Inhibiting Eph/ephrin signaling reduces vascular leak and endothelial cell dysfunction in mice with sepsis.

Sepsis is a life-threatening disease caused by a dysregulated host response to infection, resulting in 11 million deaths globally each year. Vascular endothelial cell dysfunction results in the loss of endothelial barrier integrity, which contributes to sepsis-induced multiple organ failure and mortality. Erythropoietin-producing hepatocellular carcinoma (Eph) receptors and their ephrin ligands play a key role in vascular endothelial barrier disruption but are currently not a therapeutic target in sepsis. Using a cecal ligation and puncture (CLP) mouse model of sepsis, we showed that prophylactic or therapeutic treatment of mice with EphA4-Fc, a decoy receptor and pan-ephrin inhibitor, resulted in improved survival and a reduction in vascular leak, lung injury, and endothelial cell dysfunction. EphA2-/- mice also exhibited reduced mortality and pathology after CLP compared with wild-type mice. Proteomics of plasma samples from mice with sepsis after CLP revealed dysregulation of a number of Eph/ephrins, including EphA2/ephrin A1. Administration of EphA4-Fc to cultured human endothelial cells pretreated with TNF-α or ephrin-A1 prevented loss of endothelial junction proteins, specifically VE-cadherin, with maintenance of endothelial barrier integrity. In children admitted to hospital with fever and suspected infection, we observed that changes in EphA2/ephrin A1 in serum samples correlated with endothelial and organ dysfunction. Targeting Eph/ephrin signaling may be a potential therapeutic strategy to reduce sepsis-induced endothelial dysfunction and mortality.

Optimal dosing of cefotaxime and desacetylcefotaxime for critically ill paediatric patients. Can we use microsampling?

OBJECTIVES: To describe the population pharmacokinetics of cefotaxime and desacetylcefotaxime in critically ill paediatric patients and provide dosing recommendations. We also sought to evaluate the use of capillary microsampling to facilitate data-rich blood sampling. METHODS: Patients were recruited into a pharmacokinetic study, with cefotaxime and desacetylcefotaxime concentrations from plasma samples collected at 0, 0.5, 2, 4 and 6 h used to develop a population pharmacokinetic model using Pmetrics. Monte Carlo dosing simulations were tested using a range of estimated glomerular filtration rates (60, 100, 170 and 200 mL/min/1.73 m2) and body weights (4, 10, 15, 20 and 40 kg) to achieve pharmacokinetic/pharmacodynamic (PK/PD) targets, including 100% ƒT>MIC with an MIC breakpoint of 1 mg/L. RESULTS: Thirty-six patients (0.2-12 years) provided 160 conventional samples for inclusion in the model. The pharmacokinetics of cefotaxime and desacetylcefotaxime were best described using one-compartmental model with first-order elimination. The clearance and volume of distribution for cefotaxime were 12.8 L/h and 39.4 L, respectively. The clearance for desacetylcefotaxime was 10.5 L/h. Standard dosing of 50 mg/kg q6h was only able to achieve the PK/PD target of 100% ƒT>MIC in patients >10 kg and with impaired renal function or patients of 40 kg with normal renal function. CONCLUSIONS: Dosing recommendations support the use of extended or continuous infusion to achieve cefotaxime exposure suitable for bacterial killing in critically ill paediatric patients, including those with severe or deep-seated infection. An external validation of capillary microsampling demonstrated skin-prick sampling can facilitate data-rich pharmacokinetic studies.

Medical students' perceptions and expectations regarding digital health education and training: A qualitative study.

