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The present study applied the Simon effect task to examine the pattern of functional brain reorganization in individuals with Friedreich ataxia (FRDA), using functional magnetic resonance imaging (fMRI). Thirteen individuals with FRDA and 14 age and sex matched controls participated, and were required to respond to either congruent or incongruent arrow stimuli, presented either to the left or right of a screen, via laterally-located button press responses. Although the Simon effect (incongruent minus congruent stimuli) showed common regions of activation in both groups, including the superior and middle prefrontal cortices, insulae, superior and inferior parietal lobules (LPs, LPi), occipital cortex and cerebellum, there was reduced functional activation across a range of brain regions (cortical, subcortical and cerebellar) in individuals with FRDA. The greater Simon effect behaviourally in individuals with FRDA, compared with controls, together with concomitant reductions in functional brain activation and reduced functional connectivity between cortical and sub-cortical regions, implies a likely disruption of cortico-cerebellar loops and ineffective engagement of cognitive/attention regions required for response suppression. (Contains 4 tables and 3 figures.)

Friedreich ataxia (FRDA) is the most common of the genetically inherited ataxias. We recently demonstrated that people with FRDA have impairment in motor planning--most likely because of pathology affecting the cerebral cortex and/or cerebello-cortical projections. We used the Simon interference task to examine how effective 13 individuals with FRDA were at inhibiting inappropriate automatic responses associated with stimulus-response incompatibility in comparison with control participants. Participants had to respond to arrow targets according to two features which were either congruent or incongruent. We found that individuals with FRDA were differentially affected in reaction time to incongruent, compared with congruent stimuli, when compared with control participants. There was a significant negative correlation between age of onset and the incongruency effect, suggesting an impact of FRDA on the developmental unfolding of motor cognition, independent of the effect of disease duration. Future neuroimaging studies will be required to establish whether this dysfunction is due to cerebellar impairment disrupting cerebro-ponto-cerebello-thalamo-cerebral loops (and thus cortical function), direct primary cortical pathology, or a possible combination of the two.

Introduction. Secure airway for proper ventilation during anesthesia is one important component of a successful surgery. Endotracheal intubation is one of the most important methods in this context. Intubation method and used medication are considerably important in attenuating complications. This research aimed to investigate the impact of two different doses of dexmedetomidine in mitigating cardiovascular responses to endotracheal intubation in candidate cases supporting voluntary operation. Methods. The current research contained 90 cases in the range of 18 and 50 old, with ASA I,II supporting voluntary operation, who were randomly classified into three teams, each group consisting of 30 cases. The first set (A) got 0.5 μg/ kg dexmedetomidine, the second set (B) got 1 μg/ kg dexmedetomidine and the third set (C) got an equal volume of saline as placebo, 600 seconds earlier the initiation of anesthesia. Hemodynamic parameters were recorded at baseline (T0), then after the injection and the earlier initiation of anesthesia (T1), after the induction of anesthesia and before the endotracheal intubation (T2), promptly after tracheal intubation, 180, and 300 after endotracheal intubation (T4, T5). Data was analyzed and p < 0.05 was supposed notable. Findings. In this research, 3 teams were similar regarding weight, age, height, sex and duration of laryngoscopy. The diastolic mean arterial pressure, heart rate, and systolic arterial pressure were significantly lower in dexmedetomidine teams (A,B) at all times after the endotracheal intubation compared to group C. There were no significant differences in hemodynamic factors among group A, B. Conclusion. Dexmedetomidine effectively and significantly attenuates cardiovascular and hemodynamic responses during endotracheal intubation. In addition, different doses of dexmedetomidine did not cause any significant distinct result in mitigating cardiovascular responses. [ABSTRACT FROM AUTHOR]

