the enzymes have sometimes changed as much as four-fold in the promiscuous activities. The changes in promiscuous activities tend to increase with the number of mutations, and can be largely rationalized in terms of the chemical structures of the substrates. The activities on chemically similar substrates tend to change in a coordinated fashion, potentially providing a route for systematically predicting the change in one activity based on the measurement of several others. Conclusion Our work suggests that initially neutral genetic drift can lead to substantial changes in protein functions that are not currently under selection, in effect poising the proteins to more readily undergo functional evolution should selection favor new functions in the future. Reviewers This article was reviewed by Martijn Huynen, Fyodor Kondrashov, and Dan Tawfik (nominated by Christoph Adami).

Abstract A response to Fraser HB, Hirsh AE: Evolutionary rate depends on number of protein-protein interactions independently of gene expression level. BMC Evol Biol 2004, 4:13

Abstract Background Several studies have suggested that proteins that interact with more partners evolve more slowly. The strength and validity of this association has been called into question. Here we investigate how biases in high-throughput protein–protein interaction studies could lead to a spurious correlation. Results We examined the correlation between evolutionary rate and the number of protein–protein interactions for sets of interactions determined by seven different high-throughput methods in Saccharomyces cerevisiae. Some methods have been shown to be biased towards counting more interactions for abundant proteins, a fact that could be important since abundant proteins are known to evolve more slowly. We show that the apparent tendency for interactive proteins to evolve more slowly varies directly with the bias towards counting more interactions for abundant proteins. Interactions studies with no bias show no correlation between evolutionary rate and the number of interactions, and the one study biased towards counting fewer interactions for abundant proteins actually suggests that interactive proteins evolve more rapidly. In all cases, controlling for protein abundance significantly decreases the observed correlation between interactions and evolutionary rate. Finally, we disprove the hypothesis that small data set size accounts for the failure of some interactions studies to show a correlation between evolutionary rate and the number of interactions. Conclusions The only correlation supported by a careful analysis of the data is between evolutionary rate and protein abundance. The reported correlation between evolutionary rate and protein–protein interactions cannot be separated from the biases of some protein–protein interactions studies to count more interactions for abundant proteins.

Background: Acute coronary syndrome (ACS) admissions and percutaneous coronary intervention (PCI) volume declined during periods of COVID-19 lockdown internationally in 2020. The effect of lockdown on emergency medical service (EMS) utilisation, and PCI volume during the initial phase of the pandemic in Australia has not been well described., Method: We analysed data from the Victorian Cardiac Outcomes Registry (VCOR), a state-wide PCI registry, linked with the Ambulance Victoria EMS registry. PCI volume, 30-day major adverse cardiovascular and cerebrovascular events (MACCE; composite of mortality, myocardial infarction, stent thrombosis, unplanned revascularisation, and stroke), and EMS utilisation were compared over four time periods: lockdown (26 Mar 2020-12 May 2020); pre-lockdown (26 Feb 2020-25 Mar 2020); post-lockdown (13 May 2020-10 Jul 2020); and the year prior (26 Mar 2019-12 May 2019). Interrupted time series analysis was performed to assess PCI trends within and between consecutive periods., Results: The EMS utilisation for ACS during lockdown was higher compared with other periods: lockdown 39.4% vs pre-lockdown 29.7%; vs post-lockdown 33.6%; vs year prior 27.1%; all p<0.01. Median daily PCI cases were similar: 31 (IQR 10, 38) during lockdown; 39 (15, 49) pre-lockdown; 39.5 (11, 44) post-lockdown; and, 42 (10, 49) the year prior; all p>0.05. Median door-to-procedure time for ACS indication during lockdown was shorter at 3 hours (1.2, 20.6) vs pre-lockdown 3.9 (1.7, 21); vs post-lockdown 3.5 (1.5, 21.26); and, the year prior 3.5 (1.5, 23.7); all p<0.05. Lockdown period was associated with lower odds for 30-day MACCE compared to pre-lockdown (odds ratio [OR] 0.55 [0.33-0.93]; p=0.026); post-lockdown (OR 0.66; [0.40-1.06]; p=0.087); and the year prior (OR 0.55 [0.33-0.93]; p=0.026)., Conclusions: Contrary to international trends, EMS utilisation for ACS increased during lockdown but PCI volumes remained similar throughout the initial stages of the pandemic in Victoria, with no observed adverse effect on 30-day MACCE during lockdown. These data suggest that the public health response in Victoria was not associated with poorer quality cardiovascular care in patients receiving PCI., Competing Interests: Conflicts of Interest The authors have no conflicts of interest to report., (Copyright © 2024 Australian and New Zealand Society of Cardiac and Thoracic Surgeons (ANZSCTS) and the Cardiac Society of Australia and New Zealand (CSANZ). Published by Elsevier B.V. All rights reserved.)

Background: Coronary allograft vasculopathy (CAV) remains a significant cause of morbidity and mortality after heart transplantation. The use of aspirin for CAV prophylaxis has recently garnered interest as a possible therapeutic adjunct in this setting., Methods: This 2-center retrospective cohort study included 372 patients who underwent heart transplantation between January 2009 and March 2018 and were stratified according to the commencement of aspirin during their index transplant admission. The primary outcome was the development of moderate or severe CAV (International Society for Heart and Lung Transplantation grade ≥2) at surveillance coronary angiography. Secondary endpoints included mortality at follow-up., Results: There were no differences in age, sex, and cause of heart failure. In the early aspirin group, the preponderant risk factors included use of ventricular assist devices, pretransplant smoking, and mild or moderate rejection. Multivariable analyses to assess for independent predictors of CAV development and mortality demonstrated that aspirin was associated with reduced mortality (adjusted hazard ratio = 0.19; 95% confidence interval, 0.08-0.47, P < 0.01) and a trend toward a protective effect against the development of moderate or severe CAV (adjusted hazard ratio = 0.24; 95% confidence interval, 0.54-1.19; P = 0.08)., Conclusions: In this retrospective risk-adjusted 2-center cohort study, early aspirin administration was associated with reduced risk of death and a trend toward a protective effect against CAV development. These findings warrant validation in prospective randomized trials., Competing Interests: J.B. is supported by National Health and Medical Research Council (NHMRC) and National Heart Foundation Post Graduate Scholarships. D.K. is supported by an NHMRC Investigator Grant. The other authors declare no conflicts of interest., (Copyright © 2024 Wolters Kluwer Health, Inc. All rights reserved.)

Background: Although postoperative atrial fibrillation (POAF) frequently occurs early after cardiac surgery, there is a paucity of data evaluating predictors and timing of late atrial fibrillation (AF) recurrence., Objectives: The authors sought to evaluate predictors of late AF recurrence in patients undergoing cardiac surgery., Methods: We retrospectively reviewed cardiac surgery patients from 2010 to 2018 with no preoperative diagnosis of AF or atrial flutter. We recorded incidence and timing of late AF recurrence, defined as occurring ≥12 months following surgery., Results: 1,031 patients were included (mean age at surgery 64 ± 12 years, 74% male). Early POAF was recorded in 445 patients (43%). POAF was usually transient, with total AF duration <48 hours in 72% and reversion to sinus rhythm at discharge in 91%. At 4.7 ± 2.4 years follow-up, late AF occurred in 139 patients (14%). Median time to AF recurrence was 4.4 years post-surgery (Q1-Q3: 2.6-6.2 years). Late AF was significantly more likely among patients with early POAF than those without (23% vs 6%; P < 0.001), with highest incidence (38%) in those with POAF duration >48 hours. In a multivariable analysis, early POAF duration >48 hours was a significant predictor of late AF recurrence (HR: 5.9). Surgery type and CHA 2 DS 2 -VASc score were not predictive of late AF events., Conclusions: Post-operative AF episodes of duration ≥48 hours predict recurrent AF episodes over long-term follow-up after cardiac surgery. Implications for arrhythmia surveillance and anticoagulation in patients with longer duration POAF episodes require further study., Competing Interests: Funding Support and Author Disclosures The authors have reported that they have no relationships relevant to the contents of this paper to disclose., (Copyright © 2024. Published by Elsevier Inc.)

