Pathway and Network Analyses Identify Growth Factor Signaling and MMP9 as Potential Mediators of Mitochondrial Dysfunction in Severe COVID-19.

Patients with preexisting metabolic disorders such as diabetes are at a higher risk of developing severe coronavirus disease 2019 (COVID-19). Mitochondrion, the very organelle that controls cellular metabolism, holds the key to understanding disease progression at the cellular level. Our current study aimed to understand how cellular metabolism contributes to COVID-19 outcomes. Metacore pathway enrichment analyses on differentially expressed genes (encoded by both mitochondrial and nuclear deoxyribonucleic acid (DNA)) involved in cellular metabolism, regulation of mitochondrial respiration and organization, and apoptosis, was performed on RNA sequencing (RNASeq) data from blood samples collected from healthy controls and patients with mild/moderate or severe COVID-19. Genes from the enriched pathways were analyzed by network analysis to uncover interactions among them and up- or downstream genes within each pathway. Compared to the mild/moderate COVID-19, the upregulation of a myriad of growth factor and cell cycle signaling pathways, with concomitant downregulation of interferon signaling pathways, were observed in the severe group. Matrix metallopeptidase 9 (MMP9) was found in five of the top 10 upregulated pathways, indicating its potential as therapeutic target against COVID-19. In summary, our data demonstrates aberrant activation of endocrine signaling in severe COVID-19, and its implication in immune and metabolic dysfunction.

'Trial by fire': An online survey exploring confidence of junior doctors in managing toxicology presentations to the emergency department.

INTRODUCTION: The often unknown nature of acute drug intoxication, especially with illicit drugs and emerging novel psychoactive substances, can present a significant challenge for emergency clinicians. Less experienced clinicians are particularly vulnerable to the diagnostic dilemmas of complex toxicology emergencies. We sought to better understand the confidence of junior doctors in assessing and managing toxicological emergencies across two emergency departments in Perth, Australia. METHODS: An online survey was conducted between August 2020 and February 2021. Self-rated confidence was measured on a five-point Likert Scale across 10 statements. Two open-ended questions were included to capture perceived barriers and facilitators impacting clinical confidence. Quantitative data were analysed using descriptive methods and Fisher's exact test. Free-text responses were analysed using content analysis. RESULTS: A total of 104 surveys were completed (19.2% interns, 40.4% resident medical officers and 40.4% registrars). Self-rated confidence varied across statements and by staff type. The lowest confidence rating was for managing a patient who had overdosed from an unknown substance (31.7%) and the highest rating for referring a patient to psychiatry following deliberate self-poisoning (86.6%). Confidence increased with greater clinical experience for all statements. Qualitative analysis revealed perceptions of clinical preparedness, complexity of patients and a safe and supportive culture as key factors impacting confidence. DISCUSSION AND CONCLUSIONS: Overcoming perceived deficits in knowledge and clinical experience were key to building confidence. Our findings highlight the need for improved access to toxicology-specific curricula and training, and strategies to ensure adequate supervision from senior clinicians.

The Emerging Drugs Network of Australia: A toxicosurveillance system of illicit and emerging drugs in the emergency department.

OBJECTIVE: The unprecedented rise in synthetic drugs, many containing unknown toxic agents, has made timely analytical diagnosis more difficult, and has reduced the confidence of clinicians providing ED management to this population of patients. This has also impacted the quality of evidence informing harm reduction responses. The Emerging Drugs Network of Australia (EDNA) brings together emergency physicians, toxicologists and forensic laboratories to establish a standardised ED toxicosurveillance system in Australia. METHODS: Blood analysis of intoxicated patients will be conducted by forensic laboratories to enable precise identification of the substances causing acute toxicity. This will be linked with clinical data collected at the time of ED presentation to enable analysis of the clinical effects and outcomes associated with different illicit and emerging drugs. Toxicological and clinical data collected across sentinel sites will align with a nationally endorsed minimum dataset. RESULTS: EDNA's collaborative network will establish a national system of surveillance and reporting of illicit and emerging drugs causing acute toxicity. Standardisation of data collection recorded in a national clinical registry will provide more robust data on epidemiology and associated harms. This will facilitate the translation of clinical and toxicological evidence into timely, appropriate harm reduction and policy. CONCLUSION: Our work represents a collaborative response to calls for more sophisticated data on emerging drug trends in Australia. EDNA will improve coordination between clinicians and analytical services by way of its standardised approach to surveillance and reporting.

Blood transcriptome responses in patients correlate with severity of COVID-19 disease.

