Publications by authors named "Michael Stephenson"

83 Publications

Pre-hospital heparin use for ST-elevation myocardial infarction is safe and improves angiographic outcomes.

Eur Heart J Acute Cardiovasc Care 2021 Jun 30. Epub 2021 Jun 30.

School of Public Health and Preventive Medicine, Monash University, 553 St Kilda Road, Melbourne, VIC 3004, Australia.

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.
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http://dx.doi.org/10.1093/ehjacc/zuab032DOI Listing
June 2021

Mobile Stroke Units Facilitate Prehospital Management of Intracerebral Hemorrhage.

Stroke 2021 Jun 30:STROKEAHA121034592. Epub 2021 Jun 30.

Departments of Medicine and Neurology, Melbourne Brain Centre at the Royal Melbourne Hospital, University of Melbourne, Australia. (S.R.C., H.Z., B.C.V.C., L.C., S.C., D.E., F.L., B.Y., M.W.P., G.A.D., S.M.D., N.Y.).

Background And Purpose: Mobile stroke units (MSUs) improve reperfusion therapy times in acute ischemic stroke (AIS). However, prehospital management options for intracerebral hemorrhage (ICH) are less established. We describe the initial Melbourne MSU experience in ICH.

Methods: Consecutive patients with ICH and AIS treated by the Melbourne MSU were included. We describe demographics, proportions of patients receiving specific therapies, and bypass to comprehensive/neurosurgical centers. We also compare operational time metrics between patients with MSU-ICH and MSU-AIS.

Results: During a 2-year period, the Melbourne MSU managed 49 patients with ICH, mean (SD) age 74 (12) years, median (interquartile range) National Institutes of Health Stroke Scale 17 (12-20). Intravenous antihypertensives were the commonest treatment provided (46.9%). Bypass of a primary center to a comprehensive center with neurosurgical expertise occurred in 32.7% of patients with MSU-ICH compared with 20.5% of patients with MSU-AIS. Compared with patients with MSU-AIS, patients with MSU-ICH had faster onset-to-emergency-call, and onset-to-scene-arrival times at the median and 75th percentiles.

Conclusions: MSUs can facilitate ultra-early ICH diagnosis, management, and triage.
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http://dx.doi.org/10.1161/STROKEAHA.121.034592DOI Listing
June 2021

The Impact of the COVID-19 Pandemic on Demand for Emergency Ambulances in Victoria, Australia.

Prehosp Emerg Care 2021 Jul 16:1-7. Epub 2021 Jul 16.

Received May 16, 2021 from Centre for Research and Evaluation, Ambulance Victoria, Doncaster, Australia (EA, ZN, MS, TW, KS); Department of Epidemiology and Preventive Medicine, Monash University, Melbourne, Australia (EA, ZN, MS, KS); Department of Paramedicine, Monash University, Melbourne, Australia (ZN, MS). Revision received June 8, 2021; accepted for publication June 14, 2021.

Relatively little has been reported about the impact of COVID-19 restrictions on emergency ambulance services. We describe the influence of the COVID-19 pandemic on the emergency ambulance system in Victoria, Australia. We performed an interrupted time series analysis of consecutive calls for ambulance from January 2018 to February 2021, including two waves of COVID-19. The COVID-19 lockdown period included seven months of stay-at-home restrictions (16/03/2020-18/10/2020). Nineteen weeks of post-lockdown data were included (19/10/2020-28/02/2021). In total, 2,356,326 consecutive calls were included. COVID-19 lockdown was associated with an absolute reduction of 64,991 calls (almost 2,100 calls/week). According to time series analysis, lockdown was associated with a 12.6% reduction in weekly calls (IRR = 0.874 [95% CI 0.811, 0.941]), however no change in long-term trend (IRR = 1.000 [95% CI 0.996, 1.003]). During lockdown, the long-term trend of attendances to patients with suspected acute coronary syndromes (ACS, IRR = 1.006 [95% CI 1.004, 1.009]) and mental health-related issues (IRR = 1.005 [95% CI 1.002, 1.008]) increased. After lockdown, the call volume was 5.6% below pre-COVID-19 predictions (IRR = 0.944 [95% CI 0.909, 0.980]), however attendances for suspected ACS were higher than predicted (IRR = 1.069 [95% CI 1.009, 1.132]). Ambulance response times deteriorated, and total case times were longer than prior to the pandemic, driven predominantly by extended hospital transfer times. The COVID-19 pandemic had a dramatic impact on the emergency ambulance system. Despite lower call volumes post-lockdown than predicted, we observed deteriorating ambulance response times, extended case times and hospital delays. The pattern of attendance to patients with suspected ACS potentially highlights the collateral burden of delaying treatment for urgent conditions.
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http://dx.doi.org/10.1080/10903127.2021.1944409DOI Listing
July 2021

Predicting Ambulance Patient Wait Times: A Multicenter Derivation and Validation Study.

Ann Emerg Med 2021 07 8;78(1):113-122. Epub 2021 May 8.

Faculty of Information Technology and Electrical Engineering, University of Oulu, Oulu, Finland.

Study Objective: To derive and internally and externally validate machine-learning models to predict emergency ambulance patient door-to-off-stretcher wait times that are applicable to a wide variety of emergency departments.

Methods: Nine emergency departments provided 3 years (2017 to 2019) of retrospective administrative data from Australia. Descriptive and exploratory analyses were undertaken on the datasets. Statistical and machine-learning models were developed to predict wait times at each site and were internally and externally validated.

Results: There were 421,894 episodes analyzed, and median site off-load times varied from 13 (interquartile range [IQR], 9 to 20) to 29 (IQR, 16 to 48) minutes. The global site prediction model median absolute errors were 11.7 minutes (95% confidence interval [CI], 11.7 to 11.8) using linear regression and 12.8 minutes (95% CI, 12.7 to 12.9) using elastic net. The individual site model prediction median absolute errors varied from the most accurate at 6.3 minutes (95% CI, 6.2 to 6.4) to the least accurate at 16.1 minutes (95% CI, 15.8 to 16.3). The model technique performance was the same for linear regression, random forests, elastic net, and rolling average. The important variables were the last k-patient average waits, triage category, and patient age. The global model performed at the lower end of the accuracy range compared with models for the individual sites but was within tolerable limits.