Background: Clinical outcomes of patients with renal transplant (RT) undergoing percutaneous coronary intervention (PCI) remain poorly elucidated., Method: Between 2014 and 2021, data were analysed for the following three groups of patients undergoing PCI enrolled in a multicentre Australian registry: (1) RT recipients (n=226), (2) patients on dialysis (n=992), and (3) chronic kidney disease (CKD) patients (estimated glomerular filtration rate [eGFR], 30‒60 mL/min per 1.73 m 2 ) without previous RT (n=15,534). Primary outcome was 30-day major adverse cardiac and cerebrovascular events (MACCEs)-composite of mortality, myocardial infarction, stent thrombosis, target vessel revascularisation, and stroke., Results: RT recipients were younger than dialysis and patients with CKD (61±10 vs 68±12 vs 78±8.2 years, p<0.001). Patients with RT less frequently had severe left ventricular dysfunction compared with dialysis and CKD groups (6.7% vs 14% and 8.5%); however more, often presented with acute coronary syndrome (58% vs 52% and 48%), especially STEMI (all p<0.001). Patients with RT and CKD had lower rates of 30-day MACCE (4.4% and 6.8% vs 11.6%, p<0.001) than the dialysis group. Three-year survival was similar between RT and CKD groups, however was lower in the dialysis group (80% and 83% vs 60%, p<0.001). After adjustment, dialysis was an independent predictor of 30-day MACCE (odds ratio [OR] 1.90, 95% confidence interval [CI] 1.44‒2.50, p<0.001), however RT was not (OR 0.91, CI 0.42‒1.96, p=0.802). Both RT (hazard ratio [HR] 2.07, CI 1.46‒2.95, p<0.001) and dialysis (HR 1.35, CI 1.02‒1.80, p=0.036) heightened the hazard of long-term mortality., Conclusions: RT recipients have more favourable clinical outcomes following PCI compared with patients on dialysis. However, despite having similar short-term outcomes to patients with CKD, the hazard of long-term mortality is significantly greater for RT recipients., Competing Interests: Conflicts of Interest There are no conflicts of interest to disclose., (Copyright © 2024 Australian and New Zealand Society of Cardiac and Thoracic Surgeons (ANZSCTS) and the Cardiac Society of Australia and New Zealand (CSANZ). Published by Elsevier B.V. All rights reserved.)

Objectives: We aimed to assess the healthcare costs and impact on the economy at large arising from emergency medical services (EMS) treated non-traumatic shock., Design: We conducted a population-based cohort study, where EMS-treated patients were individually linked to hospital-wide and state-wide administrative datasets. Direct healthcare costs (Australian dollars, AUD) were estimated for each element of care using a casemix funding method. The impact on productivity was assessed using a Markov state-transition model with a 3-year horizon., Setting: Patients older than 18 years of age with shock not related to trauma who received care by EMS (1 January 2015-30 June 2019) in Victoria, Australia were included in the analysis., Primary and Secondary Outcome Measures: The primary outcome assessed was the total healthcare expenditure. Secondary outcomes included healthcare expenditure stratified by shock aetiology, years of life lived (YLL), productivity-adjusted life-years (PALYs) and productivity losses., Results: A total of 21 334 patients (mean age 65.9 (±19.1) years, and 9641 (45.2%) females were treated by EMS with non-traumatic shock with an average healthcare-related cost of $A11 031 per episode of care and total cost of $A280 million. Annual costs remained stable throughout the study period, but average costs per episode of care increased (P trend =0.05). Among patients who survived to hospital, the average cost per episode of care was stratified by aetiology with cardiogenic shock costing $A24 382, $A21 254 for septic shock, $A19 915 for hypovolaemic shock and $A28 057 for obstructive shock. Modelling demonstrated that over a 3-year horizon the cohort lost 24 355 YLLs and 5059 PALYs. Lost human capital due to premature mortality led to productivity-related losses of $A374 million. When extrapolated to the entire Australian population, productivity losses approached $A1.5 billion ($A326 million annually)., Conclusion: The direct healthcare costs and indirect loss of productivity among patients with non-traumatic shock are high. Targeted public health measures that seek to reduce the incidence of shock and improve systems of care are needed to reduce the financial burden of this syndrome., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2024. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Background: Suboptimal coronary reperfusion (no reflow) is common in acute coronary syndrome percutaneous coronary intervention (PCI) and is associated with poor outcomes. We aimed to develop and externally validate a clinical risk score for angiographic no reflow for use following angiography and before PCI., Methods: We developed and externally validated a logistic regression model for prediction of no reflow among adult patients undergoing PCI for acute coronary syndrome using data from the Melbourne Interventional Group PCI registry (2005-2020; development cohort) and the British Cardiovascular Interventional Society PCI registry (2006-2020; external validation cohort)., Results: A total of 30 561 patients (mean age, 64.1 years; 24% women) were included in the Melbourne Interventional Group development cohort and 440 256 patients (mean age, 64.9 years; 27% women) in the British Cardiovascular Interventional Society external validation cohort. The primary outcome (no reflow) occurred in 4.1% (1249 patients) and 9.4% (41 222 patients) of the development and validation cohorts, respectively. From 33 candidate predictor variables, 6 final variables were selected by an adaptive least absolute shrinkage and selection operator regression model for inclusion (cardiogenic shock, ST-segment-elevation myocardial infarction with symptom onset >195 minutes pre-PCI, estimated stent length ≥20 mm, vessel diameter <2.5 mm, pre-PCI Thrombolysis in Myocardial Infarction flow <3, and lesion location). Model discrimination was very good (development C statistic, 0.808; validation C statistic, 0.741) with excellent calibration. Patients with a score of ≥8 points had a 22% and 27% risk of no reflow in the development and validation cohorts, respectively., Conclusions: The no-reflow prediction in acute coronary syndrome risk score is a simple count-based scoring system based on 6 parameters available before PCI to predict the risk of no reflow. This score could be useful in guiding preventative treatment and future trials., Competing Interests: Disclosures None.

Background: The Impella (Abiomed, Danvers, MA, USA) temporary percutaneous left ventricular assist device is increasingly used as mechanical circulatory support in patients with acute myocardial infarction-cardiogenic shock (AMICS) or those undergoing high-risk protected percutaneous coronary intervention (PCI). The optimal weaning regimen remains to be defined., Method: We implemented a structured weaning protocol in a series of 10 consecutive patients receiving Impella support for protected PCI or AMICS treated with PCI in a high volume non-cardiac surgery centre. Weaning after revascularisation was titrated to native heart recovery using both haemodynamic and echocardiographic parameters., Results: Ten patients (eight male, two female; aged 43-70 years) received Impella support for AMICS (80%) or protected PCI (20%). Cardiogenic shock was of Society for Cardiac Angiography & Interventions grade C-E of severity in 80%, and median left ventricular end-diastolic pressure was 31 mmHg. Protocol implementation allowed successful weaning in eight of 10 patients with a median support time of 29 hours (range, 4-48 hours). Explantation was associated with an increase in heart rate (81 vs 88 bpm; p=0.005), but no significant change in Cardiac Index (2.9 vs 2.9 L/min/m 2 ), mean arterial pressure (79 vs 82 mmHg), vasopressor requirement (10% vs 10%), or serum lactate (1.0 vs 1.0). Median durations of intensive care and hospital stay were 3 and 6 days, respectively. At 30 days, the mortality rate was 20%, with median left ventricular ejection fraction of 40%., Conclusions: A structured and dynamic weaning protocol for patients with AMICS and protected PCI supported by the Impella device is feasible in a non-cardiac surgery centre. Larger studies are needed to assess generalisability of such a weaning protocol., Competing Interests: Conflicts of Interest There are no conflicts of interest to disclose., (Copyright © 2023 Australian and New Zealand Society of Cardiac and Thoracic Surgeons (ANZSCTS) and the Cardiac Society of Australia and New Zealand (CSANZ). Published by Elsevier B.V. All rights reserved.)

Aims: The relationship between lower socioeconomic status (SES) and poor cardiovascular outcomes is well described; however, there exists a paucity of data exploring this association in cardiogenic shock (CS). This study aimed to investigate whether any disparities exist between SES and the incidence, quality of care or outcomes of CS patients attended by emergency medical services (EMS)., Methods and Results: This population-based cohort study included consecutive patients transported by EMS with CS between 1 January 2015 and 30 June 2019 in Victoria, Australia. Data were collected from individually linked ambulance, hospital, and mortality datasets. Patients were stratified into SES quintiles using national census data produced by the Australian Bureau of Statistics.A total of 2628 patients were attended by EMS for CS. The age-standardized incidence of CS amongst all patients was 11.8 [95% confidence interval (95% CI), 11.4-12.3] per 100 000 person-years, with a stepwise increase from the highest to lowest SES quintile (lowest quintile 17.0 vs. highest quintile 9.7 per 100 000 person-years, P-trend < 0.001). Patients in lower SES quintiles were less likely to attend metropolitan hospitals and more likely to be received by inner regional and remote centres without revascularization capabilities. A greater proportion of the lower SES groups presented with CS due to non-ST elevation myocardial infarction (NSTEMI) or unstable angina pectoris (UAP), and overall were less likely to undergo coronary angiography. Multivariable analysis demonstrated an increased 30-day all-cause mortality rate in the lowest three SES quintiles when compared with the highest quintile., Conclusion: This population-based study demonstrated discrepancies between SES status in the incidence, care metrics, and mortality rates of patients presenting to EMS with CS. These findings outline the challenges in equitable healthcare delivery within this cohort., (© The Author(s) 2023. Published by Oxford University Press on behalf of the European Society of Cardiology.)