Background: Coronavirus disease 2019 (COVID-19) is an infectious disease caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). Infected individuals display a wide spectrum of disease severity, as defined by the World Health Organization (WHO). One of the main factors underlying this heterogeneity is the host immune response, with severe COVID-19 often associated with a hyperinflammatory state. Aim: Our current study aimed to pinpoint the specific genes and pathways underlying differences in the disease spectrum and outcomes observed, through in-depth analyses of whole blood transcriptomics in a large cohort of COVID-19 participants. Results: All WHO severity levels were well represented and mild and severe disease displaying distinct gene expression profiles. WHO severity levels 1-4 were grouped as mild disease, and signatures from these participants were different from those with WHO severity levels 6-9 classified as severe disease. Severity level 5 (moderate cases) presented a unique transitional gene signature between severity levels 2-4 (mild/moderate) and 6-9 (severe) and hence might represent the turning point for better or worse disease outcome. Gene expression changes are very distinct when comparing mild/moderate or severe cases to healthy controls. In particular, we demonstrated the hallmark down-regulation of adaptive immune response pathways and activation of neutrophil pathways in severe compared to mild/moderate cases, as well as activation of blood coagulation pathways. Conclusions: Our data revealed discrete gene signatures associated with mild, moderate, and severe COVID-19 identifying valuable candidates for future biomarker discovery.

Consumer involvement in emergency medicine research: Lessons from engaging sepsis survivors.

Collaboration with consumers is an emerging focus for medical researchers worldwide. Public involvement is increasingly encouraged, and in some cases stipulated by funding bodies, in order to secure financial support. While consumer involvement could be viewed as another hurdle in the funding application process, it can add immense value to research outcomes. However, given the diverse and transient nature of our consumer group, how can we develop meaningful public engagement in emergency medicine research?

The Australasian Resuscitation In Sepsis Evaluation: Fluids or vasopressors in emergency department sepsis (ARISE FLUIDS), a multi-centre observational study describing current practice in Australia and New Zealand.

OBJECTIVES: To describe haemodynamic resuscitation practices in ED patients with suspected sepsis and hypotension. METHODS: This was a prospective, multicentre, observational study conducted in 70 hospitals in Australia and New Zealand between September 2018 and January 2019. Consecutive adults presenting to the ED during a 30-day period at each site, with suspected sepsis and hypotension (systolic blood pressure <100 mmHg) despite at least 1000 mL fluid resuscitation, were eligible. Data included baseline demographics, clinical and laboratory variables and intravenous fluid volume administered, vasopressor administration at baseline and 6- and 24-h post-enrolment, time to antimicrobial administration, intensive care admission, organ support and in-hospital mortality. RESULTS: A total of 4477 patients were screened and 591 were included with a mean (standard deviation) age of 62 (19) years, Acute Physiology and Chronic Health Evaluation II score 15.2 (6.6) and a median (interquartile range) systolic blood pressure of 94 mmHg (87-100). Median time to first intravenous antimicrobials was 77 min (42-148). A vasopressor infusion was commenced within 24 h in 177 (30.2%) patients, with noradrenaline the most frequently used (n = 138, 78%). A median of 2000 mL (1500-3000) of intravenous fluids was administered prior to commencing vasopressors. The total volume of fluid administered from pre-enrolment to 24 h was 4200 mL (3000-5661), with a range from 1000 to 12 200 mL. Two hundred and eighteen patients (37.1%) were admitted to an intensive care unit. Overall in-hospital mortality was 6.2% (95% confidence interval 4.4-8.5%). CONCLUSION: Current resuscitation practice in patients with sepsis and hypotension varies widely and occupies the spectrum between a restricted volume/earlier vasopressor and liberal fluid/later vasopressor strategy.

The Australasian Resuscitation In Sepsis Evaluation: FLUid or vasopressors In Emergency Department Sepsis, a multicentre observational study (ARISE FLUIDS observational study): Rationale, methods and analysis plan.

OBJECTIVE: There is uncertainty about the optimal i.v. fluid volume and timing of vasopressor commencement in the resuscitation of patients with sepsis and hypotension. We aim to study current resuscitation practices in EDs in Australia and New Zealand (the Australasian Resuscitation In Sepsis Evaluation: FLUid or vasopressors In Emergency Department Sepsis [ARISE FLUIDS] observational study). METHODS: ARISE FLUIDS is a prospective, multicentre observational study in 71 hospitals in Australia and New Zealand. It will include adult patients presenting to the ED during a 30 day period with suspected sepsis and hypotension (systolic blood pressure <100 mmHg) despite at least 1000 mL fluid resuscitation. We will obtain data on baseline demographics, clinical and laboratory variables, all i.v. fluid given in the first 24 h, vasopressor use, time to antimicrobial administration, admission to intensive care, organ failure and in-hospital mortality. We will specifically describe (i) the volume of fluid administered at the following time points: when meeting eligibility criteria, in the first 6 h, at 24 h and prior to vasopressor commencement and (ii) the frequency and timing of vasopressor use in the first 6 h and at 24 h. Screening logs will provide reliable estimates of the proportion of ED patients meeting eligibility criteria for a subsequent randomised controlled trial. DISCUSSION: This multicentre, observational study will provide insight into current haemodynamic resuscitation practices in patients with sepsis and hypotension as well as estimates of practice variation and patient outcomes. The results will inform the design and feasibility of a multicentre phase III trial of early haemodynamic resuscitation in patients presenting to ED with sepsis and hypotension.