Relatively little is known about long term effects of wood smoke on population health. A wood burning marker -- levoglucosan -- was measured using a highly standardized sampling and measurement method in four study areas across Europe (Oslo, the Netherlands, Munich/Augsburg, Catalonia) to assess within and between study area spatial variation. Levoglucosan was analyzed in addition to other components: PM2.5, PM2.5 absorbance, PM10, polycyclic aromatic hydrocarbons (PAH), nitrogen oxides (NOx), elemental and organic carbon (EC/OC), hopanes, steranes and elemental composition. Measurements were conducted at street, urban and regional background sites. Three two-week samples were taken per site and the annual average concentrations of pollutants were calculated using continuous measurements at one background site as a reference. Land use regression (LUR) models were developed to explain the spatial variation of levoglucosan using standardized procedures. Much larger within than between study area contrast in levoglucosan concentration was found. Spatial variation patterns differed substantially from other measured pollutants including PM2.5, NOx and EC. Levoglucosan had the highest spatial correlation with ΣPAH (r = 0.65) and the lowest with traffic markers -- NOx, Σhopanes/steranes (r = -0.22). The correlation of levoglucosan with potassium (K), which is also used as a wood burning marker, was moderate to low (median r = 0.33). Levoglucosan concentrations in the cold (heating) period were between 3 and 20 times higher compared to the warm period. The contribution of wood-smoke calculated based on levoglucosan measurements and previous European emission data to OC and PM2.5 mass were 13 to 28% and 3 to 9% respectively in the full year. Larger contributions were calculated for the cold period. The median model R² of the LUR models was 60 %. In Catalonia the model R² was the highest (71 %). The LUR models included population and natural land related variables but no traffic associated variables. In conclusion, substantial spatial variability was found in levoglucosan concentrations particularly within study areas.Wood smoke contributed substantially to especially wintertime PM2.5 OC and mass. The low to moderate correlation with PM2.5 mass and traffic markers offers the potential to assess health effects of wood smoke separate from traffic-related air pollution. [ABSTRACT FROM AUTHOR]

Recently developed small-molecule inhibitors of the lysosomal protease dipeptidyl peptidase 1 (DPP1), also known as cathepsin C (CatC), can suppress suppurative inflammation in vivo by blocking the processing of zymogenic (pro-) forms of neutrophil serine proteases (NSPs), including neutrophil elastase, proteinase 3, and cathepsin G. DPP1 also plays an important role in activating granzyme serine proteases that are expressed by cytotoxic T lymphocytes (CTL) and natural killer (NK) cells. Therefore, it is critical to determine whether DPP1 inhibition can also cause off-target suppression of CTL/NK-cell-mediated killing of virus-infected or malignant cells. Herein, we demonstrate that the processing of human granzymes A and B, transitioning from zymogen to active proteases, is not solely dependent on DPP1. Thus, the killing of target cells by primary human CD8 + T cells, NK cells, and gene-engineered anti-CD19 CAR T cells was not blocked in vitro even after prior exposure to high concentrations of the reversible DPP1 inhibitor brensocatib. Consistent with this observation, the turnover of model granzyme A/B peptide substrates in the human CTL/NK cell lysates was not significantly reduced by brensocatib. In contrast, preincubation with brensocatib almost entirely abolished (>90%) both the cytotoxic activity of mouse CD8 + T cells and granzyme substrate turnover. Overall, our finding that the effects of DPP1 inhibition on human cytotoxic lymphocytes are attenuated in comparison to those of mice indicates that granzyme processing/activation pathways differ between mice and humans. Moreover, the in vitro data suggest that human subjects treated with reversible DPP1 inhibitors, such as brensocatib, are unlikely to experience any appreciable deficits in CTL/NK-cell-mediated immunities., Competing Interests: Authors DC, K-JC, DLaS, and PMcD were employed by Insmed Incorporated. The remaining 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 © 2024 Sutton, Watt, Akhlaghi, Cipolla, Chen, LaSala, McDonald, Beavis, Munoz, Hodel, Noori, Voskoboinik and Trapani.)

Objectives: To investigate health consumers' ethical concerns towards the use of artificial intelligence (AI) in EDs., Methods: Qualitative semi-structured interviews with health consumers, recruited via health consumer networks and community groups, interviews conducted between January and August 2022., Results: We interviewed 28 health consumers about their perceptions towards the ethical use of AI in EDs. The results discussed in this paper highlight the challenges and barriers for the effective and ethical implementation of AI from the perspective of Australian health consumers. Most health consumers are more likely to support AI health tools in EDs if they continue to be involved in the decision-making process. There is considerably more approval of AI tools that support clinical decision-making, as opposed to replacing it. There is mixed sentiment about the acceptability of AI tools influencing clinical decision-making and judgement. Health consumers are mostly supportive of the use of their data to train and develop AI tools but are concerned with who has access. Addressing bias and discrimination in AI is an important consideration for some health consumers. Robust regulation and governance are critical for health consumers to trust and accept the use of AI., Conclusion: Health consumers view AI as an emerging technology that they want to see comprehensively regulated to ensure it functions safely and securely with EDs. Without considerations made for the ethical design, implementation and use of AI technologies, health consumer trust and acceptance in the use of these tools will be limited., (© 2024 The Author(s). Emergency Medicine Australasia published by John Wiley & Sons Australia, Ltd on behalf of Australasian College for Emergency Medicine.)