Conclusion: Electronic emergency demographic and flow information can be used to estimate emergency ambulance patient off-stretcher times. Models can be built with reasonable accuracy for multiple hospitals using a small number of point-of-care variables.
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http://dx.doi.org/10.1016/j.annemergmed.2021.02.010DOI Listing
July 2021

Subtelomeric assembly of a multi-gene pathway for antimicrobial defense compounds in cereals.

Nat Commun 2021 05 7;12(1):2563. Epub 2021 May 7.

National Centre for Gene Research, CAS-JIC Centre of Excellence for Plant and Microbial Science (CEPAMS), Centre of Excellence for Molecular Plant Sciences, Shanghai Institute of Plant Physiology and Ecology, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences (CAS), Shanghai, China.

Non-random gene organization in eukaryotes plays a significant role in genome evolution. Here, we investigate the origin of a biosynthetic gene cluster for production of defence compounds in oat-the avenacin cluster. We elucidate the structure and organisation of this 12-gene cluster, characterise the last two missing pathway steps, and reconstitute the entire pathway in tobacco by transient expression. We show that the cluster has formed de novo since the divergence of oats in a subtelomeric region of the genome that lacks homology with other grasses, and that gene order is approximately colinear with the biosynthetic pathway. We speculate that the positioning of the late pathway genes furthest away from the telomere may mitigate against a 'self-poisoning' scenario in which toxic intermediates accumulate as a result of telomeric gene deletions. Our investigations reveal a striking example of adaptive evolution underpinned by remarkable genome plasticity.
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http://dx.doi.org/10.1038/s41467-021-22920-8DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8105312PMC
May 2021

An open-label, non-inferiority randomized controlled trial of lidocAine Versus Opioids In MyocarDial Infarction study (AVOID-2 study) methods paper.

Contemp Clin Trials 2021 Jun 22;105:106411. Epub 2021 Apr 22.

Department of Cardiology, Alfred Hospital, Melbourne, Australia; Baker Heart and Diabetes Institute, Melbourne, Australia; Monash University, Melbourne, Australia; Department of Cardiology, Western Health, Melbourne, Australia. Electronic address:

Background There is increasing evidence that opioids interfere with the oral bioavailability of P2Y inhibitors leading to delayed onset of antiplatelet effects. Several strategies have been proposed to mitigate this interaction including utilizing alternative analgesic agents in the management of ischemic chest pain. Methods The lidocAine Versus Opioids In MyocarDial Infarction (AVOID-2) study is a phase II, pre-hospital, open-label, non-inferiority, randomized controlled trial conducted by Ambulance Victoria and Monash University in metropolitan Melbourne, Victoria, Australia. The purpose of the study is to compare the analgesic effect (reduction in pain by arrival to hospital) and safety (e.g. adverse drug reactions) (co-primary endpoints) of intravenous lidocaine versus intravenous fentanyl in 300 adult patients attended by ambulance with suspected ST-elevation myocardial infarction (STEMI). Secondary endpoints and a cardiac magnetic resonance imaging (MRI) sub-study will also compare infarct size between these two groups. Conclusions The evaluation of alternative analgesic agents in the management of acute coronary syndromes is urgently needed to manage the opioid-P2Y inhibitor interaction. The results of this trial will have significant implications on the emergency management of acute coronary syndromes internationally.
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http://dx.doi.org/10.1016/j.cct.2021.106411DOI Listing
June 2021

Effect of a resuscitation quality improvement programme on outcomes from out-of-hospital cardiac arrest.

Resuscitation 2021 05 22;162:236-244. Epub 2021 Mar 22.

Centre for Research and Evaluation, Ambulance Victoria, Blackburn North, Victoria, Australia; Department of Epidemiology and Preventive Medicine, Monash University, Melbourne, Victoria, Australia; Department of Paramedicine, Monash University, Frankston, Victoria, Australia.

Background: Many emergency medical service (EMS) agencies are implementing programmes to improve the quality and performance of resuscitation. We sought to examine the impact of a resuscitation quality improvement programme on outcomes following OHCA.

Methods: An interrupted time-series analysis of adult OHCA patients of medical aetiology. Patients treated after the implementation of a high-performance cardiopulmonary resuscitation (CPR) intervention between February 2019 and January 2020 were compared to historical controls between January 2015 and January 2019. The effect of the intervention on the risk-adjusted odds of survival were examined using logistic regression models, with and without adjustment for temporal trends.

Results: A total of 8270 and 2330 patients were treated in the control and intervention periods, respectively. Patients in the intervention period were older and less likely to arrest in public, present with an initial shockable rhythm, and receive mechanical CPR. After adjustment for arrest factors and temporal trends, there was a significant increase in the level of monthly survival to hospital discharge (AOR 1.50; 95% CI: 1.10, 2.04; p = 0.01), event survival (AOR 1.34; 95% CI: 1.09, 1.65; p = 0.006) and return of spontaneous circulation (AOR 1.38; 95% CI: 1.14, 1.65; p = 0.001). After removing the non-significant temporal trend, there was a 33% increase (AOR 1.33; 95% CI: 1.11, 1.58; p = 0.002) in the risk-adjusted odds of survival over the 12-month intervention period. The average marginal effect of the intervention resulted in 8.7 (95% CI: 3.2, 14.1) additional survivors per million population.

Conclusion: A resuscitation quality improvement programme consisting of high-performance CPR was associated with a significant increase in survival following OHCA.
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http://dx.doi.org/10.1016/j.resuscitation.2021.03.007DOI Listing
May 2021

Use of intramuscular ketamine by paramedics in the management of severely agitated patients.

Emerg Med Australas 2021 Mar 24. Epub 2021 Mar 24.

Centre for Research and Evaluation, Ambulance Victoria, Melbourne, Victoria, Australia.

Objective: Administration of a sedative agent is required for safe transport of prehospital patients with severe agitation to EDs. Ambulance services in Australasia use ketamine, droperidol or midazolam as first line agent but the optimal agent is uncertain. In Victoria, intramuscular (IM) ketamine is used. The present study aimed to examine the prehospital characteristics and ED outcomes of patients with severe agitation after IM ketamine administration.

Methods: A retrospective review was conducted for patients who received IM ketamine for severe agitation over a 2-year period. Data were sourced from Ambulance Victoria and linked to hospital data. The primary outcome was time to sedation. Data collected included baseline characteristics, adverse events and ED outcomes.