INTRODUCTION: Digital health - the convergence of digital technologies within health and health care to enhance the efficiency of health-care delivery - is fast becoming an integral part of routine medical practice. The integration of digital health into traditional practice brings significant changes. Logic dictates that for medical practitioners to operate in this new digitally enabled environment, they require specific knowledge, skills and competencies relating to digital health. However, very few medical programmes in Australia and globally include digital health within their regular curriculum. This pilot study aimed to explore medical students' perceptions and expectations of digital health education and training (ET). METHODS: An online survey and focus groups were used to collect information about medical students' perceptions and expectations relating to digital health and ET relating to this field within the medical programme at the University of Queensland. Sixty-three students took part in the survey, and 17 students were involved in four focus groups. RESULTS: Most participants had no formal ET in digital health. Most participants (n = 43; 68%) expressed a willingness to learn about digital health as part of their medical programme. DISCUSSION: Primarily, knowledge- and practice-related factors have motivated students to learn about digital health. The analysis of focus group data identified two superordinate themes: (a) drivers of digital health ET and (b) expectations relating to digital health ET. Students agreed that digital health is a relevant field for their future practice that should be taught as part of their regular curriculum.

Microsampling to support pharmacokinetic clinical studies in pediatrics.

BACKGROUND: Conventional sampling for pharmacokinetic clinical studies requires removal of large blood volumes from patients. This can result in a physiological/emotional burden for children. Microsampling to support pharmacokinetic clinical studies in pediatrics may reduce this burden. METHODS: Parents/guardians and bedside nurses completed a questionnaire describing their perception of the use of microsampling compared to conventional sampling to collect blood samples, based on their child's participation or their own role within a paired-sample pharmacokinetic clinical study. Responses were based on a seven-point Likert scale and were analyzed using frequency distributions. RESULTS: Fifty-one parents/guardians and seven bedside nurses completed a questionnaire. Parents/guardians (96%) and bedside nurses (100%) indicated that microsampling was highly acceptable and recommended as a method for collecting blood samples for pediatric patients. Responding to a question about the child indicating pain during the blood sampling procedure, 61% of parent/guardians reported no pain in their children, 14% remained neutral, and 26% reported that their child indicated pain; 71% of the bedside nurses slightly agreed that the children indicated pain. CONCLUSIONS: This study strongly suggests that parents/guardians and bedside nurses prefer microsampling to conventional sampling to conduct pediatric pharmacokinetic clinical studies. Employing microsampling may support increased participation by children in these studies. IMPACT: Pharmacokinetic clinical studies require the withdrawal of blood samples at multiple times during a dosing interval. This can result in a physiological or emotional burden, particularly for neonates or pediatric patients. Microsampling offers an important opportunity for pharmacokinetic clinical studies in vulnerable patient populations, where smaller sample volumes can be collected. However, microsampling is not commonly used in clinical studies. Understanding the perceptions of parents/guardians and bedside nurses about microsampling may ascertain if this technique offers an improvement to conventional blood sample collection to perform pharmacokinetic clinical studies for pediatric patients.

Multi-incident analysis of reviews of serious adverse clinical events in children with serious bacterial infection and/or sepsis in Queensland, Australia between 2012 and 2017.

AIM: To report on findings from a multi-incident analysis of reviews of serious paediatric adverse clinical events related to serious bacterial infection and/or sepsis (hereafter referred to as sepsis for brevity) in Queensland, Australia, between 2012 and 2017. METHODS: The Queensland Paediatric Quality Council reviewed documentation from reviews of serious adverse events occurring in children (<18 years) with a diagnosis of sepsis at Queensland public hospitals between 2012 and 2017, including clinical details, coronial reports, autopsy reports and root cause analysis documents. A multi-incident tool was designed and used by an expert panel to identify patient and facility demographics, contributing factors, and human and system factors associated with paediatric serious adverse events. RESULTS: There were 28 serious adverse clinical events reported related to paediatric sepsis, characterised by a high proportion of deaths (23) and a predominance of children aged under 4 years. Approximately half of all facilities were classified as rural and remote health services. Contributing factors included difficulty in recognising and responding to the deteriorating patient, inadequate management/treatment, diagnostic error (mainly diagnostic delay) and escalation delay/failure. Major system factors included communication issues, incorrect use of the early warning tool, inadequate coordination of care planning, policy/protocol/guideline failures and workforce problems. CONCLUSION: Multi-incident analysis is a useful tool for identifying themes that recur in similar events and presents opportunities for system-wide improvement. Common themes and contributing factors were identified which may provide possibilities for earlier identification and intervention in childhood serious bacterial infection and/or sepsis.

