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The stability of proteins from rates of oxidation (SPROX), thermal proteome profiling (TPP), and limited proteolysis (LiP) techniques were used to profile the stability of ∼2500 proteins in hippocampus tissue cell lysates from 2- and 8-months-old wild-type (C57BL/6J; n = 7) and transgenic (5XFAD; n = 7) mice with five Alzheimer's disease (AD)-linked mutations. Approximately 200-500 protein hits with AD-related stability changes were detected by each technique at each age point. The hit overlap from technique to technique was low, and all of the techniques generated protein hits that were more numerous and largely different from those identified in protein expression level analyses, which were also performed here. The hit proteins identified by each technique were enriched in a number of the same pathways and biological processes, many with known connections to AD. The protein stability hits included 25 high-value conformation biomarkers with AD-related stability changes detected using at least 2 techniques at both age points. Also discovered were subunit- and age-specific AD-related stability changes in the proteasome, which had reduced function at both age points. The different folding stability profiles of the proteasome at the two age points are consistent with a different mechanism for proteasome dysfunction at the early and late stages of AD.

Objectives: To review the epidemiology of elderly trauma at the Kind Saud Medical City (KSMC), Riyadh, Saudi Arabia, and carry out risk-adjusted analyses to benchmark outcomes with the Alfred Hospital, Melbourne, Australia, the largest Australasian trauma service., Methods: This retrospective study included records of injured patients (≥65 years) from the hospital trauma registries during 2022. Demographic and injury data were extracted. Risk-adjusted endpoints were: inpatient mortality and length of stay, analysed using logistic and median regression., Results: A total of 193 elderly patients were registered on the KSMC registry and 1233 elderly patients were registered on the Alfred Hospital registry. Kind Saud Medical City saw proportionally less major trauma (injury severity score of >12, 24.4% vs. 44.2%, p <0.001) and less females (31.1% vs 44.4%, p <0.001). The modal injury group was low level falls in both centres (≈60%). Discharge destination was different, particularly for patients discharged home (86.5% vs. 56%) or to a rehabilitation facility (0.5% vs. 28.2%). The risk-adjusted length of stay was 4.5 days less at the Alfred Hospital (95% CI: [3.25-5.77] days, p <0.001). The odds of in-hospital death were not significantly different (OR=0.72, 95% CI: [0.36-1.47], p =0.37)., Conclusion: Despite the different settings, low level falls were the major cause of injury in older patients. A longer length of stay in the acute hospital was identified for KSMC, however, this may be partly explained by discharge destination practices in the 2 countries., (Copyright: © Saudi Medical Journal.)

Background: Acute colonic pseudo-obstruction (ACPO) is characterized by severe colonic distension without mechanical obstruction. It has an uncertain pathogenesis and poses diagnostic challenges. This study aimed to explore risk factors and clinical outcomes of ACPO in polytrauma patients and contribute information to the limited literature on this condition., Methods: This retrospective study, conducted at a Level 1 trauma center, analyzed data from trauma patients with ACPO admitted between July 2009 and June 2018. A control cohort of major trauma patients was used. Data review encompassed patient demographics, abdominal imaging, injury characteristics, analgesic usage, interventions, complications, and mortality. Statistical analyses, including logistic regression and correlation coefficients, were employed to identify risk factors., Results: There were 57 cases of ACPO, with an incidence of 1.7 per 1,000 patients, rising to 4.86 in major trauma. Predominantly affecting those older than 50 years (75%) and males (75%), with motor vehicle accidents (50.8%) and falls from height (36.8%) being the commonest mechanisms. Noteworthy associated injuries included retroperitoneal bleeds (RPBs) (37%), spinal fractures (37%), and pelvic fractures (37%). Analysis revealed significant associations between ACPO and shock index >0.9, Injury Severity Score >18, opioid use, RPBs, and pelvic fractures. A cecal diameter of ≥12 cm had a significant association with cecal ischemia or perforation., Conclusion: This study underscores the significance of ACPO in polytrauma patients, demonstrating associations with risk factors and clinical outcomes. Clinicians should maintain a high index of suspicion, particularly in older patients with RPBs, pelvic fractures, and opioid use. Early supportive therapy, vigilant monitoring, and timely interventions are crucial for a favorable outcome. Further research and prospective trials are warranted to validate these findings and enhance understanding of ACPO in trauma patients., Level of Evidence: Prognostic and Epidemiological; Level IV., (Copyright © 2024 Wolters Kluwer Health, Inc. All rights reserved.)

Objectives: Protection of the cervical spine is recommended following multisystem injury. In 2021, Ambulance Victoria changed clinical practice guidelines to apply soft collars instead of semi-rigid collars for suspected cervical spine injury. The aim of this study was to describe associated changes in imaging practices and diagnoses of pressure sores, hospital acquired pneumonia, and spinal cord injury., Methods: A retrospective pre- and postintervention study was conducted including all consecutive patients that presented to an adult major trauma center in Melbourne, Australia with a cervical collar placed by emergency medical services over two 3-month periods., Results: There were 1762 patients included. A computed tomography (CT) of the cervical spine was performed in 795 (88.4%) patients in the semi-rigid collar period and 810 (93.8%) in the soft collar period ( p  = 0.001). Soft collars were associated with higher rates of clearance of the cervical spine in the emergency department (ED) (odds ratio [OR] 4.14; 95% confidence interval [CI]: 3.36-5.09). There were no differences in diagnosis of pressure sores (0.11% vs. 0.23%, p  = 0.97) or hospital acquired pneumonia (2.0% vs. 2.7%; p  = 0.44) or cervical spinal cord injury (0.45% vs. 0.81%; p  = 0.50)., Conclusions: Following a change from prehospital semi-rigid collars to soft collars, more patients were investigated with a CT scan and more frequent clearance of the cervical spine occurred in the ED. There were no differences in the rates of spinal cord injuries, pressure sores or hospital acquired pneumonia, but the study was underpowered to detect significant differences. The practice of soft collars for prehospital care of patients with suspected neck injury requires ongoing surveillance., Competing Interests: The authors declare no conflicts of interest., (© 2024 The Author(s). Journal of the American College of Emergency Physicians Open published by Wiley Periodicals LLC on behalf of American College of Emergency Physicians.)

The molecular chaperone heat shock protein 90 (Hsp90) has an essential but largely undefined role in maintaining proteostasis in Plasmodium falciparum, the most lethal malaria parasite. Herein, we identify BX-2819 and XL888 as potent P. falciparum (Pf)Hsp90 inhibitors. Derivatization of XL888's scaffold led to the development of Tropane 1, as a PfHsp90-selective binder with nanomolar affinity. Hsp90 inhibitors exhibit anti-Plasmodium activity against the liver, asexual blood, and early gametocyte life stages. Thermal proteome profiling was implemented to assess PfHsp90-dependent proteome stability, and the proteasome-the main site of cellular protein recycling-was enriched among proteins with perturbed stability upon PfHsp90 inhibition. Subsequent biochemical and cellular studies suggest that PfHsp90 directly promotes proteasome hydrolysis by chaperoning the active 26S complex. These findings expand our knowledge of the PfHsp90-dependent proteome and protein quality control mechanisms in these pathogenic parasites, as well as further characterize this chaperone as a potential antimalarial drug target., Competing Interests: Declaration of interests The authors declare no competing interests., (Copyright © 2024 Elsevier Ltd. All rights reserved.)