Patients with acute coronary syndrome (ACS)-related cardiogenic shock (CS) with or without concomitant CA may have disparate prognoses. We compared clinical characteristics and outcomes of patients with CS secondary to ACS with and without cardiac arrest (CA). Between 2014 and 2020, 1,573 patients with ACS-related CS with or without CA who underwent percutaneous coronary intervention enrolled in a multicenter Australian registry were analyzed. Primary outcome was 30-day major adverse cardiovascular and cerebrovascular events (MACCE) (composite of mortality, myocardial infarction, stent thrombosis, target vessel revascularization and stroke). Long-term mortality was obtained through linkage to the National Death Index. Compared with the no-CA group (n = 769, 49%), the CA group (n = 804, 51%) was younger (62 vs 69 years, p <0.001) and had fewer comorbidities. Patients with CA more frequently had ST-elevation myocardial infarction (92% vs 86%), occluded left anterior descending artery (43% vs 33%), and severe preprocedural renal impairment (49% vs 42%) (all p <0.001). CA increased risk of 30-day MACCE by 45% (odds ratio 1.45, 95% confidence interval 1.05 to 2.00, p = 0.024) after adjustment. CA group had higher 30-day MACCE (55% vs 42%, p <0.001) and mortality (52% vs 37%, p <0.001). Three-year survival was lower for CA compared with no-CA patients (43% vs 52%, p <0.001). In Cox regression, CS with CA was associated with a trend toward greater long-term mortality hazard (hazard ratio 1.19, 95% confidence interval 1.00 to 1.41, p = 0.055). In conclusion, concomitant CA among patients with ACS-related CS conferred a particularly heightened short-term risk with a diminishing legacy effect over time for mortality. CS survivors continue to exhibit high sustained long-term mortality hazard regardless of CA status., Competing Interests: Declaration of Competing Interest The authors have no competing interests to declare., (Copyright © 2023 Elsevier Inc. All rights reserved.)

Background: Clinical features among patients with refractory out-of-hospital cardiac arrest (OHCA) and initial shockable rhythms of ventricular fibrillation/pulseless ventricular tachycardia are not well-characterized., Methods: We compared clinical characteristics and coronary angiographic findings between patients with refractory OHCA (incessant ventricular fibrillation/pulseless ventricular tachycardia after ≥3 direct-current shocks) and those without refractory OHCA., Results: Between 2014 and 2018, a total of 204 patients with ventricular fibrillation/pulseless ventricular tachycardia OHCA (median age 62; males 78%) were divided into groups with (36%, 74/204) and without refractory arrest (64%, 130/204). Refractory OHCA patients had longer cardiopulmonary resuscitation (23 versus 15 minutes), more frequently required ≥450 mg amiodarone (34% versus 3.8%), and had cardiogenic shock (80% versus 55%) necessitating higher adrenaline dose (4.0 versus 1.0 mg) and higher rates of mechanical ventilation (92% versus 74%; all P <0.01). Of 167 patients (82%) selected for coronary angiography, 33% (n=55) had refractory OHCA ( P =0.035). Significant coronary artery disease (≥1 major vessel with >70% stenosis) was present in >70% of patients. Refractory OHCA patients frequently had acute coronary occlusion (64% versus 47%), especially left circumflex (20% versus 6.4%) and graft vessel (7.3% versus 0.9%; all P <0.05) compared with those without refractory OHCA. Refractory OHCA group had higher in-hospital mortality (45% versus 30%, P =0.036) and greater new requirement for dialysis (18% versus 6.3%, P =0.011). After adjustment, refractory OHCA was associated with over 2-fold higher odds of in-hospital mortality (odds ratio, 2.28 [95% CI, 1.06-4.89]; P =0.034)., Conclusions: Refractory ventricular fibrillation/pulseless ventricular tachycardia OHCA was associated with more intensive resuscitation, higher rates of acute coronary occlusion, and poorer in-hospital outcomes, underscoring the need for future studies in this extreme-risk subgroup., Competing Interests: Disclosures None.

Cardiogenic shock is characterized by tissue hypoxia caused by circulatory failure arising from inadequate cardiac output. In addition to treating the pathologic process causing impaired cardiac function, prompt hemodynamic support is essential to reduce the risk of developing multiorgan dysfunction and to preserve cellular metabolism. Pharmacologic therapy with the use of vasopressors and inotropes is a key component of this treatment strategy, improving perfusion by increasing cardiac output, altering systemic vascular resistance, or both, while allowing time and hemodynamic stability to treat the underlying disease process implicated in the development of cardiogenic shock. Despite the use of mechanical circulatory support recently garnering significant interest, pharmacologic hemodynamic support remains a cornerstone of cardiogenic shock management, with over 90% of patients receiving at least 1 vasoactive agent. This review aims to describe the pharmacology and hemodynamic effects of current pharmacotherapies and provide a practical approach to their use, while highlighting important future research directions.

The effective recruitment and randomisation of patients in pre-hospital clinical trials presents unique challenges. Owing to the time critical nature of many pre-hospital emergencies and limited resourcing, the use of traditional methods of randomisation that may include centralised telephone or web-based systems are often not practicable or feasible. Previous technological limitations have necessitated that pre-hospital trialists strike a compromise between implementing pragmatic, deliverable study designs, with robust enrolment and randomisation methodologies. In this commentary piece, we present a novel smartphone-based solution that has the potential to align pre-hospital clinical trial recruitment processes to that of best-in-practice in-hospital and ambulatory care based studies., (Copyright © 2023 Elsevier B.V. All rights reserved.)

Aim: The role of early coronary angiography (CAG) in the evaluation of patients presenting with out of hospital cardiac arrest (OHCA) and no ST-elevation myocardial infarction (STE) pattern on electrocardiogram (ECG) has been subject to considerable debate. We sought to assess the impact of early versus deferred CAG on mortality and neurological outcomes in patients with OHCA and no STE., Methods: OVID MEDLINE, EMBASE, Web of Science and Cochrane Library Register were searched according to Preferred Reporting Items for Systematic Reviews and Meta-Analysis guidelines from inception until July 18, 2022. Randomized clinical trials (RCTs) of patients with OHCA without STE that compared early CAG with deferred CAG were included. The primary endpoint was 30-day mortality. Secondary endpoints included mortality at discharge or 30-days, favourable neurology at 30-days, major bleeding, renal failure and recurrent cardiac arrest., Results: Of the 7,998 citations, 5 RCTs randomizing 1524 patients were included. Meta-analysis showed no difference in 30-day mortality with early versus deferred CAG (OR 1.17, CI 0.91 - 1.49, I 2  = 27%). There was no difference in favourable neurological outcome at 30 days (OR 0.88, CI 0.52 - 1.49, I 2  = 63%), major bleeding (OR 0.94, CI 0.33 - 2.68, I 2  = 39%), renal failure (OR 1.14, CI 0.77 - 1.69, I 2  = 0%), and recurrent cardiac arrest (OR 1.39, CI 0.79 - 2.43, I 2  = 0%)., Conclusions: Early CAG was not associated with improved survival and neurological outcomes among patients with OHCA without STE. This meta-analysis does not support routinely performing early CAG in this select patient cohort., Competing Interests: DS is supported by National 10.13039/100002129Heart Foundation (NHF) Fellowship and National Health and Medical Research Council (NHMRC) investigator grant. JB and LD are supported by a NHMRC and a NHF Post Graduate Scholarships. DK is supported by an NHMRC Investigator Grant., (© 2023 The Authors.)

Objective: Sex differences in patients presenting with out-of-hospital cardiac arrest (OHCA) and shockable rhythm might be associated with disparities in clinical outcomes., Methods: We conducted a retrospective cohort study and compared characteristics and short-term outcomes between male and female adult patients who presented with OHCA and shockable rhythm at two large metropolitan health services in Melbourne, Australia between the period of 2014-2018. Logistic regression was used to assess the effect of sex on clinical outcomes., Results: Of 212 patients, 166 (78%) were males and 46 (22%) were females. Both males and females presented with similar rates of ST-elevation myocardial infarction (44% vs 36%, P = 0.29), although males were more likely to have a history of coronary artery disease (32% vs 13%) and a final diagnosis of a cardiac cause for their OHCA (89% vs 72%), both P = 0.01. Rates of coronary angiography (81% vs 71%, P = 0.23) and percutaneous coronary intervention (51% vs 42%, P = 0.37) were comparable among males and females. No differences in rates of in-hospital mortality (38% vs 37%, P = 0.90) and 30-day major adverse cardiac and cerebrovascular events (composite of all-cause mortality, myocardial infarction, coronary revascularization and nonfatal stroke) (39% vs 41%, P = 0.79) were observed between males and females, respectively. Female sex was not associated with worse in-hospital mortality when adjusted for other variables (odds ratio 0.66, 95% confidence interval 0.28-1.60, P = 0.36)., Conclusion: Among patients presenting with OHCA and a shockable rhythm, baseline sex and sex differences were not associated with disparities in short-term outcomes in contemporary systems of care., (© 2022 The Authors. Emergency Medicine Australasia published by John Wiley & Sons Australia, Ltd on behalf of Australasian College for Emergency Medicine.)