Results: Three hundred and fifty-eight prehospital cases transported to 32 hospitals were included. Outcome data were available for 305 patients (21 hospitals). Median age was 31 years (IQR 23-40). 71.2% were male. Adequate sedation was achieved in 96.9% of cases in a median time of 5.0 min (IQR 3.0-7.0; range 1-31 min). Adverse events were transient hypoxia (5.0%), hyper-salivation (4.2%) and emergence reactions (0.8%). A total of 45 (14.8%) patients were intubated; two prehospital.

Conclusion: Intramuscular ketamine is effective with a low rate of prehospital complications in severely agitated patients in the prehospital setting. Given the variation in ambulance practice in Australasia, prospective, randomised trials in the prehospital setting comparing ketamine to other sedating agents such as droperidol in patients with severe agitation are required.
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http://dx.doi.org/10.1111/1742-6723.13755DOI Listing
March 2021

Family Medicine With Refugee Newcomers During the COVID-19 Pandemic.

J Am Board Fam Med 2021 Feb;34(Suppl):S210-S216

From the Department of Psychology, University of Waterloo, Waterloo, Ontario, Canada (JAS, JDB, DTB); Centre for Mental Health Research and Treatment (CMHRT), University of Waterloo, Waterloo, Ontario, Canada (JAS, DTB); Sanctuary Refugee Health Centre, Kitchener, Ontario, Canada (JDB, MB, MS); Michael G. DeGroote School of Medicine, McMaster University, Hamilton, Ontario, Canada (SS).

Certain members of society are disproportionately affected by the COVID-19 crisis and the added strain being placed on already overextended health care systems. In this article, we focus on refugee newcomers. We outline vulnerabilities refugee newcomers face in the context of COVID-19, including barriers to accessing health care services, disproportionate rates of mental health concerns, financial constraints, racism, and higher likelihoods of living in relatively higher density and multigenerational dwellings. In addition, we describe the response to COVID-19 by a community-based refugee primary health center in Ontario, Canada. This includes how the clinic has initially responded to the crisis as well as recommendations for providing services to refugee newcomers as the COVID-19 crisis evolves. Recommendations include the following actions: (1) consider social determinants of health in the new context of COVID-19; (2) provide services through a trauma-informed lens; (3) increase focus on continuity of health and mental health care; (4) mobilize International Medical Graduates for triaging patients based on COVID-19 symptoms; and (5) diversify communication efforts to educate refugees about COVID-19.
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http://dx.doi.org/10.3122/jabfm.2021.S1.200115DOI Listing
February 2021

Factors influencing patient decision delay in activation of emergency medical services for suspected ST-elevation myocardial infarction.

Eur J Cardiovasc Nurs 2021 03;20(3):243–251

Department of Epidemiology and Preventive Medicine, Monash University, Australia.

Objective: The purpose of this study was to identify factors associated with time delay to emergency medical services for patients with suspected ST-elevation myocardial infarction.

Methods: This observational study involved 1994 suspected ST-elevation myocardial infarction patients presenting to the emergency medical services in Melbourne, Australia, between October 2011-January 2014. Factors associated with delays to emergency medical services call of >1 h and emergency medical services self-referral were analyzed using multivariable logistic regression.

Results: The time of symptom onset was reported for 1819 patients (91.2%), the median symptom onset-to-call time was 52 min (interquartile range=17-176). Of all emergency medical services calls, 17% were referred by healthcare professionals. Compared to self-referred patients, patients who presented to a general practitioner or hospital had higher odds of delay >1 h to emergency medical services activation (adjusted odds ratio 7.76; 95% confidence interval 5.10-11.83; and 8.02; 3.65-17.64, respectively). The other factors associated with emergency medical services call delays of >1 h were living alone, non-English speaking background, a history of substance abuse, less severe symptoms, symptom onset at home and at rest, and self-treatment. Emergency medical services self-referred patients were more likely to be older than 75 years, have a history of ischemic heart disease or revascularization, more severe symptoms, and symptom onset at home, with activity, during the weekends and out-of-hours.

Conclusion: Almost one-fifth of emergency medical services calls for suspected ST-elevation myocardial infarction were healthcare referrals, and this was associated with increased delays. A wide range of factors could influence a patient's decision to directly and rapidly seek emergency medical services. More efforts are needed to educate at-risk populations about early self-referral to the emergency medical services.
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http://dx.doi.org/10.1177/1474515120953737DOI Listing
March 2021

Utility of Severity-Based Prehospital Triage for Endovascular Thrombectomy: ACT-FAST Validation Study.

Stroke 2021 01 22;52(1):70-79. Epub 2020 Dec 22.

Departments of Medicine and Neurology, Melbourne Brain Centre at The Royal Melbourne Hospital (H.Z., L.C., J.L.N., C.W., F.A., F.N., P.J.M., M.W.P., N.Y., S.M.D., B.C.V.C.), University of Melbourne, Australia.

Background And Purpose: Severity-based assessment tools may assist in prehospital triage of patients to comprehensive stroke centers (CSCs) for endovascular thrombectomy (EVT), but criticisms regarding diagnostic inaccuracy have not been adequately addressed. This study aimed to quantify the benefits and disadvantages of severity-based triage in a large real-world paramedic validation of the Ambulance Clinical Triage for Acute Stroke Treatment (ACT-FAST) algorithm.

Methods: Ambulance Victoria paramedics assessed the prehospital ACT-FAST algorithm in patients with suspected stroke from November 2017 to July 2019 following an 8-minute training video. All patients were transported to the nearest stroke center as per current guidelines. ACT-FAST diagnostic accuracy was compared with hospital imaging for the presence of large vessel occlusion (LVO) and need for CSC-level care (LVO, intracranial hemorrhage, and tumor). Patient-level time saving to EVT was modeled using a validated Google Maps algorithm. Disadvantages of CSC bypass examined potential thrombolysis delays in non-LVO infarcts, proportion of patients with false-negative EVT, and CSC overburdening.

Results: Of 517 prehospital assessments, 168/517 (32.5%) were ACT-FAST positive and 132/517 (25.5%) had LVO. ACT-FAST sensitivity and specificity for LVO was 75.8% and 81.8%, respectively. Positive predictive value was 58.8% for LVO and 80.0% when intracranial hemorrhage and tumor (CSC-level care) were included. Within the metropolitan region, 29/55 (52.7%) of ACT-FAST-positive patients requiring EVT underwent a secondary interhospital transfer. Prehospital bypass with avoidance of secondary transfers was modeled to save 52 minutes (95% CI, 40.0-61.5) to EVT commencement. ACT-FAST was false-positive in 8 patients receiving thrombolysis (8.1% of 99 non-LVO infarcts) and false-negative in 4 patients with EVT requiring secondary transfer (5.4% of 74 EVT cases). CSC bypass was estimated to over-triage 1.1 patients-per-CSC-per-week in our region.