RNA-protein interactions are essential to RNA function throughout biology. Identifying the protein interactions associated with a specific RNA, however, is currently hindered by the need for RNA labeling or costly tiling-based approaches. Conventional strategies, which commonly rely on affinity pull-down approaches, are also skewed to the detection of high affinity interactions and frequently miss weaker interactions that may be biologically important. Reported here is the first adaptation of stability-based mass spectrometry methods for the global analysis of RNA-protein interactions. The stability of proteins from rates of oxidation (SPROX) and thermal protein profiling (TPP) methods are used to identify the protein targets of three RNA ligands, the MALAT1 triple helix ( TH ), a viral stem loop ( SL ), and an unstructured RNA ( PolyU ), in LNCaP nuclear lysate. The 315 protein hits with RNA-induced conformational and stability changes detected by TPP and/or SPROX were enriched in previously annotated RNA-binding proteins and included new proteins for hypothesis generation. Also demonstrated are the orthogonality of the SPROX and TPP approaches and the utility of the domain-specific information available with SPROX. This work establishes a novel platform for the global discovery and interrogation of RNA-protein interactions that is generalizable to numerous biological contexts and RNA targets.

Introduction: The Glasgow Coma Scale (GCS) and pupil response to light are commonly used to assess brain injury severity and predict outcomes. The aim of this study was to investigate whether the GCS combined with pupil response (GCS-P), compared to the GCS alone, could be a better predictor of hospital mortality for patients with traumatic brain injury (TBI)., Methods: A retrospective cohort study was undertaken at an adult level one trauma centre including patients with isolated TBI of Abbreviated Injury Scale above three. The GCS and pupil response were combined to an arithmetic score (GCS score (range 3-15) minus the number of nonreacting pupils (0, 1, or 2)), or by treating each factor as separate categorical variables. The association of in-hospital mortality with GCS-P as a categorical variable was evaluated using Nagelkerke's R 2 and compared using areas under the receiver operating characteristic (AUROC) curve., Results: There were 392 patients included over the study period of 1 July 2014 and 30 September 2017, with an overall mortality rate of 15.2%. Mortality was highest at GCS-P of 1 (79%), with lowest mortality at a GCS-P 15 (1.6%). Nagelkerke's R 2 was 0.427 for GCS alone and 0.486 for GCS-P. The AUROC for GCS-P to predict mortality was 0.87 (95%CI: 0.82-0.72), higher than for GCS alone (0.85; 95%CI: 0.80-0.90; p  < .001)., Discussion: GCS-P provided a better predictor of mortality compared to the GCS. As both the GCS and pupillary response are routinely recorded on all patients, combination of these pieces of information into a single score can further simplify assessment of patients with TBI, with some improvement in performance.

Background: Up to 25% of trauma deaths are related to thoracic injuries., Objective: The primary goal was to analyse the incidence and time distribution of death in adult patients with major thoracic injuries. The secondary goal was to determine if potentially preventable deaths occurred within this time distribution and, if so, identify an associated therapeutic window., Design: Retrospective observational analysis., Setting: TraumaRegister DGU., Patients: Major thoracic injury was defined as an Abbreviated Injury Scale (AIS) 3 or greater. Patients with severe head injury (AIS ≥ 4) or injuries to other body regions with AIS being greater than the thoracic injury (AIS other >AIS thorax) were excluded to ensure that the most severe injury described was primarily thoracic related., Main Outcome Measures: Incidence and time distribution of mortality were considered the primary outcome measures. Patient and clinical characteristics and resuscitative interventions were analysed in relation to the time distribution of death., Results: Among adult major trauma cases with direct admission from the accident scene, 45% had thoracic injuries and overall mortality was 9.3%. In those with major thoracic trauma ( n  = 24 332) mortality was 5.9% ( n  = 1437). About 25% of these deaths occurred within the first hour after admission and 48% within the first day. No peak in late mortality was seen. The highest incidences of hypoxia and shock were seen in non-survivors with immediate death within 1 h and early death (1 to 6 h). These groups received the largest number of resuscitative interventions. Haemorrhage was the leading cause of death in these groups, whereas organ failure was the leading cause of death amongst those who survived the first 6 h after admission., Conclusion: About half of adult major trauma cases had thoracic injuries. In non-survivors with primarily major thoracic trauma, most deaths occurred immediately (<1h) or within the first 6 h after injury. Further research should analyse if improvements in trauma resuscitation performed within this time frame will reduce preventable deaths., Trial Registration: The present study is reported within the publication guidelines of the TraumaRegister DGU® and registered as TR-DGU project ID 2020-022., (Copyright © 2023 The Author(s). Published by Wolters Kluwer Health, Inc. on behalf of the European Society of Anaesthesiology and Intensive Care.)

Medulloblastoma is the most common malignant paediatric brain tumour, representing 20% of all paediatric intercranial tumours. Current aggressive treatment protocols and the use of radiation therapy in particular are associated with high levels of toxicity and significant adverse effects, and long-term sequelae can be severe. Therefore, improving chemotherapy efficacy could reduce the current reliance on radiation therapy. Here, we demonstrated that systems-level analysis of basal apoptosis protein expression and their signalling interactions can differentiate between medulloblastoma cell lines that undergo apoptosis in response to chemotherapy, and those that do not. Combining computational predictions with experimental BH3 profiling, we identified a therapeutically-exploitable dependence of medulloblastoma cells on BCL-XL, and experimentally validated that BCL-XL targeting, and not targeting of BCL-2 or MCL-1, can potentiate cisplatin-induced cytotoxicity in medulloblastoma cell lines with low sensitivity to cisplatin treatment. Finally, we identified MCL-1 as an anti-apoptotic mediator whose targeting is required for BCL-XL inhibitor-induced apoptosis. Collectively, our study identifies that BCL-XL and MCL-1 are the key anti-apoptotic proteins in medulloblastoma, which mediate distinct protective roles. While BCL-XL has a first-line role in protecting cells from apoptosis basally, MCL-1 represents a second line of defence that compensates for BCL-XL upon its inhibition. We provide rationale for the further evaluation of BCL-XL and MCL-1 inhibitors in the treatment of medulloblastoma, and together with current efforts to improve the cancer-specificity of BCL-2 family inhibitors, these novel treatment strategies have the potential to improve the future clinical management of medulloblastoma., (© 2023. The Author(s).)