Development and validation of a UHPLC-MS/MS method to measure cefotaxime and metabolite desacetylcefotaxime in blood plasma: a pilot study suitable for capillary microsampling in critically ill children.

Critical illness has been shown to affect the pharmacokinetics of antibiotics, which can lead to ineffective antibiotic exposure and the potential emergence of resistant bacteria. The lack of studies describing antibiotic pharmacokinetics in critically ill children has led to significant off-label dosing. This is, in part, due to the ethical and physiological challenges of removing frequent, large-volume samples from children. Capillary microsampling facilitates the collection of small volumes of blood samples to conduct clinical pharmacokinetic studies. A sensitive, rapid, and accurate ultra-high-performance liquid chromatography tandem mass spectrometry (UHPLC-MS/MS) bioanalytical method to measure cefotaxime and desacetylcefotaxime in 2.8 µL of plasma was developed and validated. Plasma samples were treated with acetonitrile and analytes were separated using a Kinetex C8 (100 × 2.1 mm) column. The chromatographic separation was established using a gradient method, with the mobile phases consisting of acetonitrile and ammonium acetate. An electrospray ionization source interface operated in a positive mode for the multiple reaction monitoring MS/MS analysis of cefotaxime, desacetylcefotaxime, and deuterated cefotaxime (internal standard). The bioanalytical method using microsample volumes met requirements for method validation for both analytes. Cefotaxime had precision within ± 7.3% and accuracy within ± 5% (concentration range of 0.5 to 500 mg/L). Desacetylcefotaxime had precision within ± 9.5% and accuracy within ± 3.5% (concentration range of 0.2 to 10 mg/L). The bioanalytical method was applied for the quantification of cefotaxime and its metabolite to 20 capillary microsamples collected at five time points in one dosing interval from five critically ill children.

Queensland Telepaediatric Service: A Review of the First 15 Years of Service.

In November 2000, the Queensland Telepaediatric Service (QTS) was established in Brisbane, Australia, to support the delivery of telehealth services to patients and clinicians in regional and remote locations. The QTS was built on a centralized coordination model, where telehealth services could be effectively managed by a dedicated telehealth coordinator. In doing so, telehealth referral and consultation processes were efficient and clinicians felt better supported as they adjusted to new processes for engaging with patients. We have conducted a retrospective review of activity associated with the QTS and summarized key activities which have arisen from this extensive program of work. Telehealth service records and associated publications were used to describe the evolution of the QTS over a 15-year period. From November 2000 to March 2016, 23,054 telehealth consultations were delivered for 37 pediatric clinical specialties. The most common service areas included child and youth mental health, neurology, burns care, surgery, and ear nose and throat services. A range of different telehealth service models were developed to align with different clinical service needs and location of services. Whilst most work involved video consultation between hospitals, some services involved the delivery of telehealth services into the home, schools or community health centres. Despite its longevity, the QTS was not immune to the usual challenges associated with telehealth implementation, service redesign and sustainability. Experience reported from the QTS will be useful for other health services seeking to develop comprehensive telehealth services in a rapidly changing healthcare environment.

A review of children with severe trauma admitted to pediatric intensive care in Queensland, Australia.