Conclusions: The overall benefits of an ACT-FAST algorithm bypass strategy in expediting EVT and avoiding secondary transfers are estimated to substantially outweigh the disadvantages of potentially delayed thrombolysis and over-triage, with only a small proportion of EVT patients missed.
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http://dx.doi.org/10.1161/STROKEAHA.120.031467DOI Listing
January 2021

Displaying emergency patient estimated wait times: A multi-centre, qualitative study of patient, community, paramedic and health administrator perspectives.

Emerg Med Australas 2020 Sep 28. Epub 2020 Sep 28.

Emergency Department, St Vincent's Hospital Melbourne, Melbourne, Victoria, Australia.

Objective: EDs have the potential ability to predict patient wait times and to display this to patients and other stakeholders. Little is known about whether consumers and stakeholders would want this information and how wait time predictions might be used. The aim of the present study was to gain perspectives from consumers and health services personnel regarding the concept of emergency wait time visibility.

Methods: We conducted a qualitative interview and focus group study in 2019. Participants included emergency medicine patients, families, paramedics, well community members, and hospital/paramedic administrators from multiple EDs and organisations in Victoria, Australia. Transcripts were coded and themes presented.

Results: One focus group and 103 semi-structured interviews were conducted in 2019 including 32 patients, 22 carers/advocates and 21 paramedics in the ED; 20 health service administrators (paramedic and hospital) and 15 community members. Consumers and paramedics face physical and psychological difficulties when wait times are not visible. Consumers believe about a 2-h wait is tolerable, beyond this most begin to consider alternative strategies for seeking care. Consumers want to see triage to doctor times; paramedics want door-to-off stretcher times (for all possible transport destinations); with 47 of 50 consumers and 30 of 31 paramedics potentially using this information. About 28 of 50 consumers would use times to inform facility or provider choice, another 19 of 50 want information once in the waiting room. During prolonged waits, 51 of 52 consumers would continue to seek care.

Conclusions: Consumers and paramedics want wait time information visibility. They would use the information in a variety of ways, both pre-hospital and while waiting for care.
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http://dx.doi.org/10.1111/1742-6723.13640DOI Listing
September 2020

Prehospital opioid dose and myocardial injury in patients with ST elevation myocardial infarction.

Open Heart 2020 07;7(2)

Department of Cardiology, Alfred Hospital, Melbourne, Victoria, Australia

Objective: To characterise the relationship between opioid dose and myocardial infarct size in patients with ST elevation myocardial infarction (STEMI).

Methods: Patients given opioid treatment by emergency medical services with confirmed STEMI were included in this secondary, retrospective cohort analysis of the Air versus Oxygen in Myocardial Infarction (AVOID) study. Patients with cardiogenic shock were excluded. The primary endpoint was comparison of cardiac biomarkers as a measure of infarct size based on opioid dose (low ≤8.75 mg, intermediate 8.76-15 mg and high >15 mg of intravenous morphine equivalent dose).

Results: 422 patients were included in the analysis. There was a significantly higher proportion of patients with Thrombolysis in Myocardial Infarction (TIMI) 0 or 1 flow pre-percutaneous coronary intervention (PCI) (94% vs 81%, p=0.005) and greater use of thrombus aspiration catheters (59% vs 30%, p<0.001) in the high compared with low-dose opioid group. After adjustment for potential confounders, every 1 mg of intravenous morphine equivalent dose was associated with a 1.4% (95% CI 0.2%, 2.7%, p=0.028) increase in peak creatine kinase; however, this was no longer significant after adjustment for TIMI flow pre-PCI.

Conclusions: Our study suggests no benefit of higher opioid dose and a dose-dependent signal between opioid dose and increased myocardial infarct size. Prospective randomised controlled trials are required to establish causality given that this may also be explained by patients with a greater ischaemic burden requiring higher opioid doses due to more severe pain. Future research also needs to focus on strategies to mitigate the opioid-P2Y12 inhibitor interaction and non-opioid analgesia to treat ischaemic chest pain.
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http://dx.doi.org/10.1136/openhrt-2020-001307DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7380835PMC
July 2020

Prehospital notification of injured patients presenting to a trauma centre in India: a prospective cohort study.

BMJ Open 2020 06 21;10(6):e033236. Epub 2020 Jun 21.

National Trauma Research Institute, The Alfred Hospital, Melbourne, VIC, Australia.

Objectives: To assess the effect of a mobile phone application for prehospital notification on resuscitation and patient outcomes.

Design: Longitudinal prospective cohort study with preintervention and postintervention cohorts.

Setting: Major trauma centre in India.

Participants: Injured patients being transported by ambulance and allocated to red (highest) and yellow (medium) triage categories.

Intervention: A prehospital notification application for use by ambulance and emergency clinicians to notify emergency departments (EDs) of an impending arrival of a patient requiring advanced lifesaving care.

Main Outcome Measures: The primary outcome was the proportion of eligible patients arriving at the hospital for which prehospital notification occurred. Secondary outcomes were the availability of a trauma cubicle, presence of a trauma team on patient arrival, time to first chest X-ray, and ED and in-hospital mortality.

Results: Data from January 2017 to January 2018 were collected with 208 patients in the preintervention and 263 patients in the postintervention period. The proportion of patients arriving after prehospital notification improved from 0% to 11% (p<0.001). After the intervention, more patients were managed with a trauma call-out (relative risk (RR) 1.30; 95% CI: 1.10 to 1.52); a trauma bay was ready for more patients (RR 1.47; 95% CI: 1.05 to 2.05) and a trauma team leader present for more patients (RR 1.50; 95% CI: 1.07 to 2.10). There was no difference in time to the initial chest X-ray (p=0.45). There was no association with mortality at hospital discharge (RR 0.94; 95% CI: 0.72 to 1.23), but the intervention was associated with significantly less risk of patients dying in the ED (RR 0.11; 95% CI: 0.03 to 0.39).

Conclusions: The prehospital notification application for severely injured patients had limited uptake but implementation was associated with improved trauma reception and reduction in early deaths. Quality improvement efforts with ongoing data collection using the trauma registry are indicated to drive improvements in trauma outcomes in India.

Trial Registration Number: NCT02877342.
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http://dx.doi.org/10.1136/bmjopen-2019-033236DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7311027PMC
June 2020

Economic evaluation of the Melbourne Mobile Stroke Unit.