Objective: To describe the frequency of hospitalisation and in-hospital death following moderate to severe traumatic brain injury (TBI) in Australia, both overall and by patient demographic characteristics and the nature and severity of the injury., Design, Setting: Cross-sectional study; analysis of Australia New Zealand Trauma Registry data., Participants: People with moderate to severe TBI (Abbreviated Injury Score [head] greater than 2) who were admitted to or died in one of the twenty-three major Australian trauma services that contributed data to the ATR throughout the study period, 1 July 2015 - 30 June 2020., Major Outcome Measures: Primary outcome: number of hospitalisations with moderate to severe TBI; secondary outcome: number of deaths in hospital following moderate to severe TBI., Results: During 2015-20, 16 350 people were hospitalised with moderate to severe TBI (mean, 3270 per year), of whom 2437 died in hospital (14.9%; mean, 487 per year). The mean age at admission was 50.5 years (standard deviation [SD], 26.1 years), and 11 644 patients were male (71.2%); the mean age of people who died in hospital was 60.4 years (SD, 25.2 years), and 1686 deaths were of male patients (69.2%). The overall number of hospitalisations did not change during 2015-20 (per year: incidence rate ratio [IRR], 1.00; 95% confidence interval [CI], 0.99-1.02) and death (IRR, 1.00; 95% CI, 0.97-1.03)., Conclusion: Injury prevention and trauma care interventions for people with moderate to severe TBI in Australia reduced neither the incidence of the condition nor the associated in-hospital mortality during 2015-20. More effective care strategies are required to reduce the burden of TBI, particularly among younger men., (© 2023 The Authors. Medical Journal of Australia published by John Wiley & Sons Australia, Ltd on behalf of AMPCo Pty Ltd.)

Reported here is the application of three protein folding stability profiling techniques (including the stability of proteins from rates of oxidation, thermal protein profiling, and limited proteolysis approaches) to identify differentially stabilized proteins in six patient-derived colorectal cancer (CRC) cell lines with different oxaliplatin sensitivities and eight CRC patient-derived xenografts (PDXs) derived from two of the patient derived cell lines with different oxaliplatin sensitivities. Compared to conventional protein expression level analyses, which were also performed here, the stability profiling techniques identified both unique and novel proteins and cellular components that differentiated the sensitive and resistant samples including 36 proteins that were differentially stabilized in at least two techniques in both the cell line and PDX studies of oxaliplatin resistance. These 36 differentially stabilized proteins included 10 proteins previously connected to cancer chemoresistance. Two differentially stabilized proteins, fatty acid synthase and elongation factor 2, were functionally validated in vitro and found to be druggable protein targets with biological functions that can be modulated to improve the efficacy of CRC chemotherapy. These results add to our understanding of CRC oxaliplatin resistance, suggest biomarker candidates for predicting oxaliplatin sensitivity in CRC, and inform new strategies for overcoming chemoresistance in CRC.

Objective: The objectives of the present study were to report the proportion of older teenagers, including the subgroup operating a motor vehicle, presenting to an adult major trauma centre after injury with a positive blood alcohol concentration (BAC) over a 12-year period., Methods: This was a registry-based cohort study, including all patients aged 16-19 years presenting to an adult major trauma centre in Victoria, Australia from January 2008 to December 2019 and included in the trauma registry. A Poisson regression model was used to test for change in incidence of positive BAC associated trauma and summarised using incidence rate ratios (IRRs) and 95% confidence intervals (CIs)., Results: There were 1658 patients included for analysis and alcohol was detected in 368 (22.2%; 95% CI 20.2-24.3). Most alcohol positive presentations were on weekend days (n = 207; 56.3%) and most were males (n = 307). Over the 12-year period, there was a reduction in the incidence of older teenagers presenting with a positive BAC (IRR 0.95; 95% CI 0.93-0.98; P = 0.001). Among patients presenting after trauma in the setting of operating a motor vehicle (n = 545), alcohol was detected in 80 (14.7%) with no significant change in incidence of positive BAC (IRR 0.95; 95% CI 0.89-1.02; P = 0.17)., Conclusions: A substantial proportion of older teenagers included in the registry had alcohol exposure prior to trauma. Despite a modest down-trending incidence, the need for continuing preventive measures is emphasised. In particular, preventive efforts should be targeted at male, older teenagers undertaking drinking activities on weekend days and driving motor vehicles., (© 2022 The Authors. Emergency Medicine Australasia published by John Wiley & Sons Australia, Ltd on behalf of Australasian College for Emergency Medicine.)

Recently, a new suite of mass spectrometry-based proteomic methods has been developed that enables evaluation of protein folding stability on the proteomic scale. These methods utilize chemical and thermal denaturation approaches (SPROX and TPP, respectively) as well as proteolysis strategies (DARTS, LiP, and PP) to assess protein folding stability. The analytical capabilities of these technique have been well-established for protein target discovery applications. However, less is known about the relative advantages and disadvantages of using these different strategies to characterize biological phenotypes. Reported here is a comparative study of SPROX, TPP, LiP, and conventional protein expression level measurements using both a mouse model of aging and a mammalian cell culture model of breast cancer. Analyses on proteins in brain tissue cell lysates derived from 1- and 18-month-old mice ( n = 4-5 at each time point) and on proteins in cell lysates derived from the MCF-7 and MCF-10A cell lines revealed a majority of the differentially stabilized protein hits in each phenotype analysis had unchanged expression levels. In both phenotype analyses, TPP generated the largest number and fraction of differentially stabilized protein hits. Only a quarter of all the protein hits identified in each phenotype analysis had a differential stability that was detected using multiple techniques. This work also reports the first peptide-level analysis of TPP data, which was required for the correct interpretation of the phenotype analyses performed here. Studies on selected protein stability hits also uncovered phenotype-related functional changes.

Background: After trauma, clearance of the cervical spine refers to the exclusion of underlying serious injuries. Accurate assessment of computed tomography (CT) is commonly required prior to clearance of the cervical spine. Delays to clearance can lead to prolonged immobilization with associated patient discomfort and adverse effects. This systematic review aimed to determine performance of non-radiologists to evaluate cervical spine CT., Methods: MEDLINE, EMBASE, Cochrane library with sources of grey literature and reference lists of selected articles were appraised from inception to April 2021. We included manuscripts that reported discordance in CT cervical spine interpretation between non-radiologists and radiologists. The Newcastle-Ottawa scale (NOS) was used to assess quality of included studies and statistical heterogeneity was assessed using the I 2 statistic., Results: There were 43 studies identified for eligibility and 4 manuscripts included in the final analysis. There were two studies that reported on the performance of radiology residents, one study on the performance of surgical residents and one on emergency physicians. The pooled discordance was 0.25 (95%CI 0.21-0.28) but was lower for radiology residents (range 0.007-0.05). There was significant statistical heterogeneity (I 2  = 99.6%, P < 0.001) among studies., Conclusion: There is a paucity of evidence documenting the ability of non-radiologists in accurately interpreting CT of the cervical spine. A number of discordant findings suggest that studies with larger sample sizes are indicated to accurately ascertain the ability of non-radiologists in this area., (© 2022 Royal Australasian College of Surgeons.)