Background: The impact of age on outcomes in cardiogenic shock (CS) is poorly described in the pre-hospital setting. We assessed the impact of age on outcomes of patients treated by emergency medical services (EMS)., Methods: This population-based cohort study included consecutive adult patients with CS transported to hospital by EMS. Successfully linked patients were stratified into tertiles by age (18-63, 64-77, and > 77 years). Predictors of 30-day mortality were assessed through regression analyses. The primary outcome was 30-day all-cause mortality., Results: A total of 3523 patients with CS were successfully linked to state health records. The average age was 68 ± 16 years and 1398 (40%) were female. Older patients were more likely to have comorbidities including pre-existing coronary artery disease, hypertension, dyslipidemia, diabetes mellitus, and cerebrovascular disease. The incidence of CS was significantly greater with increasing age (incidence rate per 100,000 person years 6.47 [95% CI: 6.1-6.8] in age 18-63 years, 34.34 [32.4-36.4] in age 64-77 years, 74.87 [70.6-79.3] in age > 77 years, P < 0.001). There was a step-wise increase in the rate of 30-day mortality with increasing age tertile. After adjustment, compared to the lowest age tertile, patients aged > 77 years had increased risk of 30-day mortality (adjusted hazard ratio = 2.26 [95% CI: 1.96-2.60]). Older patients were less likely to receive inpatient coronary angiography., Conclusion: Older patients with EMS-treated CS have significantly higher rates of short-term mortality. The reduced rates of invasive interventions in older patients underscore the need for further development of systems of care to improve outcomes for this patient group., (© 2023 JGC All rights reserved; www.jgc301.com.)

Background: Clinical factors favouring coronary angiography (CA) selection and variables associated with in-hospital mortality among patients presenting with out-of-hospital cardiac arrest (OHCA) without ST-segment elevation (STE) remain unclear., Methods: We evaluated clinical characteristics associated with CA selection and in-hospital mortality in patients with OHCA, shockable rhythm and no STE., Results: Between 2014 and 2018, 118 patients with OHCA and shockable rhythm without STE (mean age 59; males 75%) were stratified by whether CA was performed. Of 86 (73%) patients undergoing CA, 30 (35%) received percutaneous coronary intervention (PCI). CA patients had shorter return of spontaneous circulation (ROSC) time (17 vs. 25 min) and were more frequently between 50 and 60 years (29% vs. 6.5%), with initial Glasgow Coma Scale (GCS) score >8 (24% vs. 6%) (all p < 0.05). In-hospital mortality was 33% (n = 39) for overall cohort (CA 27% vs. no-CA 50%, p = 0.02). Compared to late CA, early CA ( ≤ 2 h) was not associated with lower in-hospital mortality (32% vs. 34%, p = 0.82). Predictors of in-hospital mortality included longer defibrillation time (odds ratio 3.07, 95% confidence interval 1.44-6.53 per 5-min increase), lower pH (2.02, 1.33-3.09 per 0.1 decrease), hypoalbuminemia (2.02, 1.03-3.95 per 5 g/L decrease), and baseline renal dysfunction (1.33, 1.02-1.72 per 10 ml/min/1.73 m 2 decrease), while PCI to lesion (0.11, 0.01-0.79) and bystander defibrillation (0.06, 0.004-0.80) were protective factors (all p < 0.05)., Conclusions: Among patients with OHCA and shockable rhythm without STE, younger age, shorter time to ROSC and GCS >8 were associated with CA selection, while less effective resuscitation, greater burden of comorbidities and absence of treatable coronary lesion were key adverse prognostic predictors., (© 2022 The Authors. Catheterization and Cardiovascular Interventions published by Wiley Periodicals LLC.)

Peri-procedural stroke (PPS) is an important complication in patients who underwent percutaneous coronary intervention (PCI). The extent to which PPS impacts mortality and outcomes remains to be defined. Consecutive patients who underwent PCI enrolled in the Victorian Cardiac Outcomes Registry (2014 to 2018) were categorized into PPS and no PPS groups. The primary outcome was 30-day major adverse cardiovascular events (MACEs) (composite of mortality, myocardial infarction, stent thrombosis, and unplanned revascularization). Of 50,300 patients, PPS occurred in 0.26% patients (n = 133) (71% ischemic, and 29% hemorrhagic etiology). Patients who developed PPS were older (69 vs 66 years) compared with patients with no PPS, and more likely to have pre-existing heart failure (59% vs 29%), chronic kidney disease (33% vs 20%), and previous cerebrovascular disease (13% vs 3.6%), p &lt;0.01. Among those with PPS, there was a higher frequency of presentation with ST-elevation myocardial infarction (49% vs 18%) and out-of-hospital cardiac arrest (14% vs 2.2%), PCI by way of femoral access (59% vs 46%), and adjunctive thrombus aspiration (12% vs 3.6%), all p = &lt;0.001. PPS was associated with incident 30-day MACE (odds ratio [OR] 2.97, 95% confidence intervals [CIs] 1.86 to 4.74, p &lt;0.001) after multivariable adjustment. Utilizing inverse probability of treatment weighting analysis, PPS remained predictive of 30-day MACE (OR 1.91, 95% CI 1.31 to 2.80, p = 0.001) driven by higher 30-day mortality (OR 2.0, 95% CI 1.35 to 2.96, p = 0.001). In conclusion, in this large, multi-center registry, the incidence of PPS was low; however, its clinical sequelae were significant, with a twofold increased risk of 30-day MACE and all-cause death., (Copyright © 2022 Elsevier Inc. All rights reserved.)

Background: Patient factors, such as sex and body mass index (BMI), are known to influence patient radiation exposure. Body surface area (BSA) and its association with patient radiation exposure has not been well studied., Methods and Results: We analysed height, weight, BMI and BSA in consecutive patients undergoing cardiac catheterisation and percutaneous coronary intervention (PCI) at a high-volume Australian centre between September 2016 and April 2020 to assess their association with dose-area product (DAP, Gycm 2 ). The mean age of the cohort was 64.5 ± 12.3 years with males comprising 68.8% ( n = 8100, 5124 diagnostic cardiac catheterisation cases and 2976 PCI cases). Median male BMI was 28.4 kg/m 2 [IQR 25.2-32.1] versus 28.8 kg/m 2 [24.7-33.7] for females, p = 0.01. Males had higher BSA (2.0 ± 0.2 m 2 ) than females (1.78 ± 0.2 m 2 ), p = 0.001. Each 0.4 m 2 increase in BSA conferred a 1.32x fold change in DAP (95% CI 1.29-1.36, p ≤ 0.001). Each 5 kg/m 2 increase in BMI was linked to a 1.13x DAP fold change (1.12-1.14, p ≤ 0.001). Male sex conferred a 1.23x DAP fold change (1.20-1.26, p ≤ 0.001). Multivariable modelling with BMI or BSA explained 14% of DAP variance (R 2 0.67 vs. 0.53 for both, p ≤ 0.001)., Conclusions: BSA is an important anthropometric measure between the sexes and a key predictor of radiation dose and radiation exposure beyond sex, BMI, and weight.

Abstract: Background: Regionalized systems of care for the management of cardiogenic shock (CS) are increasingly being utilized. This study aims to assess whether receiving hospital characteristics such as the availability of 24-hour coronary angiography, on-site cardiac surgery, and annual treated CS volume influence outcomes in patients transferred by emergency medical services (EMS) to hospital with CS. Methods: This population-based cohort study included consecutive adult patients with CS who were transferred to hospital by EMS between January 1, 2015 and June 30, 2019 in Victoria, Australia. Data were obtained from individually linked ambulance, hospital, and state death index data sets. The primary outcome assessed was 30-day mortality stratified by the availability of 24-hour coronary angiography (cardiac center) at the receiving hospital. Results: A total of 3,217 patients were transferred to hospital with CS. The population had an average age of 67.9 +/- 16.1 years, and 1,289 (40.1%) were female. EMS transfer to a cardiac center was associated with significantly reduced rates of 30-day mortality (adjusted odds ratio [aOR], 0.78; 95% confidence interval [CI], 0.64-0.95), compared with noncardiac centers. Compared with the lowest annual CS volume quartile (<18 cases per year), hospitals in the highest volume quartile (>55 cases per year) had reduced risk of 30-day mortality (aOR, 0.71; 95% CI, 0.56-0.91). A stepwise reduction in the adjusted probability of 30-day mortality was observed in patients transferred by EMS to trauma level 1 centers (34.6%), compared with cardiothoracic surgical centers (39.0%), noncardiac surgical metropolitan (44.9%), and rural (51.3%) cardiac centers, all P < 0.05. Conclusion: Receiving hospital characteristics are associated with survival outcomes in patients with CS. These finding have important implications for establishing regionalized systems of care for patients with CS who are transferred to hospital by EMS., Competing Interests: Conflicts of interest: The authors have no affiliations with or involvement in any organization or entity with any financial interest, or nonfinancial interest in the subject matter or materials discussed in this manuscript., (Copyright © 2022 by the Shock Society.)