Int J Stroke 2021 Jun 14;16(4):466-475. Epub 2020 Jun 14.

Stroke & Ageing Research, Department of Medicine, School of Clinical Sciences at Monash Health, 2541Monash University, Clayton, VIC, Australia.

Background: The Melbourne Mobile Stroke Unit (MSU) is the first Australian service to provide prehospital acute stroke treatment, including thrombolysis and facilitated triage for endovascular thrombectomy.

Aims: To estimate the cost-effectiveness of the MSU during the first full year of operation compared with standard ambulance and hospital stroke care pathways (standard care).

Methods: The costs and benefits of the Melbourne MSU were estimated using an economic simulation model. Operational costs and service utilization data were obtained from the MSU financial and patient tracking reports. The health benefits were estimated as disability-adjusted life years (DALYs) avoided using local data on reperfusion therapy and estimates from the published literature on their effectiveness. Costs were presented in Australian dollars. The robustness of results was assessed using multivariable (model inputs varied simultaneously: 10,000 Monte Carlo iterations) and various one-way sensitivity analyses.

Results: In 2018, the MSU was dispatched to 1244 patients during 200 days of operation. Overall, 167 patients were diagnosed with acute ischemic stroke, and 58 received thrombolysis, endovascular thrombectomy, or both. We estimated 27.94 DALYs avoided with earlier access to endovascular thrombectomy (95% confidence interval (CI) 15.30 to 35.93) and 16.90 DALYs avoided with improvements in access to thrombolysis (95% CI 9.05 to 24.68). The MSU was estimated to cost an additional $30,982 per DALY avoided (95% CI $21,142 to $47,517) compared to standard care.

Conclusions: There is evidence that the introduction of MSU is cost-effective when compared with standard care due to earlier provision of reperfusion therapies.
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http://dx.doi.org/10.1177/1747493020929944DOI Listing
June 2021

Factors associated with emergency medical service delays in suspected ST-elevation myocardial infarction in Victoria, Australia: A retrospective study.

Emerg Med Australas 2020 10 9;32(5):777-785. Epub 2020 May 9.

Department of Epidemiology and Preventive Medicine, Monash University, Melbourne, Victoria, Australia.

Objective: To assess the effect of patient and system characteristics on emergency medical service (EMS) delays prior to arrival at hospital in suspected ST-elevation myocardial infarction (STEMI).

Methods: This was a retrospective observational study of 1739 patients who presented with suspected STEMI to the EMS in Melbourne, Australia between October 2011 and January 2014. Our primary outcome measure was call-to-hospital time, defined as the time in minutes from emergency call to hospital arrival. We examined the association of patient and system characteristics on call-to-hospital time using multivariable linear regression.

Results: The mean call-to-hospital time was 60.1 min (standard deviation 20.5) and the median travel distance was 13.0 km (interquartile range 7.2-23.1). In the multivariable model, patient characteristics associated with longer call-to-hospital time were age ≥75 years (2.3 min; 95% confidence interval [CI] 0.6-4.0), female sex (1.9 min; 95% CI 0.3-3.4), pre-existing mental health disorder (4.0 min; 95% CI 1.9-6.1) or musculoskeletal disease (2.7 min; 95% CI 1.0-4.4), absence of chest pain (3.0 min; 95% CI 1.1-4.8), and presentation with clinical complications. System factors associated with call-to-hospital time include lower dispatch priority (12.7 min; 95% CI 9.0-16.5) and non-12-lead electrocardiography (ECG) capable ambulance first on scene (4.5 min; 95% CI 3.1-5.8). Patients who were not initially attended by a 12-lead capable ambulance were less likely to receive a 12-lead ECG within 10 min (18.5% vs 71.0%, P < 0.001).

Conclusion: A range of patient and system factors may influence EMS delays in STEMI. However, optimising dispatch prioritisation and widespread availability of prehospital 12-lead ECG could lead to substantial reduction in time to treatment.
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http://dx.doi.org/10.1111/1742-6723.13512DOI Listing
October 2020

Melbourne Mobile Stroke Unit and Reperfusion Therapy: Greater Clinical Impact of Thrombectomy Than Thrombolysis.

Stroke 2020 03 12;51(3):922-930. Epub 2020 Feb 12.

From the Department of Neurology, Melbourne Brain Centre (H.Z., S.C., D.E., L.C., N.Y., B.Y., B.C.V.C., M.W.P., G.A.D., S.M.D.), Royal Melbourne Hospital, Victoria, Australia.

Background and Purpose- Mobile stroke units (MSUs) are increasingly used worldwide to provide prehospital triage and treatment. The benefits of MSUs in giving earlier thrombolysis have been well established, but the impacts of MSUs on endovascular thrombectomy (EVT) and effect on disability avoidance are largely unknown. We aimed to determine the clinical impact and disability reduction for reperfusion therapies in the first operational year of the Melbourne MSU. Methods- Treatment time metrics for MSU patients receiving reperfusion therapy were compared with control patients presenting to metropolitan Melbourne stroke units via standard ambulance within MSU operating hours. The primary outcome was median time difference in first ambulance dispatch to treatment modeled using quantile regression analysis. Time savings were subsequently converted to disability-adjusted life years avoided using published estimates. Results- In the first 365-day operation of the Melbourne MSU, prehospital thrombolysis was administered to 100 patients (mean age, 73.8 years; 62% men). The median time savings per MSU patient, compared with the control cohort, was 26 minutes (<0.001) for dispatch to hospital arrival and 15 minutes (<0.001) for hospital arrival to thrombolysis. The calculated overall time saving from dispatch to thrombolysis was 42.5 minutes (95% CI, 36.0-49.0). In the same period, 41 MSU patients received EVT (mean age, 76 years; 61% men) with median dispatch-to-treatment time saving of 51 minutes ([95% CI, 30.1-71.9], <0.001). This included a median time saving of 17 minutes ([95% CI, 7.6-26.4], =0.001) for EVT hospital arrival to arterial puncture for MSU patients. Estimated median disability-adjusted life years saved through earlier provision of reperfusion therapies were 20.9 for thrombolysis and 24.6 for EVT. Conclusions- The Melbourne MSU substantially reduced time to reperfusion therapies, with the greatest estimated disability avoidance driven by the more powerful impact of earlier EVT. These findings highlight the benefits of prehospital notification and direct triage to EVT centers with facilitated workflow on arrival by the MSU.
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http://dx.doi.org/10.1161/STROKEAHA.119.027843DOI Listing
March 2020

Variations in the care of agitated patients in Australia and New Zealand ambulance services.