Haemorrhagic shock after trauma is a leading cause of death worldwide, particularly in young individuals. Despite advances in trauma systems and resuscitation strategies, mortality from haemorrhagic shock has not declined over the previous two decades. A proportion of shocked trauma patients may experience a deficiency of cortisol relative to the severity of their injury. The benefit of exogenous steroid administration in patients suffering haemorrhagic shock as a result of injury is unclear. A systematic review of four databases (Ovid Medline, Ovid Embase, Cochrane, Scopus) was undertaken. Inclusion and exclusion criteria were pre-determined and two reviewers independently screened the articles with disagreements arbitrated by a third reviewer. The primary outcome variable was 28-day mortality. Quality of studies were assessed using the Cochrane-risk-of-bias (RoB 2) tool. Of the 2919 studies yielded by the search strategy, 1274 duplicates were removed and 1645 screened on title and abstract. After the full text of 33 studies were assessed, two articles were included. Both studies were over 30 years old with small numbers of participants and with primary outcomes not including mortality. Of the data available, no statistically significant difference in mortality was detected. Hospital length of stay, reversal of shock or adverse events were not reported. Both studies were at risk of bias. There are no high quality or recent studies in the English literature investigating the use of steroids for haemorrhagic shocked trauma patients. PROSPERO: CRD42021239656., (© 2022 The Authors. Emergency Medicine Australasia published by John Wiley & Sons Australia, Ltd on behalf of Australasian College for Emergency Medicine.)

Objective: Inconsistency in the structure and function of team-based major trauma reception and resuscitation is common. A standardised trauma team training programme was initiated to improve quality and consistency among trauma teams across a large, mature trauma system. The aim of this manuscript is to outline the programme and report on the initial perception of participants., Methods: The Alfred Trauma Team Reception and Resuscitation Training (TTRRT) programme commenced in March 2019. Participants included critical care and surgical craft group members commonly involved in trauma teams. Training was site-specific and included rural, urban and tertiary referral centres. The programme consisted of prescribed pre-learning, didactic lectures, skill stations and simulated team-based scenarios. Participant perceptions of the programme were collected before and after the programme for analysis., Results: The TTRRT was delivered to 252 participants and 120 responses were received. Significant improvement in participant-reported confidence was identified across all key topic areas. There was also a significant increase in both confidence and clinical exposure to trauma team leadership roles after participation in the programme (from 53 [44.2%] to 74 [61.7%; P = 0.007]). This finding was independent of clinician experience., Conclusions: A team-based trauma reception and resuscitation education programme, introduced in a large, mature trauma system led to positive participant-reported outcomes in clinical confidence and real-life team leadership participation. Wider implementation combined with longitudinal data collection will facilitate correlation with patient and staff-centred outcomes., (© 2022 The Authors. Emergency Medicine Australasia published by John Wiley & Sons Australia, Ltd on behalf of Australasian College for Emergency Medicine.)

Metal cations have been exploited for their precipitation properties in a wide variety of studies, ranging from differentiating proteins from serum and blood to identifying the protein targets of drugs. Despite widespread recognition of this phenomenon, the mechanisms of metal-induced protein aggregation have not been fully elucidated. Recent studies have suggested that copper's (Cu) ability to induce protein aggregation may be a main contributor to Cu-induced cell death. Here, we provide the first proteome-wide analysis of the relative sensitivities of proteins across the Escherichia coli proteome to Cu-induced aggregation. We utilize a metal-induced protein precipitation (MiPP) methodology that relies on quantitative bottom-up proteomics to define the metal concentration-dependent precipitation properties of proteins on a proteomic scale. Our results establish that Cu far surpasses other metals in promoting protein aggregation and that the protein aggregation is reversible upon metal chelation. The bulk of the Cu bound in the protein aggregates is Cu1+, regardless of the Cu2+ source. Analysis of our MiPP data allows us to investigate underlying biophysical characteristics that determine a protein's sensitivity to Cu-induced aggregation, which is independent of the relative concentration of protein in the lysate. Overall, this analysis provides new insights into the mechanism behind Cu cytotoxicity, as well as metal cation-induced protein aggregation., (© The Author(s) 2022. Published by Oxford University Press.)

Background: Traumatic brain injury (TBI) is the largest contributor to death and disability in people who have experienced physical trauma. There are no national data on outcomes for people with moderate to severe TBI in Australia., Objectives: To determine the incidence and key determinants of outcomes for patients with moderate to severe TBI, both for Australia and for selected population subgroups, including Aboriginal and Torres Strait Islander Australians., Methods and Analysis: The Australian Traumatic Brain Injury National Data (ATBIND) project will analyse Australia New Zealand Trauma Registry (ATR) data and National Coronial Information Service (NCIS) deaths data. The ATR documents the demographic characteristics, injury event description and severity, processes of care, and outcomes for people with major injury, including TBI, assessed and managed at the 27 major trauma services in Australia. We will include data for people with moderate to severe TBI (Abbreviated Injury Scale [AIS] (head) score higher than 2) who had Injury Severity Scores [ISS] higher than 12 or who died in hospital. People will also be included if they died before reaching a major trauma service and the coronial report details were consistent with moderate to severe TBI. The primary research outcome will be survival to discharge. Secondary outcomes will be hospital discharge destination, hospital length of stay, ventilator-free days, and health service cost., Ethics Approval: The Alfred Ethics Committee approved ATR data extraction (project reference number 670/21). Further ethics approval has been sought from the NCIS and multiple Aboriginal health research ethics committees. The ATBIND project will conform with Indigenous data sovereignty principles., Dissemination of Results: Our findings will be disseminated by project partners with the aim of informing improvements in equitable system-level care for all people in Australia with moderate to severe TBI., Study Registration: Not applicable., (© 2022 The Authors. Medical Journal of Australia published by John Wiley & Sons Australia, Ltd on behalf of AMPCo Pty Ltd.)

New, more effective therapeutics are required for the treatment of paediatric cancers. Current treatment protocols of cytotoxic treatments including chemotherapy trigger cancer-cell death by engaging the apoptosis pathway, and chemotherapy efficacy is frequently impeded by apoptosis dysregulation. Apoptosis dysregulation, through genetic or epigenetic mechanisms, is a feature of many cancer types, and contributes to reduced treatment response, disease progression and ultimately treatment resistance. Novel approaches are required to overcome dysregulated apoptosis signalling, increase the efficacy of cancer treatment and improve patient outcomes. Here, we provide an insight into current knowledge of how the apoptosis pathway is dysregulated in paediatric nervous system tumours, with a focus on TRAIL receptors, the BCL-2 proteins and the IAP family, and highlight preclinical evidence demonstrating that pharmacological manipulation of the apoptosis pathway can restore apoptosis signalling and sensitise cancer cells to treatment. Finally, we discuss the potential clinical implications of these findings., (© 2022. The Author(s).)