BACKGROUND: The aim of this study is to review patient characteristics, injury patterns, and outcomes of trauma cases admitted to pediatric intensive care in Children's Health Queensland, Brisbane, Queensland, Australia. METHODS: Routinely recorded data collected prospectively from the Children's Health Queensland Trauma Service registry from November 2008 to October 2015 were reviewed. Demographic and clinical characteristics of trauma cases in children under 16 years of age are described, and their association with age and mortality analyzed. RESULTS: There were 542 cases of pediatric trauma identified and 66.4% were male. The overall mortality since January 2012 was 11.1%. The median injury severity score (ISS) was 11 (IQR = 9-22), 48.2% (n = 261) had an ISS > 12 and 41.7% (n = 226) patients had an ISS > 15. The most common injury patterns were isolated head injury (29.7%; n = 161) and multiple trauma (31.2%; n = 169). In 28.4% of cases (n = 154) surgery was required. The home was reported to be the most common place of injury (37.6%; n = 204). Children aged 0-4 years were least likely to survive their injury (15.3% mortality) compared with the 5-9 (5.6% mortality) and 10-15 (9.0% mortality) age groups. Higher mortality was associated with more severe injuries, abdomen/spine/thorax injuries, inflicted injuries, drowning and hanging. CONCLUSION: This description of major pediatric trauma cases admitted to pediatric intensive care in Children's Health Queensland, Australia, will inform future pediatric major trauma service requirements as it identifies injury patterns and profiles, injury severity, management and mortality across different age groups.

Implementation and strength of root cause analysis recommendations following serious adverse events involving paediatric patients in the Queensland public health system between 2012 and 2014.

AIM: This study evaluates the implementation rate and strength of the recommendations developed in all root cause analyses (RCAs) performed following serious clinical incidents involving children that have resulted in permanent harm or death in Queensland public hospitals over a 3-year period. METHODS: Severity assessment classification 1 events were identified from a Queensland Paediatric Quality Council database of paediatric clinical incidents that occurred in Queensland between 1 January 2012 and 31 December 2014. There were 150 recommendations extracted from RCAs pertaining to the 42 serious adverse events involving paediatric patients. RESULTS: Of the recommendations, 82% were implemented; 33% of recommendations were classified as stronger, 33% as intermediate and 34% weaker in terms of their potential to improve patient safety. CONCLUSIONS: This study describes the implementation of recommendations and classifies them in terms of potential to prevent patient harm and save lives. Future research is needed to determine if the RCA process does indeed prevent harm.

Particle and bioaerosol characteristics in a paediatric intensive care unit.

The paediatric intensive care unit (PICU) provides care to critically ill neonates, infants and children. These patients are vulnerable and susceptible to the environment surrounding them, yet there is little information available on indoor air quality and factors affecting it within a PICU. To address this gap in knowledge we conducted continuous indoor and outdoor airborne particle concentration measurements over a two-week period at the Royal Children's Hospital PICU in Brisbane, Australia, and we also collected 82 bioaerosol samples to test for the presence of bacterial and viral pathogens. Our results showed that both 24-hour average indoor particle mass (PM10) (0.6-2.2µgm-3, median: 0.9µgm-3) and submicrometer particle number (PN) (0.1-2.8×103pcm-3, median: 0.67×103pcm-3) concentrations were significantly lower (p<0.01) than the outdoor concentrations (6.7-10.2µgm-3, median: 8.0µgm-3 for PM10 and 12.1-22.2×103pcm-3, median: 16.4×103pcm-3 for PN). In general, we found that indoor particle concentrations in the PICU were mainly affected by indoor particle sources, with outdoor particles providing a negligible background. We identified strong indoor particle sources in the PICU, which occasionally increased indoor PN and PM10 concentrations from 0.1×103 to 100×103pcm-3, and from 2µgm-3 to 70µgm-3, respectively. The most substantial indoor particle sources were nebulization therapy, tracheal suction and cleaning activities. The average PM10 and PN emission rates of nebulization therapy ranged from 1.29 to 7.41mgmin-1 and from 1.20 to 3.96pmin-1×1011, respectively. Based on multipoint measurement data, it was found that particles generated at each location could be quickly transported to other locations, even when originating from isolated single-bed rooms. The most commonly isolated bacterial genera from both primary and broth cultures were skin commensals while viruses were rarely identified. Based on the findings from the study, we developed a set of practical recommendations for PICU design, as well as for medical and cleaning staff to mitigate aerosol generation and transmission to minimize infection risk to PICU patients.