Emerg Med Australas 2020 06 15;32(3):438-445. Epub 2019 Dec 15.

Emergency and Trauma Centre, Alfred Hospital, Melbourne, Victoria, Australia.

Objective: The objective of the present study is to examine variations in paramedic care of the agitated patient, including verbal de-escalation, physical restraint and sedation, provided by ambulance services in Australia and New Zealand.

Methods: To examine the care of agitated patients, we first identified and reviewed all clinical practice guidelines for the management of agitated patients in Australian and New Zealand ambulance services between September and November 2018. We then conducted a structured questionnaire to obtain further information on the training, assessment and care of agitated patients by the ambulance services. Two authors extracted the data independently, and all interpretations and results were reviewed and confirmed by relevant ambulance services.

Results: There were 10 independent clinical practice guidelines for the care of agitated patients in the 10 ambulance services. All services reported training in the management of agitated patients, and two services used a validated tool to assess the level of agitation. All services used physical restraint, although six services required police presence to restrain the patient. All ambulance services used some form of sedation, typically divided into the management of mild to moderate, and severe agitation. The most common agent for sedation was midazolam, while ketamine was the most common agent for sedating severely agitated patients. The maximum dose was varied, and contraindications for sedating agents varied between services.

Conclusions: There were wide variations across the ambulance services in terms of the assessment of agitation, as well as the use of physical restraint and sedation.
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http://dx.doi.org/10.1111/1742-6723.13431DOI Listing
June 2020

A noncanonical vacuolar sugar transferase required for biosynthesis of antimicrobial defense compounds in oat.

Proc Natl Acad Sci U S A 2019 Dec 5. Epub 2019 Dec 5.

Department of Metabolic Biology, John Innes Centre, NR4 7UH Norwich, United Kingdom;

Plants produce an array of natural products with important ecological functions. These compounds are often decorated with oligosaccharide groups that influence bioactivity, but the biosynthesis of such sugar chains is not well understood. Triterpene glycosides (saponins) are a large family of plant natural products that determine important agronomic traits, as exemplified by avenacins, antimicrobial defense compounds produced by oats. Avenacins have a branched trisaccharide moiety consisting of l-arabinose linked to 2 d-glucose molecules that is critical for antifungal activity. Plant natural product glycosylation is usually performed by uridine diphosphate-dependent glycosyltransferases (UGTs). We previously characterized the arabinosyltransferase that initiates the avenacin sugar chain; however, the enzymes that add the 2 remaining d-glucose molecules have remained elusive. Here we characterize the enzymes that catalyze these last 2 glucosylation steps. AsUGT91G16 is a classical cytosolic UGT that adds a 1,2-linked d-glucose molecule to l-arabinose. Unexpectedly, the enzyme that adds the final 1,4-linked d-glucose (AsTG1) is not a UGT, but rather a sugar transferase belonging to Glycosyl Hydrolase family 1 (GH1). Unlike classical UGTs, AsTG1 is vacuolar. Analysis of oat mutants reveals that corresponds to , a previously uncharacterized locus shown by mutation to be required for avenacin biosynthesis. and form part of the avenacin biosynthetic gene cluster. Our demonstration that a vacuolar transglucosidase family member plays a critical role in triterpene biosynthesis highlights the importance of considering other classes of carbohydrate-active enzymes in addition to UGTs as candidates when elucidating pathways for the biosynthesis of glycosylated natural products in plants.
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http://dx.doi.org/10.1073/pnas.1914652116DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6936528PMC
December 2019

Drivers of metabolic diversification: how dynamic genomic neighbourhoods generate new biosynthetic pathways in the Brassicaceae.

New Phytol 2020 08 28;227(4):1109-1123. Epub 2019 Dec 28.

Department of Metabolic Biology, John Innes Centre, Norwich Research Park, Colney Lane, Norwich, NR4 7UH, UK.

Plants produce an array of specialized metabolites with important ecological functions. The mechanisms underpinning the evolution of new biosynthetic pathways are not well-understood. Here, we exploit available genome sequence resources to investigate triterpene biosynthesis across the Brassicaceae. Oxidosqualene cyclases (OSCs) catalyze the first committed step in triterpene biosynthesis. Systematic analysis of 13 sequenced Brassicaceae genomes was performed to identify all OSC genes. The genome neighbourhoods (GNs) around a total of 163 OSC genes were investigated to identify Pfam domains significantly enriched in these regions. All-vs-all comparisons of OSC neighbourhoods and phylogenomic analysis were used to investigate the sequence similarity and evolutionary relationships of the numerous candidate triterpene biosynthetic gene clusters (BGCs) observed. Functional analysis of three representative BGCs was carried out and their triterpene pathway products were elucidated. Our results indicate that plant genomes are remarkably plastic, and that dynamic GNs generate new biosynthetic pathways in different Brassicaceae lineages by shuffling the genes encoding a core palette of triterpene-diversifying enzymes, presumably in response to strong environmental selection pressure. These results illuminate a genomic basis for diversification of plant-specialized metabolism through natural combinatorics of enzyme families, which can be mimicked using synthetic biology to engineer diverse bioactive molecules.
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http://dx.doi.org/10.1111/nph.16338DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7383575PMC
August 2020

Identification of key enzymes responsible for protolimonoid biosynthesis in plants: Opening the door to azadirachtin production.

Proc Natl Acad Sci U S A 2019 08 1;116(34):17096-17104. Epub 2019 Aug 1.