Recent studies have demontrated that immune checkpoint receptors are expressed on the surface of oesophageal adenocarcinoma (OAC) cells and might confer a survival advantage. This study explores the role of PD-1 and TIGIT signalling in OAC cells in either promoting or inhibiting the survival of OAC cells under characteristic features of the tumour microenvironment including nutrient-deprivation and hypoxia. PD-1 and TIGIT are expressed in normal and pre-malignant oesophageal epithelial cells and this expression significantly decreases along the normal- Barrett's Oesophagus- OAC disease sequence. However, glucose-deprivation and hypoxia significantly upregulated PD-1 and TIGIT on the surface of OAC cells in vitro. PD-1 blockade decreased OAC cell proliferation under normoxia but enhanced proliferation and decreased cell death in OAC cells under hypoxia and glucose-deprivation. TIGIT blockade decreased proliferation and induced OAC cell death, an effect that was maintained under nutrient-deprivation and hypoxia. Basal respiration and glycolytic reserve were enhanced and GLUT1 was upregulated on the surface of a subpopulation of OAC cells following PD-1 blockade. In contrast, TIGIT blockade enhanced a glycolytic phenotype in OAC cells, yet decreased other metabolic parameters including oxidative phosphorylation and basal respiration. Interestingly, inhibition of oxidative phosphorylation significantly upregulated TIGIT expression and inhibition of oxidative phosphorylation and glycolysis significantly decreased PD-1 on the surface of a subpopulation of OAC cells in vitro. These findings suggest an immune-independent mechanism for PD-1 inhibitor resistance in hypoxic tumours and suggest that TIGIT might be a more effective therapeutic target in OAC compared with PD-1 for treating hypoxic tumours., (Copyright © 2022. Published by Elsevier Inc.)

The intermolecular interactions of noble gases in biological systems are associated with numerous biochemical responses, including apoptosis, inflammation, anesthesia, analgesia, and neuroprotection. The molecular modes of action underlying these responses are largely unknown. This is in large part due to the limited experimental techniques to study protein-gas interactions. The few techniques that are amenable to such studies are relatively low-throughput and require large amounts of purified proteins. Thus, they do not enable the large-scale analyses that are useful for protein target discovery. Here, we report the application of stability of proteins from rates of oxidation (SPROX) and limited proteolysis (LiP) methodologies to detect protein-xenon interactions on the proteomic scale using protein folding stability measurements. Over 5000 methionine-containing peptides and over 5000 semi-tryptic peptides, mapping to ∼1500 and ∼950 proteins, respectively, in the yeast proteome, were assayed for Xe-interacting activity using the SPROX and LiP techniques. The SPROX and LiP analyses identified 31 and 60 Xe-interacting proteins, respectively, none of which were previously known to bind Xe. A bioinformatics analysis of the proteomic results revealed that these Xe-interacting proteins were enriched in those involved in ATP-driven processes. A fraction of the protein targets that were identified are tied to previously established modes of action related to xenon's anesthetic and organoprotective properties. These results enrich our knowledge and understanding of biologically relevant xenon interactions. The sample preparation protocols and analytical methodologies developed here for xenon are also generally applicable to the discovery of a wide range of other protein-gas interactions in complex biological mixtures, such as cell lysates.

Migraine is a neurological disorder with a prominent sex difference such that two thirds of sufferers are female. The mechanisms behind the preponderance of migraine in women have yet to be elucidated. With data on 51,872 participants from the Swedish Twin Registry, we report results from two distinct analyses intended to clarify the degree to which genetic and environmental factors contribute to sex differences in migraine. First, we fit a sex-limitation model to determine if quantitative genetic differences (i.e., is migraine equally heritable across men and women) and/or qualitative genetic differences (i.e., are different genes involved in migraine across men and women) were present. Next, we used a multilevel logistic regression model to compare the prevalence of migraine in individuals from opposite-sex and same-sex twin pairs to determine whether differences in the prenatal hormone environment contribute to migraine risk. In the final analytic sample, women were found to have a significantly higher rate of migraine without aura relative to men (17.6% vs. 5.5%). The results from an ADE sex-limitation model indicate that migraine is equally heritable in men and women, with a broad sense heritability of 0.45, (95% CI = 0.40-0.50), while results from a reduced AE sex-limitation model provide subtle evidence for differences in the genes underlying migraine across men and women. The logistic regression analysis revealed a significant increase in migraine risk for females with a male co-twin relative to females with a female co-twin (OR = 1.51, 95% CI = 1.26-1.81). These results suggest that the prominent sex difference in migraine prevalence is not entirely accounted for by genetic factors, while demonstrating that masculinization of the prenatal environment may increase migraine risk for females. This effect points to a potential prenatal neuroendocrine factor in the development of migraine., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2021 Fitzgerald, Saelzler and Panizzon.)

Moderate to severe traumatic brain injury (TBI) contributes to a significant burden across Australia. However, the data required to inform targeted equitable system-level improvements in emergency TBI care do not exist. The incidence and determinants of outcomes following moderate to severe TBI in Australia remain unknown. The variation in the impact of moderate to severe TBI, according to patient demographics and injury mechanism, is poorly defined. The Australian Traumatic Brain Injury National Data Project will lead to a clear understanding, across Australia and pre-specified subgroups (including Aboriginal and Torres Strait Islander peoples), of the incidence, determinants and impact of priority outcomes following moderate to severe TBI, including survival to discharge home. Furthermore, this project will establish a set of national clinical quality indicators for patients experiencing a moderate to severe TBI. The Australian Traumatic Brain Injury National Data Project will inform where to target emergency care system-wide improvements. Without baseline data, efforts are wasted., (© 2021 Australasian College for Emergency Medicine.)