Diagnostic testing in influenza and pertussis related paediatric intensive care unit admissions,Queensland, Australia, 1997-2013.

Severe respiratory infections make up a large proportion of Australian paediatric intensive care unit (ICU) admissions each year. Identification of the causative pathogen is important and informs clinical management. We investigated the use of polymerase chain reaction (PCR) in the ICU-setting using data collated by the Australian and New Zealand Paediatric Intensive Care (ANZPIC) Registry from five ICUs in Queensland, Australia. We describe diagnostic testing use among pertussis and influenza-related paediatric ICU admissions between 01 January 1997 and 31 December 2013.

Comparing Pediatric Rotations at Two University of Queensland Clinical Schools.

BACKGROUND: The University of Queensland (UQ), Ochsner Clinical School (OCS) is a partnership between Ochsner Health System in New Orleans, LA, and UQ in Brisbane, Australia. OCS medical students are trained on both continents, receiving their didactic education in Australia and their clinical education in the United States. METHODS: We review the OCS experience and compare the pediatric rotations at OCS and UQ. RESULTS: Students in the pediatric rotations in Australia and in the United States receive their clinical instruction in the real-world learning environment of hospitals and clinics. In addition, lectures, online learning modules, case-based tutorials, and rigorous assessment at the end of the rotation help prepare medical students for future contact with pediatric patients. Sixty-nine third-year OCS students and 499 fourth-year UQ students completed the pediatric rotation in 2014. In 2015, 105 third-year OCS students and approximately 400 fourth-year UQ students completed the pediatric rotation. CONCLUSION: In a unique educational collaboration, OCS has used e-learning and face-to-face tutorials to produce a well-rounded curriculum that assimilates global healthcare and international medicine. This article demonstrates the feasibility of delivering a standardized curriculum across two continents using modern e-learning tools.

Epidemiology of pertussis-related paediatric intensive care unit (ICU) admissions in Australia, 1997-2013: an observational study.

OBJECTIVE: To review the epidemiology of pertussis-related intensive care unit (ICU) admissions across Australia, over a 17-year period. DESIGN: Retrospective descriptive study. SETTING: Australian ICUs contributing data to the Australian and New Zealand Paediatric Intensive Care (ANZPIC) Registry. The number of contributing ICUs increased over the study period, from 8 specialist paediatric ICUs in 1997 to 8 specialist paediatric and 13 general ICUs in 2013. PARTICIPANTS: All paediatric (<16 years) ICU admissions, coded as pertussis-related, between 1 January 1997 and 31 December 2013. RESULTS: A total of 373 pertussis-coded ICU admissions were identified in the ANZPIC Registry over the study period. Of these cases, 52.8% occurred during the 4 years of the recent Australian epidemic (2009-2012). ICU admissions were most likely to occur in infants aged younger than 6 weeks (41.8%, n=156) and aged 6 weeks to 4 months (42.9%, n=160). The median length of stay for pertussis-related ICU admissions was 3.6 days, with 77.5% of cases staying in ICU for <7 days. Approximately half of all admissions (54.8%) required some form of respiratory support, with 32.7% requiring invasive respiratory support. Over the study period, 23 deaths were recorded (6.2% of pertussis-related ICU admissions), of which 20 (87.0%) were infants <4 months old. CONCLUSIONS: Pertussis-related ICU admissions occur primarily in infants too young to be fully protected from active immunisation. More needs to be done to protect these high-risk infants, such as maternal immunisation.

Epidemiology of Australian Influenza-Related Paediatric Intensive Care Unit Admissions, 1997-2013.