Background: A noninvasive and accurate method of determining fluid responsiveness in ventilated patients would help to mitigate unnecessary fluid administration. Although carotid ultrasound has been previously studied for this purpose, several studies have recently been published. We performed an updated systematic review and meta-analysis to evaluate the accuracy of carotid ultrasound as a tool to predict fluid responsiveness in ventilated patients., Methods: Studies eligible for review investigated the accuracy of carotid ultrasound parameters in predicting fluid responsiveness in ventilated patients, using sensitivity and specificity as markers of diagnostic accuracy (International Prospective Register of Systematic Reviews [PROSPERO] CRD42022380284). All included studies had to use an independent method of determining cardiac output and exclude spontaneously ventilated patients. Six bibliographic databases and 2 trial registries were searched. Medline, Embase, Emcare, APA PsycInfo, CINAHL, and the Cochrane Library were searched on November 4, 2022. Clinicaltrials.gov and Australian New Zealand Clinical Trials Registry were searched on February 24, 2023. Results were pooled, meta-analysis was conducted where possible, and hierarchical summary receiver operating characteristic models were used to compare carotid ultrasound parameters. Bias and evidence quality were assessed using the Quality Assessment of Diagnostic Accuracy Studies (QUADAS) tool and the Grading of Recommendations, Assessment, Development, and Evaluations (GRADE) guidelines., Results: Thirteen prospective clinical studies were included (n = 648 patients), representing 677 deliveries of volume expansion, with 378 episodes of fluid responsiveness (58.3%). A meta-analysis of change in carotid Doppler peak velocity (∆CDPV) yielded a sensitivity of 0.79 (95% confidence interval [CI], 0.74-0.84) and a specificity of 0.85 (95% CI, 0.76-0.90). Risk of bias relating to recruitment methodology, the independence of index testing to reference standards and exclusionary clinical criteria were evaluated. Overall quality of evidence was low. Study design heterogeneity, including a lack of clear parameter cutoffs, limited the generalizability of our results., Conclusions: In this meta-analysis, we found that existing literature supports the ability of carotid ultrasound to predict fluid responsiveness in mechanically ventilated adults. ∆CDPV may be an accurate carotid parameter in certain contexts. Further high-quality studies with more homogenous designs are needed to further validate this technology., Competing Interests: The authors declare no conflicts of interest., (Copyright © 2024 International Anesthesia Research Society.)

Background: A noninvasive and accurate method of identifying fluid responsiveness in hemodynamically unstable patients has long been sought by physicians. Carotid ultrasound (US) is one such modality previously canvassed for this purpose. The aim of this novel systematic review and meta-analysis is to investigate whether critically unwell patients who are requiring intravenous (IV) fluid resuscitation (fluid responders) can be identified accurately with carotid US., Methods: The protocol was registered with PROSPERO on the 30/11/2022 (ID number: CRD42022380284). Studies investigating carotid ultrasound accuracy in assessing fluid responsiveness in hemodynamically unstable patients were included. Studies were identified through searches of six databases, all run on 4 November 2022, Medline, Embase, Emcare, APA PsycInfo, CINAHL, and Cochrane Library. Risk of bias was assessed using the QUADAS-2 and the Grading of Recommendations, Assessment, Development, and Evaluations (GRADE) guidelines. Results were pooled, meta-analysis was conducted where amenable, and hierarchical summary receiver operating characteristic models were established to compare carotid ultrasound measures., Results: Seventeen studies were included ( n  = 842), with 1048 fluid challenges. 441 (42.1%) were fluid responsive. Four different carotid US measures were investigated, including change in carotid doppler peak velocity (∆CDPV), carotid blood flow (CBF), change in carotid artery velocity time integral (∆CAVTI), and carotid flow time (CFT). Pooled carotid US had a pooled sensitivity, specificity, and AUROC with 95% confidence intervals (CI) of 0.73 (0.66-0.78), 0.82 (0.72-0.90), and 0.81 (0.78-0.85), respectively. ∆CDPV had sensitivity, specificity, and AUROC with 95% CI of 0.72 (0.64-0.80), 0.87 (0.73-0.94), and 0.82 (0.78-0.85), respectively. CBF had sensitivity, specificity, and AUROC with 95% CI of 0.70 (0.56-0.80), 0.80 (0.50-0.94), and 0.77 (0.78-0.85), respectively. Risk of bias and assessment was undertaken using the QUADAS-2 and GRADE tools. The QUADAS-2 found that studies generally had an unclear or high risk of bias but with low applicability concerns. The GRADE assessment showed that ∆CDPV and CBF had low accuracy for sensitivity and specificity., Conclusion: It appears that carotid US has a limited ability to predict fluid responsiveness in critically unwell patients. ∆CDPV demonstrates the greatest accuracy of all measures analyzed. Further high-quality studies using consistent study design would help confirm this., Competing Interests: The authors declare that they have no conflicts of interest., (Copyright © 2024 Samuel C. D. Walker et al.)