The development of phenotypic models of Parkinson's disease (PD) has enabled screening and identification of phenotypically active small molecules that restore complex biological pathways affected by PD toxicity. While these phenotypic screening platforms are powerful, they do not inherently enable direct identification of the cellular targets of promising lead compounds. To overcome this, chemoproteomic platforms like Thermal Proteome Profiling (TPP) and Stability of Proteins from Rates of Oxidation (SPROX) can be implemented to reveal protein targets of biologically active small molecules. Here we utilize both of these chemoproteomic strategies to identify targets of an N -arylbenzimidazole compound, NAB2, which was previously identified for its ability to restore viability in cellular models of PD-associated α-synuclein toxicity. The combined results from our TPP and SPROX analyses of NAB2 and the proteins in a neuroblastoma-derived SHSY5Y cell lysate reveal a previously unrecognized protein target of NAB2. This newly recognized target, Rab1a, is a small GTPase that acts as a molecular switch to regulate ER-to-Golgi trafficking, a process that is disrupted by α-synuclein toxicity and restored by NAB2 treatment. Further validation reveals that NAB2 binds to Rab1a with selectivity for its GDP-bound form and that NAB2 treatment phenocopies Rab1a overexpression in alleviation of α-synuclein toxicity. Finally, we conduct a preliminary investigation into the relationship between Rab1a and the E3 ubiquitin ligase, Nedd4, a previously identified NAB2 target. Together, these efforts expand our understanding of the mechanism of NAB2 in the alleviation of α-synuclein toxicity and reinforce the utility of chemoproteomic identification of the targets of phenotypically active small molecules that regulate complex biological pathways., Competing Interests: There are no conflicts of interest to declare., (This journal is © The Royal Society of Chemistry.)

Here, we utilize the stability of proteins from rates of oxidation (SPROX) technique, to profile the thermodynamic stabilities of proteins in brain tissue cell lysates from Huα-Syn(A53T) transgenic mice at three time points including at 1 month ( n = 9), at 6 months ( n = 7), and at the time (between 9 and 16 months) a mouse became symptomatic ( n = 8). The thermodynamic stability profiles generated here on 332 proteins were compared to thermodynamic stability profiles generated on the same proteins from similarly aged wild-type mice using a two-way unbalanced analysis of variance (ANOVA) analysis. This analysis identified a group of 22 proteins with age-related protein stability changes and a group of 11 proteins that were differentially stabilized in the Huα-Syn(A53T) transgenic mouse model. A total of 9 of the 11 proteins identified here with disease-related stability changes have been previously detected in human cerebral spinal fluid and thus have potential utility as biomarkers of Parkinson's disease (PD). The differential stability observed for one protein, glutamate decarboxylase 2 (Gad2), with an age-related change in stability, was consistent with the differential presence of a known, age-related truncation product of this protein, which is shown here to have a higher folding stability than full-length Gad2. Mass spectrometry data were deposited at ProteomeXchange (PXD016985).

Objective: The longer-term impact of injury is increasingly recognized, but the early phases of recovery are less well understood. The best tools to measure early recovery of mobility and physical function following traumatic injury are unclear. The purpose of this study was to assess the clinical utility, validity, reliability, and responsiveness of 4 mobility and physical function measures in patients following traumatic injury., Methods: In this cohort, measurement-focused study (n = 100), the modified Iowa Level of Assistance Score, Acute Care Index of Function, Activity Measure for Post-Acute Care "6 Clicks" short forms, and Functional Independence Measure were completed during first and last physical therapy sessions. Clinical utility and floor and ceiling effects were documented. Known-groups validity (early vs late in admission and by discharge destination), predictive validity (using 6-month postinjury outcomes data), and responsiveness were established. Interrater reliability was assessed in 30 patients with stable mobility and function., Results: Participants had a median age of 52 years (interquartile range = 33-68 years), and 68% were male. The modified Iowa Level of Assistance Score, Acute Care Index of Function, and "6 Clicks" short forms were quick to administer (an extra median time of 30 seconds-1 minute), but the Functional Independence Measure took much longer (extra median time of 5 minutes). At the last physical therapy session, ceiling effects were present for all measures except the Functional Independence Measure (18%-33% of participants). All had strong known-groups validity (early vs late in admission and by discharge destination). All were responsive (effect sizes >1.0) and had excellent interrater reliability (intraclass correlation coefficients = 0.79-0.94)., Conclusion: All 4 measures were reliable, valid, and responsive; however, their clinical utility varied, and ceiling effects were common at physical therapy discharge., Impact: This study is an important step toward evidence-based measurement in acute trauma physical therapy care. It provides critical information to guide assessment of mobility and physical function in acute trauma physical therapy, which may facilitate benchmarking across different hospitals and trauma centers and further progress the science and practice of physical therapy following traumatic injury., (© The Author(s) 2021. Published by Oxford University Press on behalf of the American Physical Therapy Association. All rights reserved. For permissions, please email: journals.permissions@oup.com.)

Introduction: Injury is a major global health burden. Trauma registries have been used for decades to monitor the burden of injury and inform trauma care. However, the extent to which trauma registries have fulfilled their potential remains uncertain. The aims of this study were to determine the current and priority uses of trauma registries across Australia and New Zealand and to establish the priority clinical outcomes, the probability for which, if known for an individual trauma patient, would better inform that same patient's care, during hospital admission., Methods: A prospective observational study using survey methodology was conducted. Participants were sourced from the Australia New Zealand Trauma Registry (ATR) participating hospitals. The survey questions included: the current uses and priorities for both single-site trauma registries and the binational trauma registry; the five top-ranked priority outcomes for which knowing the probability, for an individual patient, would inform care; and the priority timepoints for applying patient-level outcome prediction models., Results: Of the 26 ATR-participating hospitals, 25 were represented by a total of 54 participants in the survey, including trauma service directors and trauma nurse coordinators. The main trauma registry use and priority for the single site registries was to inform the quality improvement program; for the ATR, the main use was periodic reporting and the main priority was benchmarking. For each potential purpose of the registry, the future priority level was ranked more highly than the current level of utilisation. The most highly ranked priority patient-level outcomes requiring prediction were: preventable death, missed injury, quality of life, admission costs, pulmonary embolism, post-traumatic stress disorder, length of hospital stay, errors in decision-making and deep venous thrombosis. The time period between leaving the emergency department and the 24 h mark following presentation was considered the preferred time for patient-level priority outcome prediction., Conclusion: There is a mismatch between current trauma registry uses and future priorities. The priority outcomes demanding prediction in the first 24 h of a trauma patient's stay are preventable death, missed injury, quality of life, hospital costs, thromboembolism, post-traumatic stress disorder, length of hospital stay and errors in clinical decision-making., (Copyright © 2021. Published by Elsevier Ltd.)

Emerging Plasmodium parasite drug resistance is threatening progress towards malaria control and elimination. While recent efforts in cell-based, high-throughput drug screening have produced first-in-class drugs with promising activities against different Plasmodium life cycle stages, most of these antimalarial agents have elusive mechanisms of action. Though challenging to address, target identification can provide valuable information to facilitate lead optimization and preclinical drug prioritization. Recently, proteome-wide methods for direct assessment of drug-protein interactions have emerged as powerful tools in a number of systems, including Plasmodium. In this review, we will discuss current chemoproteomic strategies that have been adapted to antimalarial drug target discovery, including affinity- and activity-based protein profiling and the energetics-based techniques thermal proteome profiling and stability of proteins from rates of oxidation. The successful application of chemoproteomics to the Plasmodium blood stage highlights the potential of these methods to link inhibitors to their molecular targets in more elusive Plasmodium life stages and intracellular pathogens in the future., (© 2021 Wiley-VCH GmbH.)