BACKGROUND: Influenza virus predictably causes an annual epidemic resulting in a considerable burden of illness in Australia. Children are disproportionately affected and can experience severe illness and complications, which occasionally result in death. METHODS: We conducted a retrospective descriptive study using data collated in the Australian and New Zealand Paediatric Intensive Care (ANZPIC) Registry of influenza-related intensive care unit (ICU) admissions over a 17-year period (1997-2013, inclusive) in children <16 years old. National laboratory-confirmed influenza notifications were used for comparison. RESULTS: Between 1997 and 2013, a total of 704 influenza-related ICU admissions were recorded, at a rate of 6.2 per 1,000 all-cause ICU admissions. Age at admission ranged from 0 days and 15.9 years (median = 2.1 years), with 135 (19.2%) aged <6 months. Pneumonia/pneumonitis and bronchiolitis were the most common primary diagnoses among influenza-related admissions (21.9% and 13.6%, respectively). More than half of total cases (59.2%) were previously healthy (no co-morbidities recorded), and in the remainder, chronic lung disease (16.7%) and asthma (12.5%) were the most common co-morbidities recorded. Pathogen co-detection occurred in 24.7% of cases, most commonly with respiratory syncytial virus or a staphylococcal species. Median length of all ICU admissions was 3.2 days (range 2.0 hours- 107.4 days) and 361 (51.3%) admissions required invasive respiratory support for a median duration of 4.3 days (range 0.2 hours- 107.5 days). There were 27 deaths recorded, 14 (51.9%) in children without a recorded co-morbidity. CONCLUSION: Influenza causes a substantial number of ICU admissions in Australian children each year with the majority occurring in previously healthy children.

EPHA4-FC TREATMENT REDUCES ISCHEMIA/REPERFUSION-INDUCED INTESTINAL INJURY BY INHIBITING VASCULAR PERMEABILITY.

The inflammatory response is characterized by increased endothelial permeability, which permits the passage of fluid and inflammatory cells into interstitial spaces. The Eph/ephrin receptor ligand system plays a role in inflammation through a signaling cascade, which modifies Rho-GTPase activity. We hypothesized that blocking Eph/ephrin signaling using an EphA4-Fc would result in decreased inflammation and tissue injury in a model of ischemia/reperfusion (I/R) injury. Mice undergoing intestinal I/R pretreated with the EphA4-Fc had significantly reduced intestinal injury compared to mice injected with the control Fc. This reduction in I/R injury was accompanied by significantly reduced neutrophil infiltration, but did not affect intestinal inflammatory cytokine generation. Using microdialysis, we identified that intestinal I/R induced a marked increase in systemic vascular leakage, which was completely abrogated in EphA4-Fc-treated mice. Finally, we confirmed the direct role of Eph/ephrin signaling in endothelial leakage by demonstrating that EphA4-Fc inhibited tumor necrosis factor-α-induced vascular permeability in human umbilical vein endothelial cells. This study identifies that Eph/ephrin interaction induces proinflammatory signaling in vivo by inducing vascular leak and neutrophil infiltration, which results in tissue injury in intestinal I/R. Therefore, therapeutic targeting of Eph/ephrin interaction using inhibitors, such as EphA4-Fc, may be a novel method to prevent tissue injury in acute inflammation by influencing endothelial integrity and by controlling vascular leak.

Isotonic versus hypotonic solutions for maintenance intravenous fluid administration in children.