Objective: To assess Australian and New Zealand emergency clinicians' attitudes towards the use of artificial intelligence (AI) in emergency medicine., Methods: We undertook a qualitative interview-based study based on grounded theory. Participants were recruited through ED internal mailing lists, the Australasian College for Emergency Medicine Bulletin, and the research teams' personal networks. Interviews were transcribed, coded and themes presented., Results: Twenty-five interviews were conducted between July 2021 and May 2022. Thematic saturation was achieved after 22 interviews. Most participants were from either Western Australia (52%) or Victoria (16%) and were consultants (96%). More participants reported feeling optimistic (10/25) than neutral (6/25), pessimistic (2/25) or mixed (7/25) towards the use of AI in the ED. A minority expressed scepticism regarding the feasibility or value of implementing AI into the ED. Multiple potential risks and ethical issues were discussed by participants including skill loss from overreliance on AI, algorithmic bias, patient privacy and concerns over liability. Participants also discussed perceived inadequacies in existing information technology systems. Participants felt that AI technologies would be used as decision support tools and not replace the roles of emergency clinicians. Participants were not concerned about the impact of AI on their job security. Most (17/25) participants thought that AI would impact emergency medicine within the next 10 years., Conclusions: Emergency clinicians interviewed were generally optimistic about the use of AI in emergency medicine, so long as it is used as a decision support tool and they maintain the ability to override its recommendations., (© 2023 The Authors. Emergency Medicine Australasia published by John Wiley & Sons Australia, Ltd on behalf of Australasian College for Emergency Medicine.)

Nowadays, it is well-established that the consumption of poultry meat, especially chicken meat products has been drastically increasing. Even though more attentions are being paid to the major foodborne pathogens, it seems that scientists in the area of food safety and public health would prefer tackling the minor food borne zoonotic emerging or reemerging pathogens, namely Helicobacter species. Recently, understanding the novel aspects of zoonotic Enterohepatic Helicobacter species, including pathogenesis, isolation, identification, and genomic features is regarded as a serious challenge. In this regard, considerable attention is given to emerging elusive zoonotic Enterohepatic Helicobacter species, comprising Helicobacter pullorum and Helicobacter canadensis. In conclusion, the current review paper would attempt to elaborately summarize and somewhat compare the etiology, pathogenesis, cultivation process, identification, genotyping, and antimicrobial resistance profile of both H. pullorum and H. Canadensis. Further, H. pullorum has been introduced as the most significant food borne pathogen in chicken meat products., Competing Interests: Declaration of competing interest The authors declare no conflict of interest., (Copyright © 2024 Elsevier B.V. All rights reserved.)

Background: Irritable Bowel Syndrome (IBS) is a common gastrointestinal disorder causing abdominal pain, altered bowel habits and bloating without structural issues. Gallbladder dysfunction may be linked to IBS due to disrupted cholecystokinin release. This study aims to assess gallbladder function and related hemodynamic parameters using Doppler ultrasound in IBS before and after meals., Method: In this case-control study, we investigated gallbladder function differences between constipation-predominant IBS (C-IBS) patients and healthy volunteers. Participants underwent ultrasonography to measure gallbladder parameters before and after consuming a predefined meal. Gallbladder volume, wall thickness and resistance index (RI) of cystic and superior mesenteric arteries (SMA) were assessed. Student t-test and paired t-test were used to compare case and control groups and pre- and post-meal data, respectively., Results: A total of 34 people (18 C-IBS and 16 healthy control) were included. The mean (Standard deviation) of gallbladder fasting volume was measured 24.74 (8.85) and 29.73 (9.65) cubic millimeter for case and controls, respectively. Postprandial volume was 11.34 (5.66) and 16.9 (6.16) cubic millimeter for case and controls respectively. We observed a statistically significant difference in emptying fractions (EF) between groups (p value = 0.009). IBS patients had a smaller fasting SMA RI (p value = 0.016) but the fraction of change after meal was not significant (p value = 0.10). The cystic artery RI did not reach statistical significance between the fasting and post-meal values (p value = 0.067)., Conclusion: IBS patients have a higher emptying fraction and lower change in SMA RI compared to healthy controls. Further studies with larger sample size, inclusion of patients with different coexisting conditions and subtypes of IBS and combining colon transit study with gallbladder ejection fraction evaluation can be used to further provide more meaning to this study.