Objective: This retrospective observational study aimed to compare the impact of the Prevent Alcohol and Risk-Related Trauma Youth (P.A.R.T.Y.) Program when delivered as In-hospital or Outreach models to rural and regional students., Methods: The study population were consented participants from regional areas between 2013 and 2017 who completed pre-programme, immediately post-programme and 3-5 months post-programme surveys. Responses from the metropolitan In-hospital programme participants and regional Outreach programme participants were analysed within groups across the three time points. The primary outcome variable was a change in self-reported perception of driving after drinking alcohol. Secondary outcome variables were designating a safe driver after drinking, perception of risk of injury if not wearing a seatbelt, risks of injury if undertaking physical risk-taking activities and likelihood of the programme changing perceptions., Results: There were 1314 participants invited to participate and 547 (42%) sets of complete surveys were received, of whom 296 (54%) were Outreach participants. Pre-programme, a significantly lower proportion of Outreach participants reported 'definitely not' to driving after drinking (84% vs 91%), and perceived a 'definite' likelihood of sustaining injury if not wearing a seatbelt (57% vs 66%). Outreach participants displayed improvements in likelihood to drive after drinking alcohol immediately post-programme and on follow up (P = 0.028). Responses to all other secondary outcome measures demonstrated some improvement., Conclusions: Although demographically similar, baseline perceptions toward alcohol, risk-taking and injury differed between groups. Improvements in perception were demonstrated across both models. These findings support P.A.R.T.Y. as an injury prevention initiative for regional youth., (© 2020 Australasian College for Emergency Medicine.)

Patients treated with splenic artery embolization (SAE) >48 hours after a blunt injury for a delayed splenic rupture (DSR) were assessed for the need for a subsequent splenectomy. Thirty-four patients underwent SAE for DSR over 10 years at our level 1 trauma center, performed at a median of 4.5 days after the injury (interquartile range = 5.5), and the patients were followed up for a median of 11 months (interquartile range = 31). There were 3 occurrences of rebleeds, and 2 patients required splenectomy (5.9%). This study showed that treatment with SAE after DSR results in splenic salvage in 94.1% of patients., (Copyright © 2020 SIR. Published by Elsevier Inc. All rights reserved.)

Introduction : Delayed Intracranial Hemorrhage (D-ICH), defined as finding of ICH on subsequent imaging after a normal computed tomography of the brain (CTB), is a feared complication after head trauma. The aim of this study was to determine the incidence and severity of D-ICH. Methods : This retrospective cohort study included patients that presented directly from the scene of injury to an adult major trauma center from Jan 2013 to Dec 2018. Results : There were 6536 patients who had an initial normal CTB and 23 (0.3%; 95%CI: 0.20-0.47) had D-ICH. There were 653 patients who had a repeat CTB (incidence of D-ICH 3.5%; 95%CI: 2.2-5.2). There was no significant association of D-ICH with age>65 years (OR 1.33; 95%CI: 0.54-3.29), presenting GCS <15 (OR 1.21; 95% CI: 0.52-2.80) and anti-platelet medications (OR 0.68; 95%CI: 0.26-1.74). Exposure to anti-coagulant medications was associated with lower odds of D-ICH (OR 0.23; 95%CI: 0.05-0.99). All cases of D-ICH were diffuse injury type II lesions on the Marshall classification. There were no cases that underwent neurosurgical intervention and no deaths were attributed to D-ICH. Conclusions : These results question observation of patients with head injury in hospital after a normal CTB for the sole purpose of excluding D-ICH.

Background: During hemorrhagic shock and subsequent resuscitation, pathways reliant upon calcium such as platelet function, intrinsic and extrinsic hemostasis, and cardiac contractility are disrupted. The objective of this systematic review was to examine current literature for associations between pretransfusion, admission ionized hypocalcemia, and composite outcomes including mortality, blood transfusion requirements, and coagulopathy in adult trauma patients., Methods: This review was reported using the Preferred Reporting Items for Systematic Reviews and Meta-Analyses checklist. We searched Ovid MEDLINE and grey literature from database inception till May 3, 2020. Case series and reports were excluded. Reference lists of appraised studies were also screened for articles that the aforementioned databases might not have captured. The Newcastle-Ottawa Scale was used to assess study quality., Results: A total of 585 abstracts were screened through database searching and alternative sources. Six unique full-text studies were reviewed, of which three were excluded. Admission ionized hypocalcemia was present in up to 56.2% of the population in studies included in this review. Admission ionized hypocalcemia was also associated with increased mortality in all three studies, with increased blood transfusion requirements in two studies, and with coagulopathy in one study., Conclusion: Hypocalcemia is a common finding in shocked trauma patients. While an association between admission ionized hypocalcemia and mortality, blood transfusion requirements, and coagulopathy has been identified, further prospective trials are essential to corroborating this association., Level of Evidence: Systematic review, level III., (Copyright © 2020 The Author(s). Published by Wolters Kluwer Health, Inc.)

The ability of metal ionophores to induce cellular metal hyperaccumulation endows them with potent antimicrobial activity; however, the targets and mechanisms behind these outcomes are not well understood. This work describes the first utilization of proteome-wide measurements of protein folding stability in combination with protein expression level analysis to identify protein targets of copper, thereby providing new insight into ionophore-induced copper toxicity in E. coli . The protein folding stability analysis employed a one-pot protocol for p ulse p roteolysis (PP) in combination with a s emi- t ryptic peptide e nrichment strategy for p roteolysis p rocedures (STEPP) to generate stability profiles for proteins in cell lysates derived from E. coli exposed to copper with and without two ionophores, the antimicrobial agent pyrithione and its β-lactamase-activated prodrug, PcephPT. As part of this work, the above cell lysates were also subject to protein expression level analysis using conventional quantitative bottom-up proteomic methods. The protein folding stability and expression level profiles generated here enabled the effects of ionophore vs copper to be distinguished and revealed copper-driven stability changes in proteins involved in processes spanning metabolism, translation, and cell redox homeostasis. The 159 differentially stabilized proteins identified in this analysis were significantly more numerous (∼3×) than the 53 proteins identified with differential expression levels. These results illustrate the unique information that protein stability measurements can provide to decipher metal-dependent processes in drug mode of action studies.