Background: Adrenaline is routinely administered during cardiac arrest resuscitation. Using a novel murine model of cardiac arrest, this study evaluates the effects of adrenaline use on survival and end-organ injury., Methods: A total of 58 mice, including cardiac arrest (CA) and sham (SHAM) groups received intravenous potassium chloride either as a bolus (CA) or slow infusion (SHAM), inducing ECG-confirmed asystole (in CA only) for 4-minutes prior to intravenous adrenaline (+ADR;250 ul,32 ug/ml) or saline (-ADR;250 ul) and manual chest compressions (300 BPM) for 4-minutes. Mice with return of spontaneous circulation (ROSC) were assessed at 24- or 72-h timepoints., Results: Among animals that underwent CA, rates of ROSC ( n  = 21 (95 %) vs n  = 14 (82 %), P  = 0.18) and survival to the planned endpoint ( n  = 11 (50 %) vs n  = 12 (71 %), P  = 0.19) were similar when comparing those treated with (CA+ADR) and without (CA-ADR) adrenaline. However, in CA animals that initially achieved ROSC, subsequent mortality was approximately 3-fold greater with adrenaline treatment (48 % vs 14 %, P  = 0.042). Among SHAM animals, adrenaline use had no impact on survival rates or other endpoints. Greater myocardial injury occurred in CA+ADR vs CA-ADR, with increased Hs-Troponin levels measured at 24- (26.0 ± 0.9 vs 9.4 ± 5.3 ng/mL, P  = 0.015) and 72-h (20.9 ± 8.3 vs 5.0 ± 2.4 ng/mL, P  = 0.012), associated with increased expression of pro-inflammatory and fibrotic genes within cardiac and renal tissue., Conclusion: Adrenaline did not improve ROSC or overall survival but following successful ROSC, its use resulted in 3-fold greater mortality rates. Adrenaline was also associated with increased myocardial injury, end-organ inflammation, and fibrosis. These findings underscore the need for further preclinical evaluation of alternate pharmacologic adjuncts for cardiopulmonary resuscitation that improve survival and limit end-organ injury., Competing Interests: The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (© 2022 The Author(s).)

Cardiogenic shock is associated with a high risk for morbidity and mortality. The impact of gender on treatment and outcomes is poorly defined. This study aimed to evaluate whether gender influences the clinical management and outcomes of patients with prehospital cardiogenic shock. Consecutive adult patients with cardiogenic shock who were transferred to hospital by emergency medical services (EMS) between January 1, 2015 and June 30, 2019 in Victoria, Australia were included. Data were obtained from individually linked ambulance, hospital, and state death index datasets. The primary outcome assessed was 30-day mortality, stratified by patient gender. Propensity score matching was performed for risk adjustment. Over the study period a total of 3,465 patients were identified and 1,389 patients (40.1%) were women. Propensity score matching yielded 1,330 matched pairs with no differences observed in baseline characteristics, including age, initial vital signs, pre-existing co-morbidities, etiology of shock, and prehospital interventions. In the matched cohort, women had higher rates of 30-day mortality (44.7% vs 39.2%, p = 0.009), underwent less coronary angiography (18.3% vs 27.2%, p <0.001), and revascularization with percutaneous coronary intervention (8.9% vs 14.2%, p <0.001), compared with men. In conclusion, in this large population-based study, women with cardiogenic shock who were transferred by EMS to hospital had significantly worse survival outcomes and reduced rates of invasive cardiac interventions compared to men. These data underscore the urgent need for targeted public health measures to redress gender differences in outcomes and variation with clinical care for patients with cardiogenic shock., Competing Interests: Disclosures The authors have no conflicts of interest to declare., (Copyright © 2022 Elsevier Inc. All rights reserved.)

Purpose: During the COVID-19 pandemic, widespread public health measures were implemented to control community transmission. The association between these measures and health-related quality of life (HRQOL) among patients following percutaneous coronary intervention has not been studied., Methods: We included consecutive patients undergoing percutaneous coronary intervention (PCI) in the state-wide Victorian Cardiac Outcomes Registry between 1/3/2020 and 30/9/2020 (COVID-19 period; n = 5024), with a historical control group from the identical period one year prior (control period; n = 5041). HRQOL assessment was performed via telephone follow-up 30 days following PCI using the 3-level EQ-5D questionnaire and Australian-specific index values., Results: Baseline characteristics were similar between groups, but during the COVID-19 period indication for PCI was more common for acute coronary syndromes. No patients undergoing PCI were infected with COVID-19 at the time of their procedure. EQ-5D visual analogue score (VAS), index score, and individual components were higher at 30 days following PCI during the COVID-19 period (all P < 0.01). In multivariable analysis, the COVID-19 period was independently associated with higher VAS and index scores. No differences were observed between regions or stage of restrictions in categorical analysis. Similarly, in subgroup analysis, no significant interactions were observed., Conclusion: Measures of HRQOL following PCI were higher during the COVID-19 pandemic compared to the previous year. These data suggest that challenging community circumstances may not always be associated with poor patient quality of life., (© 2021. The Author(s), under exclusive licence to Springer Nature Switzerland AG.)

Background: Problematic mitral regurgitation (MR) may develop following lung transplantation (LTx). There is limited information on the management of MR in LTx patients, as such we sought to evaluate our centre's experience., Methods: From 2000 to 2019, 1,054 patients underwent LTx at our centre (896 bilateral, 158 single). We identified patients in whom significant MR developed at any point post-LTx. The aetiology of MR, management and outcome were retrospectively analysed., Results: Eight (8) patients developed severe MR post-LTx, six following bilateral LTx and two following single LTx. Lung transplantation indications included interstitial lung disease (n=5), chronic obstructive pulmonary disease (n=2) and pulmonary arterial hypertension (n=1). Severe MR occurred intraoperatively (n=1), postoperative day 1 (n=1) with the remaining six cases between 80 and 263 days post-LTx. The aetiology was noted to be due to severe left ventricular dysfunction following unmasking of a chronically pulmonary hypertension-related under-preloaded left ventricle in one case, and in the remaining seven patients causes included myxomatous degeneration, ischaemic MR, and functional MR due to annular dilatation. In the patient with intraoperative severe MR, the MR became mild with veno-arterial extracorporeal membrane oxygenation (VA-ECMO) and in the remaining seven patients a variety of procedures were used, including mitral valve repair, valve replacement and transcatheter edge-to-edge mitral valve repair. All patients survived the mitral procedure. Two (2) deaths occurred at 12.9 years (stroke) and 5 years (cancer) from mitral valve surgery., Conclusions: Development of significant mitral valve regurgitation is a rare but morbid complication after lung transplantation. This may represent the progressive natural history of pre-existing degenerative mitral valve disease and rarely, early after transplantation may be related to changes in ventricular geometry. Management of severe MR can follow the same management approach as in the non-transplant community, with the expectation of similarly good results., (Copyright © 2021 Australian and New Zealand Society of Cardiac and Thoracic Surgeons (ANZSCTS) and the Cardiac Society of Australia and New Zealand (CSANZ). Published by Elsevier B.V. All rights reserved.)

Objectives: This study sought to assess the association between cardiac surgery availability and percutaneous coronary intervention (PCI) volume with clinical outcomes of cardiogenic shock (CS) complicating acute coronary syndrome (ACS)., Background: CS remains a grave complication of ACS with high mortality rates despite timely reperfusion and improved heart failure therapies., Methods: The study analyzed data from consecutive patients with CS complicating ACS who underwent PCI and were prospectively enrolled in the VCOR (Victorian Cardiac Outcomes Registry) from 26 hospitals in Victoria. We compared patients treated at cardiac surgical centers (CSCs) versus non-CSCs as well as the annual CS PCI volume (stratified into tiers of <10, 10-25, and >25 cases) for in-hospital major adverse cardiac and cerebrovascular events (MACCE) and long-term mortality., Results: Of 1,179 patients with CS, the mean age of patients was 65 years; males comprised 74%, and 22% had diabetes mellitus. Cardiac arrest occurred in 38% of patients, while 90% presented with ST-segment elevation myocardial infarction and 26% received intra-aortic balloon pump support. Overall, in-hospital and long-term mortality were 42% and 51%, respectively. There was no difference among patients treated non-CSCs compared with a CSCs for in-hospital MACCE and mortality (both P > 0.05). Similarly, there was no association between tiers of annual CS PCI volume with in-hospital MACCE and mortality (both P > 0.05)., Conclusions: Comparable short- and long-term mortality rates among patients with ACS complicated by CS treated by PCI irrespective of cardiac surgery availability and CS PCI volume support the emergent treatment of these gravely ill patients at their presenting PCI-capable hospital., Competing Interests: Funding Support and Author Disclosures The Victorian Cardiac Outcomes Registry was originally co-funded by the Victorian Department of Health in 2011 and by a one-off grant from Medibank Private. It is currently funded by the Department of Health and Human Services, Victoria, with in-kind funding from Monash University. Dr Noaman is supported by the Australian National Health Foundation (Health Professional Scholarship Award ID 102336) and the National Health and Medical Research Council Centre of Research Excellence in Cardiovascular Outcome Improvement (CRECOI Scholarship). The authors have reported that they have no relationships relevant to the contents of this paper to disclose., (Copyright © 2022 American College of Cardiology Foundation. Published by Elsevier Inc. All rights reserved.)