BACKGROUND: Maintenance intravenous fluids are frequently used in hospitalised children who cannot maintain adequate hydration through enteral intake. Traditionally used hypotonic fluids have been associated with hyponatraemia and subsequent morbidity and mortality. Use of isotonic fluid has been proposed to reduce complications. OBJECTIVES: To establish and compare the risk of hyponatraemia by systematically reviewing studies where isotonic is compared with hypotonic intravenous fluid for maintenance purposes in children.Secondly, to compare the risk of hypernatraemia, the effect on mean serum sodium concentration and the rate of attributable adverse effects of both fluid types in children. SEARCH METHODS: We ran the search on 17 June 2013. We searched the Cochrane Injuries Group Specialised Register, Cochrane Central Register of Controlled Trials (CENTRAL, The Cochrane Library), MEDLINE (OvidSP), Embase (OvidSP), and ISI Web of Science. We also searched clinical trials registers and screened reference lists. We updated this search in October 2014 but these results have not yet been incorporated. SELECTION CRITERIA: We included randomised controlled trials that compared isotonic versus hypotonic intravenous fluids for maintenance hydration in children. DATA COLLECTION AND ANALYSIS: At least two authors assessed and extracted data for each trial. We presented dichotomous outcomes as risk ratios (RR) with 95% confidence intervals (CIs) and continuous outcomes as mean differences with 95% CIs. MAIN RESULTS: Ten studies met the inclusion criteria, with a total of 1106 patients. The majority of the studies were performed in surgical or intensive care populations (or both). There was considerable variation in the composition of intravenous fluid, particularly hypotonic fluid, used in the studies. There was a low risk of bias for most of the included studies. Ten studies provided data for our primary outcome, a total of 449 patients in the analysis received isotonic fluid, while 521 received hypotonic fluid. Those who received isotonic fluid had a substantially lower risk of hyponatraemia (17% versus 34%; RR 0.48; 95% CI 0.38 to 0.60, high quality evidence). It is unclear whether there is an increased risk of hypernatraemia when isotonic fluids are used (4% versus 3%; RR 1.24; 95% CI 0.65 to 2.38, nine studies, 937 participants, low quality evidence), although the absolute number of patients developing hypernatraemia was low. Most studies had safety restrictions included in their methodology, preventing detailed investigation of serious adverse events. AUTHORS' CONCLUSIONS: Isotonic intravenous maintenance fluids with sodium concentrations similar to that of plasma reduce the risk of hyponatraemia when compared with hypotonic intravenous fluids. These results apply for the first 24 hours of administration in a wide group of primarily surgical paediatric patients with varying severities of illness.

The effectiveness of telemedicine for paediatric retrieval consultations: rationale and study design for a pragmatic multicentre randomised controlled trial.

BACKGROUND: In many health systems, specialist services for critically ill children are typically regionalised or centralised. Studies have shown that high-risk paediatric patients have improved survival when managed in specialist centres and that volume of cases is a predictor of care quality. In acute cases where distance and time impede access to specialist care, clinical advice may be provided remotely by telephone. Emergency retrieval services, attended by medical and nursing staff may be used to transport patients to specialist centres. Even with the best quality retrieval services, stabilisation of the patient and transport logistics may delay evacuation to definitive care. Several studies have examined the use of telemedicine for providing specialist consultations for critically ill children. However, no studies have yet formally examined the clinical effectiveness and economic implications of using telemedicine in the context of paediatric patient retrieval. METHODS/DESIGN: The study is a pragmatic, multicentre randomised controlled trial running over 24 months which will compare the use of telemedicine with the use of the telephone for paediatric retrieval consultations between four referring hospitals and a tertiary paediatric intensive care unit. We aim to recruit 160 children for whom a specialist retrieval consultation is required. The primary outcome measure is stabilisation time (time spent on site at the referring hospital by the retrieval team) adjusted for initial risk. Secondary outcome measures are change in patient's physiological status (repeated measure, two time points) scored using the Children's Emergency Warning Tool; change in diagnosis (repeated measure taken at three time points); change in destination of retrieved patients at the tertiary hospital (general ward or paediatric intensive care unit); retrieval decision, and length of stay in the Paediatric Intensive Care Unit for retrieved patients. The trial has been approved by the Human Research Ethics Committees of Children's Health Services Queensland and The University of Queensland, Australia. DISCUSSION: Health services are adopting telemedicine, however formal evidence to support its use in paediatric acute care is limited. Generalisable evidence is required to inform clinical use and health system policy relating to the effectiveness and economic implications of the use in telemedicine in paediatric retrieval. TRIAL REGISTRATION: Australian and New Zealand Clinical Trials Registry ACTRN12612000156886 .