Background: Telemedicine offers a unique opportunity to improve coordination and administration for urgent patient care remotely. In an emergency setting, it has been used to support first responders by providing telephone or video consultation with specialists at hospitals and through the exchange of prehospital patient information. This technological solution is evolving rapidly, yet there is a concern that it is being implemented without a demonstrated clinical need and effectiveness as well as without a thorough economic evaluation., Objective: Our objective is to systematically review whether the clinical outcomes achieved, as reported in the literature, favor telemedicine decision support for medical interventions during prehospital care., Methods: This systematic review included peer-reviewed journal articles. Searches of 7 databases and relevant reviews were conducted. Eligibility criteria consisted of studies that covered telemedicine as data- and information-sharing and two-way teleconsultation platforms, with the objective of supporting medical decisions (eg, diagnosis, treatment, and receiving hospital decision) in a prehospital emergency setting. Simulation studies and studies that included pediatric populations were excluded. The procedures in this review followed the PRISMA (Preferred Reporting Items for Systematic Reviews and Meta-Analyses) statement. The Risk Of Bias In Non-randomised Studies-of Interventions (ROBINS-I) tool was used for the assessment of risk of bias. The results were synthesized based on predefined aspects of medical decisions that are made in a prehospital setting, which include diagnostic decision support, receiving facility decisions, and medical directions for treatment. All data extractions were done by at least two reviewers independently., Results: Out of 42 full-text reviews, 7 were found eligible. Diagnostic support and medical direction and decision for treatments were often reported. A key finding of this review was the high agreement between prehospital diagnoses via telemedicine and final in-hospital diagnoses, as supported by quantitative evidence. However, a majority of the articles described the clinical value of having access to remote experts without robust quantitative data. Most telemedicine solutions were evaluated within a feasibility or short-term preliminary study. In general, the results were positive for telemedicine use; however, biases, due to preintervention confounding factors and a lack of documentation on quality assurance and protocol for telemedicine activation, make it difficult to determine the direct effect on patient outcomes., Conclusions: The information-sharing capacity of telemedicine enables access to remote experts to support medical decision making on scene or in prolonged field care. The influence of human and technology factors on patient care is poorly understood and documented., (©Yesul Kim, Christopher Groombridge, Lorena Romero, Steven Clare, Mark Christopher Fitzgerald. Originally published in the Journal of Medical Internet Research (http://www.jmir.org), 08.12.2020.)

Background and Objective: Despite multiple interventions, mortality due to severe traumatic brain injury (sTBI) within mature Trauma Systems has remained unchanged over the last decade. During this time, the use of vasoactive infusions (commonly norepinephrine) to achieve a target blood pressure and cerebral perfusion pressure (CPP) has been a mainstay of sTBI management. However, evidence suggests that norepinephrine, whilst raising blood pressure, may reduce cerebral oxygenation. This study aimed to review the available evidence that links norepinephrine augmented CPP to clinical outcomes for these patients., Methods: A systematic review examining the evidence for norepinephrine augmented CPP in TBI patients was undertaken. Strict inclusion and exclusion criteria were developed for a dedicated literature search of multiple scientific databases. Two dedicated reviewers screened articles, whilst a third dedicated reviewer resolved conflicts., Results: The systematic review yielded 4,809 articles, of which 1,197 duplicate articles were removed. After abstract/title screening, 45 articles underwent full text review, resulting in the identification of two articles that investigated the effect of norepinephrine administration on clinical outcomes in patients following TBI when compared to other vasopressors. Neither study found a difference in neurological outcome between the vasopressor groups. No articles measured the effect of norepinephrine compared to no vasopressor use on the clinical outcome of patients with sTBI., Conclusions: Despite being a mainstay of pharmacological management for hypotension in patients following sTBI, there is minimal clinical evidence supporting the use of norepinephrine in targeting a CPP for either improving neurological outcomes or reducing mortality. Outcomes-based clinical trials exploring the role of brain tissue perfusion and oxygenation monitoring are required to validate any benefit., Competing Interests: Declaration of Competing Interest Prof. A Udy declares he is the recipient of a grant as lead-author on the BONANZArandomized control trial. This study deals with a similar research topic, however no funding from this grant was used for the purposes of this review. No other authors declare any competing interests., (Copyright © 2020 The Author(s). Published by Elsevier Ltd.. All rights reserved.)

Objective: The objective of this study was to report the procedural incidence and patient outcomes after the 2009 introduction of an institutional resuscitative thoracotomy (RT) programme. Emergency physicians, general surgeons and emergency nursing trauma team members were trained to perform RT on thoracic trauma patients with an unresponsive systolic blood pressure (SBP) <70 mmHg within 30 min of arrival, prior to cardiothoracic team back-up., Methods: A retrospective cohort study was conducted on patients who underwent RT from 2009 to 2017. The primary outcome measures were the incidence of the procedure and patients' survival to hospital discharge. Variables associated with survival were assessed using univariable logistic regression analyses., Results: There were 12 399 major trauma patients, including 7657 with major thoracic trauma and 315 presenting with SBP <70 mmHg. There were 32 RTs performed (incidence of 0.4%; 95% confidence interval [CI] 0.3-0.6) among patients with major thoracic trauma and 10.2% (99% CI 7.3-13.4) among patients with major thoracic trauma and SBP <70 mmHg. There were eight (25%; 95% CI 13.2-42.1) survivors to hospital discharge and no late mortality (mean follow-up 2.8 years). Survival was significantly associated with the procedure performed within 30 min of arrival (odds ratio 0.09; 95% CI 0.01-0.67) while mortality was associated with the procedure being performed in the setting of traumatic cardiac arrest (odds ratio 18.3; 95% CI 2.4-140.4)., Conclusions: A formal training and credentialing programme was associated with a low incidence of the procedure, yet achieved a survival rate of 25%, which is comparable to other reported literature., (© 2020 Australasian College for Emergency Medicine.)

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., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2020. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Purpose: The association between pathological complete response (pCR) in patients receiving neoadjuvant chemotherapy (NAC) for breast cancer and Circulating Tumour Cells (CTCs) is not clear. The aim of this study was to assess whether CTC enumeration could be used to predict pathological response to NAC in breast cancer as measured by the Miller-Payne grading system., Methods: Twenty-six patients were recruited, and blood samples were taken pre- and post-NAC. CTCs were isolated using the ScreenCell device and stained using a modified Giemsa stain. CTCs were enumerated by 2 pathologists and classified as single CTCs, doublets, clusters/microemboli and correlated with the pathological response as measured by the Miller-Payne grading system. χ 2 or ANOVA was performed in SPSS 24.0 statistics software for associations., Results: 89% of patients had invasive ductal carcinoma (IDC) and 11% invasive lobular carcinoma (ILC). At baseline 85% of patients had CTCs present, median 7 (0-161) CTCs per 3 ml of whole blood. Post-chemotherapy, 58% had an increase in CTCs. This did not correlate with the Miller-Payne grade of response. No significant association was identified between the number of CTCs and clinical characteristics; however, we did observe a correlation between pre-treatment CTC counts and body mass index, p < 0.05., Conclusions: Patients with a complete response to NAC still had CTCs present, suggesting enumeration is not sufficient to aid surgery stratification. Additional characterisation and larger studies are needed to further characterise CTCs isolated pre- and post-chemotherapy. Long-term follow-up of these patients will determine the significance of CTCs in NAC breast cancer patients.