Importance: Nontraumatic shock is a challenging clinical condition, presenting urgent and unique demands in the prehospital setting. There is a paucity of data assessing its incidence, etiology, and clinical outcomes., Objective: To assess the incidence, etiology, and clinical outcomes of patients treated by emergency medical services (EMS) with nontraumatic shock using a large population-based sample., Design, Setting, and Participants: This population-based cohort study included consecutive adult patients with shock not related to trauma who received care by EMS between January 1, 2015, and June 30, 2019, in Victoria, Australia. Data were obtained from individually linked ambulance, hospital, and state death index data sets. During the study period there were 2 485 311 cases attended by EMS, of which 16 827 met the study's inclusion criteria for shock., Main Outcomes and Measures: The primary outcome was 30-day mortality. Secondary outcomes included length of hospital stay, emergency department discharge disposition, rates of coronary angiography and revascularization procedures, and the use of mechanical circulatory support., Results: A total of 12 695 patients were successfully linked, with a mean (SD) age of 65.7 (19.1) years; 6411 (50.5%) were men. The overall population-wide incidence of EMS-treated prehospital shock was 76 (95% CI, 75-77) per 100 000 person-years. An increased incidence was observed in men (79 [77-81] per 100 000 person-years), older patients (eg, aged 70-79 years: 177 [171-183] per 100 000 person-years), regional locations (outer regional or remote: 100 [94-107] per 100 000 person-years), and in areas with increased socioeconomic disadvantage (lowest socioeconomic status quintile: 92 [89-95] per 100 000 person-years). Patients with hospital outcome data were stratified into shock etiologies; 3615 (28.5%) had cardiogenic shock: 3998 (31.5%), septic shock; 1457 (11.5%), hypovolemic shock; and 3625 (28.6%), other causes of shock. Nearly one-third of patients (4158 [32.8%]) were deceased at 30 days. In multivariable analyses, increased age (all etiologies: hazard ratio [HR], 1.04; 95% CI, 1.03-1.04), female sex (cardiogenic shock: HR, 1.26; 95% CI, 1.12-1.42), increased initial heart rate (all etiologies: 1.01; 95% CI, 1.00-1.01), prehospital intubation (all etiologies: HR, 3.93; 95% CI, 3.48-4.44), and preexisting comorbidities (eg, chronic kidney disease, all etiologies: HR, 1.25; 95% CI, 1.10-1.42) were independently associated with 30-day mortality, while higher socioeconomic status (all etiologies: HR, 0.96; 95% CI, 0.94-0.98) and increased initial systolic blood pressure (all etiologies: HR, 0.99; 95% CI, 0.99-0.99) were associated with lower risk., Conclusions and Relevance: This population-level cohort study found that EMS-treated nontraumatic shock was a common condition, with a high risk of morbidity and mortality regardless of etiology. It disproportionately affected men, older patients, patients in regional areas, and those with social disadvantage. Further studies are required to assess how current systems of care can be optimized to improve outcomes.

Aims: This study aims to evaluate if pre-hospital heparin administration by paramedics is safe and improves clinical outcomes., Methods and Results: Using the multicentre Victorian Cardiac Outcomes Registry, linked with state-wide ambulance records, we identified consecutive patients undergoing primary percutaneous coronary intervention for STEMI between January 2014 and December 2018. Information on thrombolysis in myocardial infarction (TIMI) flow at angiography was available in a subset of cases. Patients receiving pre-hospital heparin were compared to those who did not receive heparin. Findings at coronary angiography and 30-day clinical outcomes were compared between groups. Propensity-score matching was performed for risk adjustment. We identified a total of 4720 patients. Of these, 1967 patients had TIMI flow data available. Propensity-score matching in the entire cohort yielded 1373 matched pairs. In the matched cohort, there was no observed difference in 30-day mortality (no-heparin 3.5% vs. heparin 3.0%, P = 0.25), MACCE (no-heparin 7% vs. heparin 6.2%, P = 0.44), and major bleeding (no-heparin 1.9% vs. heparin 1.4%, P = 0.64) between groups. Propensity-score analysis amongst those with TIMI data produced 552 matched pairs. The proportion of cases with TIMI 0 or 1 flow in the infarct-related artery (IRA) was lower among those receiving pre-hospital heparin (66% vs. 76%, P < 0.001) compared to those who did not., Conclusion: In this multicentre, propensity-score matched study, the use of pre-hospital heparin by paramedics was safe and is associated with fewer occluded IRAs in patients presenting with STEMI., (Published on behalf of the European Society of Cardiology. All rights reserved. © The Author(s) 2021. For permissions, please email: journals.permissions@oup.com.)

Background: Chromosome 15q11-q13 duplication syndrome (Dup15q) is a neurogenetic disorder caused by duplications of the maternal copy of this region. In addition to hypotonia, motor deficits, and language impairments, patients with Dup15q commonly meet the criteria for autism spectrum disorder and have a high prevalence of seizures. It is known from mouse models that synaptic impairments are a strong component of Dup15q pathophysiology; however, cellular phenotypes that relate to seizures are less clear. The development of patient-derived induced pluripotent stem cells provides a unique opportunity to study human neurons with the exact genetic disruptions that cause Dup15q., Methods: Here, we explored electrophysiological phenotypes in induced pluripotent stem cell-derived neurons from 4 patients with Dup15q compared with 6 unaffected control subjects, 1 patient with a 15q11-q13 paternal duplication, and 3 patients with Angelman syndrome., Results: We identified several properties of Dup15q neurons that could contribute to neuronal hyperexcitability and seizure susceptibility. Compared with control neurons, Dup15q neurons had increased excitatory synaptic event frequency and amplitude, increased density of dendritic protrusions, increased action potential firing, and decreased inhibitory synaptic transmission. Dup15q neurons also showed impairments in activity-dependent synaptic plasticity and homeostatic synaptic scaling. Finally, Dup15q neurons showed an increased frequency of spontaneous action potential firing compared with control neurons, in part due to disruption of KCNQ2 potassium channels., Conclusions: Together, these data point to multiple electrophysiological mechanisms of hyperexcitability that may provide new targets for the treatment of seizures and other phenotypes associated with Dup15q., (Copyright © 2021 Society of Biological Psychiatry. Published by Elsevier Inc. All rights reserved.)

Background: The renin-angiotensin-aldosterone system plays a key role in blood pressure (BP) regulation and is the target of several antihypertensive medications. Renal denervation (RDN) is thought to interrupt the sympathetic-mediated neurohormonal pathway as part of its mechanism of action to reduce BP., Objectives: The purpose of this study was to evaluate plasma renin activity (PRA) and aldosterone before and after RDN and to assess whether these baseline neuroendocrine markers predict response to RDN., Methods: Analyses were conducted in patients with confirmed absence of antihypertensive medication. Aldosterone and PRA levels were compared at baseline and 3 months post-procedure for RDN and sham control groups. Patients in the SPYRAL HTN-OFF MED Pivotal trial were separated into 2 groups, those with baseline PRA ≥0.65 ng/ml/h (n = 110) versus <0.65 ng/ml/h (n = 116). Follow-up treatment differences between RDN and sham control groups were adjusted for baseline values using multivariable linear regression models., Results: Baseline PRA was similar between RDN and control groups (1.0 ± 1.1 ng/ml/h vs. 1.1 ± 1.1 ng/ml/h; p = 0.37). Change in PRA at 3 months from baseline was significantly greater for RDN compared with control subjects (-0.2 ± 1.0 ng/ml/h; p = 0.019 vs. 0.1 ± 0.9 ng/ml/h; p = 0.14), p = 0.001 for RDN versus control subjects, and similar differences were seen for aldosterone: RDN compared with control subjects (-1.2 ± 6.4 ng/dl; p = 0.04 vs. 0.4 ± 5.4 ng/dl; p = 0.40), p = 0.011. Treatment differences at 3 months in 24-h and office systolic blood pressure (SBP) for RDN versus control patients were significantly greater for patients with baseline PRA ≥0.65 ng/ml/h versus <0.65 ng/ml/h, despite similar baseline BP. Differences in office SBP changes according to baseline PRA were also observed earlier at 2 weeks post-RDN., Conclusions: Plasma renin activity and aldosterone levels for RDN patients were significantly reduced at 3 months when compared with baseline as well as when compared with sham control. Higher baseline PRA levels were associated with a significantly greater reduction in office and 24-h SBP. (SPYRAL PIVOTAL - SPYRAL HTN-OFF MED Study; NCT02439749)., Competing Interests: Funding Support and Author Disclosures The SPYRAL HTN-OFF MED Pivotal trial was sponsored by Medtronic. Profs. Mahfoud and Böhm are supported by Deutsche Forschungsgemeinschaft (SFB TRR219). Prof. Mahfoud is supported by Deutsche Gesellschaft für Kardiologie; and has received scientific support and speaker honoraria from Bayer, Boehringer Ingelheim, Medtronic, and ReCor Medical. Prof. Townsend has received consultant fees from Medtronic, Axio, and Regeneron. Dr. Kandzari has received institutional research/grant support from Medtronic CardioVascular and Ablative Solutions; and has received personal consulting honoraria from Medtronic CardioVascular. Prof. Kario has received scientific support and speaker honoraria from Daichi-Sankyo, Sanwa Chemical, Boehringer Ingelheim, Omron Healthcare, A&D Inc., Fukudadenshi Inc., Medtronic, and ReCor Medical. Prof. Schmieder has received consultant fees from Medtronic and Recor; and has received grant support from Medtronic, Recor, and Ablative Solutions. Dr. Tsioufis has received honoraria for advisory boards and lectures from Medtronic, Servier, Bayer, Menarini, Novartis, AstraZeneca, Boehringer Inc., Pfizer, Pythagoras, Sanofi, and Amgen. Dr. Pocock has received consultant fees from Medtronic. Dr. Walton has served as a proctor for Medtronic and Abbott; has served on the medical advisory board for Medtronic; and has received grant support from Medtronic, Abbott, and Edwards. Prof. T. Weber has received scientific support from I.E.M. GmbH. Dr. Cohen and Mr. Fahy are employees and shareholders for Medtronic. Prof. Böhm has received consulting fees from Abbott Vascular, Bayer AG, Amgen, AstraZeneca, Servier, Medtronic, Vifor, and Boehringer Ingelheim. Prof. M. Weber has received consulting fees from Medtronic, ReCor, and Ablative Solutions. All other authors have reported that they have no relationships relevant to the contents of this paper to disclose., (Copyright © 2021 The Authors. Published by Elsevier Inc. All rights reserved.)