Background: Emerging evidence suggests that traumatic brain injury (TBI) is a major risk factor for developing neurodegenerative disease later in life. Quantitative susceptibility mapping (QSM) has been used by an increasing number of studies in investigations of pathophysiological changes in TBI. However, generating artefact-free quantitative susceptibility maps in brains with large focal lesions, as in the case of moderate-to-severe TBI (ms-TBI), is particularly challenging. To address this issue, we utilized a novel two-pass masking technique and reconstruction procedure (two-pass QSM) to generate quantitative susceptibility maps (QSMxT; Stewart et al., 2022, Magn Reson Med.) in combination with the recently developed virtual brain grafting (VBG) procedure for brain repair (Radwan et al., 2021, NeuroImage) to improve automated delineation of brain areas. We used QSMxT and VBG to generate personalised QSM profiles of individual patients with reference to a sample of healthy controls., Methods: Chronic ms-TBI patients (N = 8) and healthy controls (N = 12) underwent (multi-echo) GRE, and anatomical MRI (MPRAGE) on a 3T Siemens PRISMA scanner. We reconstructed the magnetic susceptibility maps using two-pass QSM from QSMxT. We then extracted values of magnetic susceptibility in grey matter (GM) regions (following brain repair via VBG) across the whole brain and determined if they deviate from a reference healthy control group [Z-score < -3.43 or > 3.43, relative to the control mean], with the aim of obtaining personalised QSM profiles., Results: Using two-pass QSM, we achieved susceptibility maps with a substantial increase in quality and reduction in artefacts irrespective of the presence of large focal lesions, compared to single-pass QSM. In addition, VBG minimised the loss of GM regions and exclusion of patients due to failures in the region delineation step. Our findings revealed deviations in magnetic susceptibility measures from the HC group that differed across individual TBI patients. These changes included both increases and decreases in magnetic susceptibility values in multiple GM regions across the brain., Conclusions: We illustrate how to obtain magnetic susceptibility values at the individual level and to build personalised QSM profiles in ms-TBI patients. Our approach opens the door for QSM investigations in more severely injured patients. Such profiles are also critical to overcome the inherent heterogeneity of clinical populations, such as ms-TBI, and to characterize the underlying mechanisms of neurodegeneration at the individual level more precisely. Moreover, this new personalised QSM profiling could in the future assist clinicians in assessing recovery and formulating a neuroscience-guided integrative rehabilitation program tailored to individual TBI patients., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 The Authors. Published by Elsevier GmbH.. All rights reserved.)

Objective: Artificial intelligence (AI) has gradually found its way into healthcare, and its future integration into clinical practice is inevitable. In the present study, we evaluate the accuracy of a novel AI algorithm designed to predict admission based on a triage note after clinical implementation. This is the first of such studies to investigate real-time AI performance in the emergency setting., Methods: The novel AI algorithm that predicts admission using a triage note was translated into clinical practice and integrated within St Vincent's Hospital Melbourne's electronic emergency patient management system. The data were collected from 1 January 2021 to 17 August 2022 to evaluate the diagnostic accuracy of the AI system after implementation., Results: A total of 77 125 ED presentations were included. The live AI algorithm has a sensitivity of 73.1% (95% confidence interval 72.5-73.8), specificity of 74.3% (73.9-74.7), positive predictive value of 50% (49.6-50.4) and negative predictive value of 88.7% (88.5-89) with a total accuracy of 74% (73.7-74.3). The accuracy of the system was at the lowest for admission to psychiatric units (34%) and at the highest for gastroenterology and medical admission (84% and 80%, respectively)., Conclusion: Our study showed the diagnostic evaluation of a real-time AI clinical decision-support tool became less accurate than the original. Although real-time sensitivity and specificity of the AI tool was still acceptable as a decision-support tool in the ED, we propose that continuous training and evaluation of AI-enabled clinical support tools in healthcare are conducted to ensure consistent accuracy and performance to prevent inadvertent consequences., (© 2023 The Authors. Emergency Medicine Australasia published by John Wiley & Sons Australia, Ltd on behalf of Australasian College for Emergency Medicine.)