Department of Metabolic Biology, John Innes Centre, Norwich Research Park, Norwich NR4 7UH, Norfolk, United Kingdom;

Limonoids are natural products made by plants belonging to the Meliaceae (Mahogany) and Rutaceae (Citrus) families. They are well known for their insecticidal activity, contribution to bitterness in citrus fruits, and potential pharmaceutical properties. The best known limonoid insecticide is azadirachtin, produced by the neem tree (). Despite intensive investigation of limonoids over the last half century, the route of limonoid biosynthesis remains unknown. Limonoids are classified as tetranortriterpenes because the prototypical 26-carbon limonoid scaffold is postulated to be formed from a 30-carbon triterpene scaffold by loss of 4 carbons with associated furan ring formation, by an as yet unknown mechanism. Here we have mined genome and transcriptome sequence resources for 3 diverse limonoid-producing species (, , and ) to elucidate the early steps in limonoid biosynthesis. We identify an oxidosqualene cyclase able to produce the potential 30-carbon triterpene scaffold precursor tirucalla-7,24-dien-3β-ol from each of the 3 species. We further identify coexpressed cytochrome P450 enzymes from (MaCYP71CD2 and MaCYP71BQ5) and (CsCYP71CD1 and CsCYP71BQ4) that are capable of 3 oxidations of tirucalla-7,24-dien-3β-ol, resulting in spontaneous hemiacetal ring formation and the production of the protolimonoid melianol. Our work reports the characterization of protolimonoid biosynthetic enzymes from different plant species and supports the notion of pathway conservation between both plant families. It further paves the way for engineering crop plants with enhanced insect resistance and producing high-value limonoids for pharmaceutical and other applications by expression in heterologous hosts.
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http://dx.doi.org/10.1073/pnas.1906083116DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6708365PMC
August 2019

Australian private emergency departments can assist ambulance services by taking public emergency patients during surge and disasters.

Emerg Med Australas 2019 10 2;31(5):886-888. Epub 2019 Jun 2.

Emergency Department, Cabrini Health, Melbourne, Victoria, Australia.

We describe a novel ambulance diversion programme, piloted in Victoria. This article discusses creating increased emergency capacity during surge or disasters by utilising private EDs, tested during a recent thunderstorm asthma disaster and an influenza epidemic. Public hospitals and EDs often run at or over capacity during normal operations. This leaves limited ability to manage surges in demand, resulting in suboptimal outcomes for patients, public ED staff and ambulance services. It is feasible to create surge capacity in private EDs for public ambulance patients. Other states could consider this option to help manage health disasters.
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http://dx.doi.org/10.1111/1742-6723.13328DOI Listing
October 2019

The EXACT protocol: A multi-centre, single-blind, randomised, parallel-group, controlled trial to determine whether early oxygen titration improves survival to hospital discharge in adult OHCA patients.

Resuscitation 2019 06 19;139:208-213. Epub 2019 Apr 19.

Department of Epidemiology and Preventive Medicine, Monash University, Australia; Alfred Hospital, Australia; Ambulance Victoria, Australia.

Background: Experimental and observational research suggests hyperoxia following resuscitation from cardiac arrest is associated with neurological injury and worse clinical outcomes. This paper describes the rationale and design of the EXACT trial. EXACT aims to determine whether reducing oxygen in the acute phase of post-resuscitation care for out-of-hospital cardiac arrest (OHCA) improves survival.

Methods: EXACT is a multi-centre, randomised (1:1), single-blind, parallel trial. Presumed cardiac OHCA cases who achieve a return of spontaneous circulation will be eligible if they are comatose, with an advanced airway and have an oxygen saturation (SpO) ≥95% on >10 L/min (or 100% oxygen). Paramedics will randomise 1416 eligible cases to receive oxygen therapy targeting an SpO of 90-94% (intervention) or 98-100% (control). Study treatment will continue until admission to an intensive care unit or hospital ward. The primary outcome is survival to hospital discharge. Secondary outcomes include 12-month survival and quality of life.

Results: The study has commenced in the Australian states of Victoria and South Australia, and has enrolled 167 eligible cases to date (80 intervention and 87 control). Further sites are due to commence in 2019, recruitment is expected to take three years.

Conclusion: This study will determine if early reduction of oxygen leads to improved outcomes in OHCA. Such a finding may potentially change clinical practice with implications on future OHCA survival outcomes.

Trial Registration Number: NCT03138005.
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http://dx.doi.org/10.1016/j.resuscitation.2019.04.023DOI Listing
June 2019

Can pre-hospital administration reduce time to initial antibiotic therapy in septic patients?

Emerg Med Australas 2019 08 28;31(4):669-672. Epub 2019 Mar 28.

Australian and New Zealand Intensive Care Research Centre, Monash University, Melbourne, Victoria, Australia.

Objective: To quantify the potential time saved with pre-hospital antibiotic therapy in sepsis.

Methods: Study data for adult patients transported by Ambulance Victoria (AV), and enrolled into the Australasian Resuscitation In Sepsis Evaluation (ARISE), were linked with pre-hospital electronic records.

Results: An AV record was identified for 240 of 341 ARISE patients. The pre-hospital case notes referred to potential infection in 165 patients. The median time to first antibiotic administration from loading the patient into the ambulance was 107 (74-160) min.

Conclusions: ARISE patients in Victoria were frequently identified pre-hospital. An opportunity exists to study the feasibility of pre-hospital antibiotic therapy.
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http://dx.doi.org/10.1111/1742-6723.13282DOI Listing
August 2019

Depression's response to fear tactics: An integration of health promotion principles, eye-tracking technology and clinical tools.

Patient Educ Couns 2019 06 8;102(6):1178-1186. Epub 2019 Mar 8.

Department of Communication, Texas A&M University, College Station TX, USA.

Objective: The main objective of this study was to utilize eye-tracking technology and self-report measures to test the effectiveness of varying strengths of fear appeals when educating about the seriousness of depression and motivate depressed individuals to engage in health-information-seeking.

Methods: We analyzed data from 117 university employees affected by a range of depression symptoms who were randomly assigned to a low-threat, moderate threat, and high-threat message condition in a lab-based experimental setting. Attention patterns were captured while participants viewed the health message. A particular emphasis was placed on understanding the role of valence and arousal in determining attention patterns.

Results: Attentional processes induced emotions (valence) and intensity (arousal) and differed by strength of fear appeal, but were not influenced by symptoms of depression in this study. Arousal mediated the effects of strong fear appeals on attitudes toward information-seeking, whereas negative emotions did not.

Conclusion And Practice Implications: Until further research suggests otherwise, caution is warranted when utilizing fear appeals that are highly arousing for health education and promotion.
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http://dx.doi.org/10.1016/j.pec.2019.02.001DOI Listing
June 2019

The protosteryl and dammarenyl cation dichotomy in polycyclic triterpene biosynthesis revisited: has this 'rule' finally been broken?

Nat Prod Rep 2019 08;36(8):1044-1052

John Innes Centre, Norwich Research Park, Norwich, NR47UH, UK.