Aims: We aimed to assess the impact of the severity of chronic kidney disease (CKD) with long-term clinical outcomes in patients undergoing percutaneous coronary intervention (PCI)., Methods: We analyzed data on consecutive patients undergoing PCI enrolled in the Victorian Cardiac Outcomes Registry (VCOR) from January 2014 to December 2018. Patients were stratified into tertiles of renal function; estimated glomerular filtration (eGFR) ≥60, 30-59 and < 30 ml/min/1.73 m 2 (including dialysis). The primary outcome was long-term all-cause mortality obtained from linkage with the Australian National Death Index (NDI). The secondary endpoint was a composite of 30 day major adverse cardiac and cerebrovascular events., Results: We identified a total of 51,480 patients (eGFR ≥60, n = 40,534; eGFR 30-59, n = 9,521; eGFR <30, n = 1,425). Compared with patients whose eGFR was ≥60, those with eGFR 30-59 and eGFR<30 were on average older (77 and 78 vs. 63 years) and had a greater burden of cardiovascular risk factors. Worsening CKD severity was independently associated with greater adjusted risk of long-term NDI mortality: eGFR<30 hazard ratio 4.21 (CI 3.7-4.8) and eGFR 30-59; 1.8 (CI 1.7-2.0), when compared to eGFR ≥60, all p < .001., Conclusion: In this large, multicentre PCI registry, severity of CKD was associated with increased risk of all-cause mortality underscoring the high-risk nature of this patient cohort., (© 2020 Wiley Periodicals LLC.)

Loss of UBE3A expression, a gene regulated by genomic imprinting, causes Angelman syndrome (AS), a rare neurodevelopmental disorder. The UBE3A gene encodes an E3 ubiquitin ligase with three known protein isoforms in humans. Studies in mouse suggest that the human isoforms may have differences in localization and neuronal function. A recent case study reported mild AS phenotypes in individuals lacking one specific isoform. Here we have used CRISPR/Cas9 to generate isogenic human embryonic stem cells (hESCs) that lack the individual protein isoforms. We demonstrate that isoform 1 accounts for the majority of UBE3A protein in hESCs and neurons. We also show that UBE3A predominantly localizes to the cytoplasm in both wild type and isoform-null cells. Finally, we show that neurons lacking isoform 1 display a less severe electrophysiological AS phenotype., (© The Author(s) 2020. Published by Oxford University Press. All rights reserved. For Permissions, please email: journals.permissions@oup.com.)

In rule-based modeling, molecular interactions are systematically specified in the form of reaction rules that serve as generators of reactions. This provides a way to account for all the potential molecular complexes and interactions among multivalent or multistate molecules. Recently, we introduced rule-based modeling into the Virtual Cell (VCell) modeling framework, permitting graphical specification of rules and merger of networks generated automatically (using the BioNetGen modeling engine) with hand-specified reaction networks. VCell provides a number of ordinary differential equation and stochastic numerical solvers for single-compartment simulations of the kinetic systems derived from these networks, and agent-based network-free simulation of the rules. In this work, compartmental and spatial modeling of rule-based models has been implemented within VCell. To enable rule-based deterministic and stochastic spatial simulations and network-free agent-based compartmental simulations, the BioNetGen and NFSim engines were each modified to support compartments. In the new rule-based formalism, every reactant and product pattern and every reaction rule are assigned locations. We also introduce the rule-based concept of molecular anchors. This assures that any species that has a molecule anchored to a predefined compartment will remain in this compartment. Importantly, in addition to formulation of compartmental models, this now permits VCell users to seamlessly connect reaction networks derived from rules to explicit geometries to automatically generate a system of reaction-diffusion equations. These may then be simulated using either the VCell partial differential equations deterministic solvers or the Smoldyn stochastic simulator., (Copyright © 2017 Biophysical Society. Published by Elsevier Inc. All rights reserved.)

Background: The androgen receptor (AR) is a key oncogenic driver of prostate cancer, and has been the primary focus of prostate cancer treatment for several decades. We have previously demonstrated that the AR is also an immunological target antigen, recognized in patients with prostate cancer, and targetable by means of vaccines in rodent models with delays in prostate tumor growth. The current study was performed to determine the safety and immunological efficacy of a GMP-grade plasmid DNA vaccine encoding the ligand-binding domain (LBD) of the AR, pTVG-AR., Methods: Groups of male mice (n = 6-10 per group) were evaluated after four or seven immunizations, using different schedules and inclusion of GM-CSF as a vaccine adjuvant. Animals were assessed for toxicity using gross observations, pathological analysis, and analysis of serum chemistries. Animals were analyzed for evidence of vaccine-augmented immunity by tetramer analysis. Survival studies using different immunization schedules and inclusion of GM-CSF were conducted in an autochthonous genetically engineered mouse model., Results: No significant toxicities were observed in terms of animal weights, histopathology, hematological changes, or changes in serum chemistries, although there was a trend to lower serum glucose in animals treated with the vaccine. There was specifically no evidence of toxicity in other tissues that express AR, including liver, muscle, hematopoietic, and brain. Vaccination was found to elicit AR LBD-specific CD8+ T cells. In a subsequent study of tumor-bearing animals, animals treated with vaccine had prolonged survival compared with control-immunized mice., Conclusions: These studies demonstrate that, in immunocompetent mice expressing the target antigen, immunization with the pTVG-AR vaccine was both safe and effective in eliciting AR-specific cellular immune responses, and prolonged the survival of prostate tumor-bearing mice. These findings support the clinical evaluation of pTVG-AR in patients with recurrent prostate cancer. Prostate 77:812-821, 2017. © 2017 Wiley Periodicals, Inc., (© 2017 Wiley Periodicals, Inc.)

Introduction: In December 2013, our institution changed the target temperature management (TTM) for the first 24h in ventricular fibrillation out-of-hospital cardiac arrest (VF-OHCA) patients from 33°C to 36°C. This study aimed to examine the impact this change had on measured temperatures and patient outcomes., Methods: We conducted a retrospective cohort study of consecutive VF-OHCA patients admitted to a tertiary referral hospital in Melbourne (Australia) between January 2013 and August 2015. Outcomes were adjusted for age and duration of cardiac arrest., Results: Over the 30-month period, 76 VF-OHCA cases were admitted (24 before and 52 after the TTM change). Patient demographics, cardiac arrest features and hospital interventions were similar between the two periods. After the TTM change, less patients received active cooling (100% vs. 70%, p < 0.001), patients spent less time at target temperature (87% vs. 50%, p < 0.001), and fever rates increased (0% vs. 19%, p = 0.03). ​During the 36°C period, there was a decrease in the proportion of patients who were discharged: alive (71% vs. 58%, p=0.31), home (58% vs. 40%, p=0.08); and, with a favourable neurological outcome (cerebral performance category score 1-2: 71% vs. 56%, p=0.22)., Conclusion: After the change from a TTM target of 33°C to 36°C, we report low compliance with target temperature, higher rates of fever, and a trend towards clinical worsening in patient outcomes. Hospitals adopting a 36°C target temperature to need to be aware that this target may not be easy to achieve, and requires adequate sedation and muscle-relaxant to avoid fever., (Copyright © 2017 Elsevier B.V. All rights reserved.)