Perforin is a pore-forming protein whose normal function enables cytotoxic T and natural killer (NK) cells to kill virus-infected and transformed cells. Conversely, unwanted perforin activity can also result in auto-immune attack, graft rejection and aberrant responses to pathogens. Perforin is critical for the function of the granule exocytosis cell death pathway and is therefore a target for drug development. In this study, by screening a fragment library using NMR and surface plasmon resonance, we identified 4,4-diaminodiphenyl sulfone (dapsone) as a perforin ligand. We also found that dapsone has modest (mM) inhibitory activity of perforin lytic activity in a red blood cell lysis assay in vitro. Sequential modification of this lead fragment, guided by structural knowledge of the ligand binding site and binding pose, and supported by SPR and ligand-detected 19 F NMR, enabled the design of nanomolar inhibitors of the cytolytic activity of intact NK cells against various tumour cell targets. Interestingly, the ligands we developed were largely inert with respect to direct perforin-mediated red blood cell lysis but were very potent in the context of perforin's action on delivering granzymes in the immune synapse, the context in which it functions physiologically. Our work indicates that a fragment-based, structure-guided drug discovery strategy can be used to identify novel ligands that bind perforin. Moreover, these molecules have superior physicochemical properties and solubility compared to previous generations of perforin ligands., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023 The Authors. Published by Elsevier Masson SAS.. All rights reserved.)

Background and Purpose: Approximately 65% of moderate-to-severe traumatic brain injury (m-sTBI) patients present with poor long-term behavioural outcomes, which can significantly impair activities of daily living. Numerous diffusion-weighted MRI studies have linked these poor outcomes to decreased white matter integrity of several commissural tracts, association fibres and projection fibres in the brain. However, most studies have focused on group-based analyses, which are unable to deal with the substantial between-patient heterogeneity in m-sTBI. As a result, there is increasing interest and need in conducting individualised neuroimaging analyses., Materials and Methods: Here, we generated a detailed subject-specific characterisation of microstructural organisation of white matter tracts in 5 chronic patients with m-sTBI (29 - 49y, 2 females), presented as a proof-of-concept. We developed an imaging analysis framework using fixel-based analysis and TractLearn to determine whether the values of fibre density of white matter tracts at the individual patient level deviate from the healthy control group (n = 12, 8F, M age  = 35.7y, age range 25 - 64y)., Results: Our individualised analysis revealed unique white matter profiles, confirming the heterogenous nature of m-sTBI and the need of individualised profiles to properly characterise the extent of injury. Future studies incorporating clinical data, as well as utilising larger reference samples and examining the test-retest reliability of the fixel-wise metrics are warranted., Conclusions: Individualised profiles may assist clinicians in tracking recovery and planning personalised training programs for chronic m-sTBI patients, which is necessary to achieve optimal behavioural outcomes and improved quality of life., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023 The Authors. Published by Elsevier B.V. All rights reserved.)

Graph theoretical analysis of the structural connectome has been employed successfully to characterize brain network alterations in patients with traumatic brain injury (TBI). However, heterogeneity in neuropathology is a well-known issue in the TBI population, such that group comparisons of patients against controls are confounded by within-group variability. Recently, novel single-subject profiling approaches have been developed to capture inter-patient heterogeneity. We present a personalized connectomics approach that examines structural brain alterations in five chronic patients with moderate to severe TBI who underwent anatomical and diffusion magnetic resonance imaging. We generated individualized profiles of lesion characteristics and network measures (including personalized graph metric GraphMe plots, and nodal and edge-based brain network alterations) and compared them against healthy reference cases ( N = 12) to assess brain damage qualitatively and quantitatively at the individual level. Our findings revealed alterations of brain networks with high variability between patients. With validation and comparison to stratified, normative healthy control comparison cohorts, this approach could be used by clinicians to formulate a neuroscience-guided integrative rehabilitation program for TBI patients, and for designing personalized rehabilitation protocols based on their unique lesion load and connectome., (© 2022 Massachusetts Institute of Technology.)

Background: Ketamine is a fast-acting, dissociative anesthetic with a favorable adverse effect profile that is effective for managing acute agitation as a chemical restraint in the prehospital and emergency department (ED) settings. However, some previously published individual studies have reported high intubation rates when ketamine was administered prehospitally., Objective: This systematic review aims to determine the rate and settings in which intubation following prehospital administration of ketamine for agitation is occurring, as well as associated indications and adverse events., Methods: We searched PubMed, Scopus, Ovid MEDLINE, Embase, CINAHL Plus, PsycINFO, the Cochrane Library, ClinicalTrials.gov, OpenGrey, Open Access Theses and Dissertation, and Google Scholar from the earliest possible date until 13/February/2022. Inclusion criteria required studies to describe agitated patients who received ketamine in the prehospital setting as a first-line drug to control acute agitation. Reference lists of appraised studies were screened for additional relevant articles. Study quality was assessed using the Newcastle-Ottawa quality assessment scale. Synthesis of results was completed via meta-analysis, and the GRADE tool was used for certainty assessment., Results: The search yielded 1466 unique records and abstracts, of which 50 full texts were reviewed, resulting in 18 being included in the analysis. All studies were observational in nature and 15 were from USA. There were 3476 patients in total, and the overall rate of intubation was 16% (95% confidence interval [CI] = 8%-26%). Most intubations occurred in the ED. Within the studies, the prehospital intubation rate ranged from 0% to 7.9% and the ED intubation rate ranged from 0 to 60%. The overall pooled prehospital intubation rate was 1% (95% CI = 0%-2%). The overall pooled ED intubation rate was 19% (95% CI = 11%-30%). The most common indications for intubation were for airway protection and respiratory depression/failure., Conclusions: There is wide variation in intubation rates between and within studies. The majority of intubations performed following prehospital administration of ketamine for agitation took place in the ED.