Covering: 1948 up to the end of 2018. The triterpene alcohols represent an important and diverse class of natural products. This diversity is believed to originate from the differential enzymatically controlled cyclisation of 2,3-oxidosqualene. It is now a well-established presumption that all naturally occurring tetra- and penta-cyclic triterpene alcohols can be rationalised by the resolution of one of two intermediary tetracyclic cations, termed the protosteryl and dammarenyl cations. Here, a discussion of typical key triterpene structures and their proposed derivation from either of these progenitors is followed by comparison with a recently reported novel pentacyclic triterpene orysatinol which appears to correspond to an unprecedented divergence from this dichotomous protosteryl/dammarenyl view of triterpene biogenesis. Not only does this discovery widen the potential scope of triterpene scaffolds that could exist in nature, it could call into question the reliability of stereochemical assignments of some existing triterpene structures that are supported by only limited spectroscopic evidence. The discovery of orysatinol provides direct experimental evidence to support considering more flexibility in the stereochemical interpretation of the biogenic isoprene rule.
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http://dx.doi.org/10.1039/c8np00096dDOI Listing
August 2019

Complete Genome Sequences of 18 Paenibacillus larvae Phages from the Western United States.

Microbiol Resour Announc 2018 Oct 4;7(13). Epub 2018 Oct 4.

Department of Microbiology and Molecular Biology, Brigham Young University, Provo, Utah, USA.

We present here the complete genomes of 18 phages that infect Paenibacillus larvae, the causative agent of American foulbrood in honeybees. The phages were isolated between 2014 and 2016 as part of an undergraduate phage discovery course at Brigham Young University. The phages were isolated primarily from bee debris and lysogens.
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http://dx.doi.org/10.1128/MRA.00966-18DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6256562PMC
October 2018

Analysis of Two New Arabinosyltransferases Belonging to the Carbohydrate-Active Enzyme (CAZY) Glycosyl Transferase Family1 Provides Insights into Disease Resistance and Sugar Donor Specificity.

Plant Cell 2018 12 14;30(12):3038-3057. Epub 2018 Nov 14.

Department of Metabolic Biology, John Innes Centre, Norwich NR4 7UH, UK

Glycosylation of small molecules is critical for numerous biological processes in plants, including hormone homeostasis, neutralization of xenobiotics, and synthesis and storage of specialized metabolites. Glycosylation of plant natural products is usually performed by uridine diphosphate-dependent glycosyltransferases (UGTs). Triterpene glycosides (saponins) are a large family of plant natural products that determine important agronomic traits such as disease resistance and flavor and have numerous pharmaceutical applications. Most characterized plant natural product UGTs are glucosyltransferases, and little is known about enzymes that add other sugars. Here we report the discovery and characterization of AsAAT1 (UGT99D1), which is required for biosynthesis of the antifungal saponin avenacin A-1 in oat (). This enzyme adds l-Ara to the triterpene scaffold at the C-3 position, a modification critical for disease resistance. The only previously reported plant natural product arabinosyltransferase is a flavonoid arabinosyltransferase from Arabidopsis (). We show that AsAAT1 has high specificity for UDP-β-l-arabinopyranose, identify two amino acids required for sugar donor specificity, and through targeted mutagenesis convert AsAAT1 into a glucosyltransferase. We further identify a second arabinosyltransferase potentially implicated in the biosynthesis of saponins that determine bitterness in soybean (). Our investigations suggest independent evolution of UDP-Ara sugar donor specificity in arabinosyltransferases in monocots and eudicots.
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http://dx.doi.org/10.1105/tpc.18.00641DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6354260PMC
December 2018

Effect of Early Sustained Prophylactic Hypothermia on Neurologic Outcomes Among Patients With Severe Traumatic Brain Injury: The POLAR Randomized Clinical Trial.

JAMA 2018 12;320(21):2211-2220

Australian and New Zealand Intensive Care Research Centre, Monash University, Melbourne, Victoria, Australia.

Importance: After severe traumatic brain injury, induction of prophylactic hypothermia has been suggested to be neuroprotective and improve long-term neurologic outcomes.

Objective: To determine the effectiveness of early prophylactic hypothermia compared with normothermic management of patients after severe traumatic brain injury.

Design, Setting, And Participants: The Prophylactic Hypothermia Trial to Lessen Traumatic Brain Injury-Randomized Clinical Trial (POLAR-RCT) was a multicenter randomized trial in 6 countries that recruited 511 patients both out-of-hospital and in emergency departments after severe traumatic brain injury. The first patient was enrolled on December 5, 2010, and the last on November 10, 2017. The final date of follow-up was May 15, 2018.

Interventions: There were 266 patients randomized to the prophylactic hypothermia group and 245 to normothermic management. Prophylactic hypothermia targeted the early induction of hypothermia (33°C-35°C) for at least 72 hours and up to 7 days if intracranial pressures were elevated, followed by gradual rewarming. Normothermia targeted 37°C, using surface-cooling wraps when required. Temperature was managed in both groups for 7 days. All other care was at the discretion of the treating physician.

Main Outcomes And Measures: The primary outcome was favorable neurologic outcomes or independent living (Glasgow Outcome Scale-Extended score, 5-8 [scale range, 1-8]) obtained by blinded assessors 6 months after injury.

Results: Among 511 patients who were randomized, 500 provided ongoing consent (mean age, 34.5 years [SD, 13.4]; 402 men [80.2%]) and 466 completed the primary outcome evaluation. Hypothermia was initiated rapidly after injury (median, 1.8 hours [IQR, 1.0-2.7 hours]) and rewarming occurred slowly (median, 22.5 hours [IQR, 16-27 hours]). Favorable outcomes (Glasgow Outcome Scale-Extended score, 5-8) at 6 months occurred in 117 patients (48.8%) in the hypothermia group and 111 (49.1%) in the normothermia group (risk difference, 0.4% [95% CI, -9.4% to 8.7%]; relative risk with hypothermia, 0.99 [95% CI, 0.82-1.19]; P = .94). In the hypothermia and normothermia groups, the rates of pneumonia were 55.0% vs 51.3%, respectively, and rates of increased intracranial bleeding were 18.1% vs 15.4%, respectively.

Conclusions And Relevance: Among patients with severe traumatic brain injury, early prophylactic hypothermia compared with normothermia did not improve neurologic outcomes at 6 months. These findings do not support the use of early prophylactic hypothermia for patients with severe traumatic brain injury.

Trial Registration: clinicaltrials.gov Identifier: NCT00987688; Anzctr.org.au Identifier: ACTRN12609000764235.
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http://dx.doi.org/10.1001/jama.2018.17075DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6583488PMC
December 2018
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