Prostate cancer is the most commonly diagnosed malignancy for men in the United States. Metastatic prostate cancer, the lethal form of the disease, has a life expectancy of approximately five years. Identification of factors associated with this transition to metastatic disease is crucial for future therapies. One such factor is the SSX gene family, a family of cancer/testis antigens (CTA) transcription factors which have been shown to be aberrantly expressed in other cancers and associated with the epithelial to mesenchymal transition (EMT). We have previously shown that SSX expression in prostate cancers was restricted to metastatic tissue and not primary tumors. In this study, we have identified SSX2 as the predominant SSX family member expressed in prostate cancer, and found its expression in the peripheral blood of 19 of 54 (35%) prostate cancer patients, with expression restricted to circulating tumor cells, and in 7 of 15 (47%) metastatic cDNA samples. Further, we examined SSX2 function in prostate cancer through knockdown and overexpression in prostate cancer cell lines. While overexpression had little effect on morphology or gene transcript changes, knockdown of SSX2 resulted in an epithelial morphology, increased cell proliferation, increased expression of genes involved in focal adhesion, decreased anchorage independent growth, increased invasion, and increased tumorigenicity in vivo. We conclude from these findings that SSX2 expression in prostate cancer is not a driver of EMT, but is involved in processes associated with EMT including loss of focal adhesion that may be related to tumor cell dissemination., Competing Interests: CONFLICTS OF INTERESTS The authors declare no competing financial interests.

Background: Methamphetamine abuse is a growing public health problem, and increasing numbers of patients are admitted with methamphetamine-associated cardiomyopathy (MAC)., Aim: We sought to characterise the patterns of this disease and identify predictors of recovery., Methods: We retrospectively studied consecutive patients diagnosed with MAC between January 2006 and July 2015., Results: We identified 20 patients (14 males, 6 females) with mean age 35 ± 9 years. Most had very severe systolic dysfunction (mean left ventricular ejection fraction (LVEF) 19.7 ± 11.4%) at presentation with 14 requiring inotropes and 5 requiring mechanical support. The pattern of systolic dysfunction was global in 14 patients, while 6 patients had a 'reverse Takotsubo' (RT) pattern with severely hypokinetic basal-mid segments and apical preservation. RT patients were predominantly female, had a short history of methamphetamine abuse and had higher cardiac enzyme levels. Patients with global dysfunction tended to have mid-wall fibrosis on cardiac magnetic resonance imaging. On follow-up transthoracic echocardiography, 6 out of 19 (32%) had normalisation of LVEF (LVEF ≥ 50%) within 6 weeks. Smaller left ventricular and left atrial size, shorter duration of methamphetamine use and RT pattern appeared to predict early recovery., Conclusion: A subset of MAC patients, particularly those with a RT pattern and lesser ventricular dilatation have the potential for early recovery of ventricular function. By contrast, those with evidence of myocardial fibrosis and ventricular enlargement have limited scope for recovery., (© 2016 Royal Australasian College of Physicians.)

Evaluation of: Kawaguchi S, Tsukahara T, Ida K et al. SYT-SSX breakpoint peptide vaccines in patients with synovial sarcoma: a study from the Japanese Musculoskeletal Oncology Group. Cancer Sci. 103(9), 1625-1630 (2012). The identification of genetic translocations as key tumor-initiating events has led to the development of novel antigen-specific vaccines targeting these tumor-specific breakpoint regions. Previous studies have evaluated vaccines targeting the breakpoints in the BCR-ABL translocation in patients with chronic myelogenous leukemia and EWS-FLI1 in patients with Ewing sarcoma. In the article under evaluation, the authors evaluated a peptide vaccine targeting the breakpoint in the SYT-SSX translocation, the genetic translocation essentially pathognomonic for synovial sarcoma. This is the second small clinical trial reported by this group using HLA-A24-binding peptides as vaccine antigens. In this four-arm trial, using a native or HLA-A24-optimized SYT-SSX peptide with or without adjuvant plus IFN-α, they immunized patients with metastatic synovial sarcoma. Immune responses were evaluated by delayed-type hypersensitivity testing and tetramer analysis. No robust evidence of immune response to the target epitope was detected. Some patients treated with peptide in adjuvant plus IFN-α had stable disease. These results suggest that future similar studies might best evaluate patients with a lower burden of disease, consider alternative immunization approaches to the SYT-SSX target antigen and consider the efficacy of IFN-α alone for the treatment of synovial sarcoma.

Background: Traditionally, glucocorticoid injection for the treatment of shoulder pain has been performed guided by anatomical landmarks alone. With the advent of readily available imaging tools such as ultrasound, image-guided injections have increasingly become accepted into routine care. While there is some evidence that the use of imaging improves accuracy, it is unclear from current evidence whether or not it improves patient-relevant outcomes., Objectives: The aim of this review was to assess whether image-guided glucocorticoid injections improve patient-relevant outcomes compared to landmark-guided or systemic intramuscular injections in patients with shoulder pain., Search Methods: We searched the Cochrane Central Register of Controlled Trials (CENTRAL, via The Cochrane Library), MEDLINE (Ovid), and EMBASE (Ovid) to June 2011. We also searched the World Health Organisation International Clinical Trials Registry Platform (http://www.who.int/trialsearch/Default.aspx) to identify ongoing trials and screened reference lists of retrieved review articles and trials to identify potentially relevant studies., Selection Criteria: We included randomised controlled trials (RCTs) and quasi-randomised controlled clinical trials that compared image-guided glucocorticoid injection to landmark-guided or systemic intramuscular injection. Outcomes of interest included pain, function, range of motion, proportion of participants with overall improvement and adverse events. There were no restrictions on language or date of publication., Data Collection and Analysis: Two review authors independently selected the studies for inclusion, extracted the data and performed a risk of bias assessment. Disagreement about inclusion or exclusion of individual studies and risk of bias was resolved by a third review author., Main Results: Five studies (290 participants) were included in the review. The image-guided groups in all trials used ultrasound to guide injection. Four studies included participants with rotator cuff disease; in three the comparator was local landmarks to direct injection into the subacromial bursa and in the fourth the comparator was systemic intramuscular injection into the upper gluteal muscles in the buttock region. One study included participants with adhesive capsulitis and injection was directed into the glenohumeral joint by either ultrasound or anatomical landmark guidance.No significant differences between groups were observed with respect to reduction in pain at one to two weeks (two trials, 146 participants, standardized mean difference (SMD) -1.44, 95% CI -4.14 to 1.26), or function at one to two weeks (two trials, 146 participants, SMD 0.95, 95% confidence interval (CI) -1.29 to 3.20; back-translated to mean difference (MD) 4 points, 95% CI -5 to 13, on a 0 to 100 point scale, higher score means better function) or six weeks (three trials, 207 participants, SMD 0.63, 95% CI -0.06 to 1.33; back-translated to MD -3 points, 95% CI -11 to 5, on a 0 to 100 point scale) and the sensitivity analyses did not alter these results. While there was a significant difference between groups with respect to reduction in pain at six weeks favouring image guidance (three trials, 207 participants, SMD -0.80, 95% CI -1.46 to -0.14), there was considerable statistical heterogeneity and after removing trials with inadequate allocation concealment and inadequate blinding in a sensitivity analysis, the difference was no longer significant (one trial, 106 participants, MD -0.60 points, 95% CI -1.44 to 0.24 points on a 9-point scale).No statistical difference in adverse events between groups was identified (10/104 image-guided group versus 16/103 comparator; risk ratio (RR) 0.55, 95% CI 0.17 to 1.85). Minor adverse events reported included transient post-injection pain, facial redness and warmth., Authors' Conclusions: Based upon moderate evidence from five trials, our review was unable to establish any advantage in terms of pain, function, shoulder range of motion or safety, of ultrasound-guided glucocorticoid injection for shoulder disorders over either landmark-guided or intramuscular injection. The lack of any added benefit of ultrasound guided subacromial bursal injection over glucocorticoid injection administered into the upper gluteal muscles of the buttock suggests that the benefits of glucocorticoid may arise through systemic rather than local effects. Therefore, although ultrasound guidance may improve the accuracy of injection to the putative site of pathology in the shoulder, it is not clear that this improves its efficacy to justify the significant added cost.

The long half-life of botulinum neurotoxin serotype A (BoNT/A) in cells poses a challenge in developing post-exposure therapeutics complementary to existing antitoxin strategies. Delivery vehicles consisting of the toxin heavy chain (HC), including the receptor-binding domain and translocation domain, connected to an inhibitory cargo offer a possible solution for rescuing intoxicated neurons in victims paralyzed from botulism. Here, we report the expression and purification of soluble recombinant prototype green fluorescent protein (GFP) cargo proteins fused to the entire BoNT/A-HC (residues 544-1295) in Escherichia coli with up to a 40 amino acid linker inserted between the cargo and BoNT/A-HC vehicle. We show that these GFP-HC fusion proteins are functionally active and readily taken up by cultured neuronal cells as well as by neuronal cells in mouse motor nerve endings.

The erythrocytes of a normal man were agglutinated more weakly than normal cells by several anti-P1PPK sera, and exhibited a decreased capacity to absorb these antibodies. Analysis of his erythrocyte glycosphingolipids revealed that the globoside (P antigen) content was less than 25% of normal, and trihexosyl ceramide (the PK antigen) was 30-40% of normal. The ganglioside content of his erythrocytes was approximately four times normal and sialosylparagloboside was increased about sixfold. It appears that his erythrocytes was unable to synthesize normal quantities of trihexosyl ceramide, and that these serological and chemical features constitute a new phenotype in the P blood group system.