Assault is the leading preventable cause of death, traumatic brain injury (TBI), and associated mental health problems. The COVID-19 pandemic has had a profound impact on patterns of interpersonal violence across the world. In this retrospective cross-sectional study, we analysed medical records of 1232 assault victims (domestic violence: 111, random assault: 900, prison assault: 221) with head injuries who presented to the emergency department (ED) at St Vincent's Hospital in Melbourne, Australia, a city with one of the longest and most severe COVID-19 restrictions worldwide. We examined changes in prevalence in the assault group overall and in domestic violence, random assault, and prison assault victims, comparing data from 19.5 months before and after the first day of COVID-19 restrictions in Melbourne. Moreover, we investigated differences driven by demographic factors ( Who : age group, sex, and nationality) and clinical variables ( Where : assault location, and When : time of arrival to the ED and time from moment of injury until presentation at ED). Descriptive statistics and chi-square analyses were performed. We found the COVID-19 pandemic significantly affected the Where of assault-related TBI, with a shift in the location of assaults from the street to the home, and the increase at home being driven by random assaults on middle-aged adults. Overall, we observed that 86% of the random assault cases were males, whereas 74% of the domestic assault cases were females. Meanwhile, nearly half (44%) of the random assault victims reported alcohol consumption versus a fifth (20%) of domestic violence victims. These findings will have direct implications for developing screening tools and better preventive and ameliorative interventions to manage the sequelae of assault TBI, particularly in the context of future large-scale health crises or emergencies.

Objective: The World Health Organization declared the COVID-19 pandemic on 11 March 2020. In 2021, several vaccines were provisionally approved to reduce the risk of transmission and hospitalisation of COVID-19 infection. A surge in COVID-19 vaccination was seen between August and October 2021 in Victoria, Australia. We hypothesised this led to an increase in ED presentations., Methods: Patients in the present study were adults who presented to the ED within 21 days of receiving a dose of a COVID-19 vaccine between 11 August 2021 and 14 November 2021. All cases underwent chart reviews to extract epidemiological features, clinical presentations, ED assessments, investigations and disposition., Results: Notably, 968 patients were included in the study, comprising 6.1% of all ED presentations during the study period. The median age was 31 years. 82.9% of patients were younger than 45 years. 20.1% of patients arrived by ambulance. Chest pain was the most common presenting complaint (43.6%), followed by headache (10.3%) and palpitations (8.2%). The most common investigations were a full blood examination (73.5%), an ECG (63.8%) and serum troponin (49.1%). 64.8% of patients were directly discharged home and 22.1% were sent home after a short stay admission. Only 2.2% of patients were admitted to the hospital., Conclusion: A majority of patients who presented to the ED after their COVID vaccinations were young and discharged home after the initial assessment. These presentations have significantly increased the workload in prehospital settings and EDs, contributing to increased investigation usage, ED treatment space occupancy, and increased costs to the health system., (© 2022 The Authors. Emergency Medicine Australasia published by John Wiley & Sons Australia, Ltd on behalf of Australasian College for Emergency Medicine.)

Objectives: Alcohol is the most widely consumed psychoactive substance in Australia and the consequences of alcohol consumption have enormous personal and social impacts. This study aimed to describe the principal diagnoses of emergency department (ED) presentations involving alcohol use in the previous 12 hours at eight hospitals in Victoria and the Australian Capital Territory, Australia., Methods: Twelve months' data (1 July 2018 - 30 June 2019) were collected from eight EDs, including demographics, ICD-10 codes, hospital location and self-reported drinking in the preceding 12 hours. The ten most common ICD-10 discharge codes were analysed based on age, sex and hospital geographic area., Results: ICD codes pertaining to mental and behavioural disorders due to alcohol use accounted for the highest proportion in most EDs. Suicide ideation/attempt was in the five highest ICD codes for all but one hospital. It was the second most common alcohol-related presentation for both males and females., Conclusions: Alcohol plays a major role in a range of presentations, especially in relation to mental health and suicide., Implications for Public Health: The collection of alcohol involvement in ED presentations represents a major step forward in informing the community about the burden of alcohol on their health resources., (© 2022 The Authors.)

New drugs that precisely target the immune mechanisms critical for cytotoxic T lymphocyte (CTL) and natural killer (NK) cell driven pathologies are desperately needed. In this perspective, we explore the cytolytic protein perforin as a target for therapeutic intervention. Perforin plays an indispensable role in CTL/NK killing and controls a range of immune pathologies, while being encoded by a single copy gene with no redundancy of function. An immunosuppressant targeting this protein would provide the first-ever therapy focused specifically on one of the principal cell death pathways contributing to allotransplant rejection and underpinning multiple autoimmune and postinfectious diseases. No drugs that selectively block perforin-dependent cell death are currently in clinical use, so this perspective will review published novel small molecule inhibitors, concluding with in vivo proof-of-concept experiments performed in mouse models of perforin-mediated immune pathologies that provide a potential pathway toward a clinically useful therapeutic agent.

The COVID-19 pandemic has imposed significant mental health burdens upon the general population worldwide, either directly owing to the disease or indirectly through aggressive public health measures to control spread of the virus that causes COVID-19. In this narrative review, we used a systematic approach to summarize the impact of restrictive lockdown measures on the general mental health of people living in Victoria, Australia during 2020 and to identify the groups with an increased risk of adverse mental health outcomes. A systematic database search (Ovid Medline, PsycINFO, Embase) for articles examining the mental health of Victorians in the context of the COVID-19 pandemic during 2020 yielded 88 articles, of which 15 articles were finally included in this review. We found that the general mental health of Victorians was negatively affected by COVID-19 restrictions during 2020. Although studies reported heterogeneous mental health outcomes, we found that the general population consistently used coping strategies and demonstrated mental health help-seeking behaviors in response to the restrictions. Women, children, young people, carers, people who became unemployed owing to the pandemic, and those with pre-existing psychiatric conditions had a higher risk of adverse mental health consequences during the COVID-19 pandemic in 2020.

Background: Healthcare inequity has widely affected marginalized and immigrant communities globally during the COVID-19 pandemic., Aims: This study assessed the effect of COVID-19 pandemic on health care delivery to immigrant populations in Isfahan Province, Islamic Republic of Iran., Methods: All 67 hospitals across Isfahan Province were included in this study conducted from 1 March to 31 May 2020. Data on clinical manifestations, comorbidities, patient management, and outcomes of patients during hospital admission were extracted from medical records and analysed using SPSS for chi-square and odds ratio (OR)., Results: One hundred and sixty-eight (3.3%) of 5128 PCR-confirmed COVID-19 cases during the study period were immigrants and were included in the study. There were no differences in sex, clinical presentation, comorbidities, and length of hospital stay between the non-immigrant and immigrant groups. Immigrant patients were significantly younger and had poorer outcomes, including tracheal intubation [OR = 1.9, 95% confidence interval (CI): 1.2-3.1); P = 0.009] and in-hospital mortality (OR = 1.6; 95% CI: 1.1-2.4; P = 0.02)., Conclusion: Adverse health outcomes among immigrant communities may be an indication of health inequity and should be addressed by the relevant policymakers., (Copyright © Authors 2022; licensee World Health Organization. EMHJ is an open access journal. This paper is available under the Creative Commons Attribution Non-Commercial ShareAlike 3.0 IGO licence (CC BY-NC-SA 3.0 IGO; https://creativecommons.org/licenses/by-nc-sa/3.0/igo).)

Objective: To quantify the attitude ED clinicians hold towards patients presenting with different medical conditions, including a novel pandemic condition., Methods: A cross-sectional study of emergency doctors and nurses utilising the Medical Condition Regard Scale (MCRS); a validated tool used to capture the bias and emotions of clinicians towards individual medical conditions. The five conditions presented to participants each represent a classical medical, complex medical, psychiatric/substance use, somatoform and a novel medical condition., Results: One hundred and ninety-six clinicians were included in the study including 116 nurses and 80 doctors. Concerning each condition, both medical and nursing staff demonstrated the highest regard for a classical medical condition (58 ± 5 and 57 ± 6, respectively). Significantly different from the classical medical condition, the lowest MCRS scores were for the somatoform condition (36 ± 10) for emergency doctors and the substance use condition (39 ± 11) for emergency nurses. Regard for a novel condition (i.e., COVID-19 infection) was comparably high among both cohorts., Conclusion: Emergency doctors and nurses generally hold lower regard for complex medical conditions with behavioural components, including substance use disorders and somatoform conditions., (© 2022 Australasian College for Emergency Medicine.)