Evidence that the EphA2 receptor exacerbates ischemic brain injury.

Ephrin (Eph) signaling within the central nervous system is known to modulate axon guidance, synaptic plasticity, and to promote long-term potentiation. We investigated the potential involvement of EphA2 receptors in ischemic stroke-induced brain inflammation in a mouse model of focal stroke. Cerebral ischemia was induced in male C57Bl6/J wild-type (WT) and EphA2-deficient (EphA2(-/-)) mice by middle cerebral artery occlusion (MCAO; 60 min), followed by reperfusion (24 or 72 h). Brain infarction was measured using triphenyltetrazolium chloride staining. Neurological deficit scores and brain infarct volumes were significantly less in EphA2(-/-) mice compared with WT controls. This protection by EphA2 deletion was associated with a comparative decrease in brain edema, blood-brain barrier damage, MMP-9 expression and leukocyte infiltration, and higher expression levels of the tight junction protein, zona occludens-1. Moreover, EphA2(-/-) brains had significantly lower levels of the pro-apoptotic proteins, cleaved caspase-3 and BAX, and higher levels of the anti-apoptotic protein, Bcl-2 as compared to WT group. We confirmed that isolated WT cortical neurons express the EphA2 receptor and its ligands (ephrin-A1-A3). Furthermore, expression of all four proteins was increased in WT primary cortical neurons following 24 h of glucose deprivation, and in the brains of WT mice following stroke. Glucose deprivation induced less cell death in primary neurons from EphA2(-/-) compared with WT mice. In conclusion, our data provide the first evidence that the EphA2 receptor directly contributes to blood-brain barrier damage and neuronal death following ischemic stroke.

The KIDS SAFE checklist for pediatric intensive care units.

BACKGROUND: Checklists have been recognized by multiple industries as a valuable tool to reduce errors of omission. In the busy environment of a pediatric intensive care unit, adverse events are common and can have severe consequences. Researchers have focused on developing evidence-based practice guidelines; however, the nature of human error means that consistent application of this evidence in practice is challenging. OBJECTIVE: To develop an evidence-based checklist as a tool to reduce preventable adverse events and enhance clinical care in pediatric intensive care units. METHODS: After a systematic review of literature and a retrospective review of local reporting of adverse events in pediatric intensive care units, nominal group technique was used to determine the structure and content for the checklist. RESULTS: An 8-element mnemonic checklist (KIDS SAFE) was developed: kids' development needs, infection, deep-vein thrombosis prophylaxis, skin integrity, sedation, analgesia, family, and enteral needs. CONCLUSION: Prevention of adverse events is better than cure. Use of the KIDS SAFE checklist has the potential to reduce errors of omission in pediatric intensive care units.

Eph/Ephrin signaling in injury and inflammation.

The Eph/ephrin receptor-ligand system plays an important role in embryogenesis and adult life, principally by influencing cell behavior through signaling pathways, resulting in modification of the cell cytoskeleton and cell adhesion. There are 10 EphA receptors, and six EphB receptors, distinguished on sequence difference and binding preferences, that interact with the six glycosylphosphatidylinositol-linked ephrin-A ligands and the three transmembrane ephrin-B ligands, respectively. The Eph/ephrin proteins, originally described as developmental regulators that are expressed at low levels postembryonically, are re-expressed after injury to the optic nerve, spinal cord, and brain in fish, amphibians, rodents, and humans. In rodent spinal cord injury, the up-regulation of EphA4 prevents recovery by inhibiting axons from crossing the injury site. Eph/ephrin proteins may be partly responsible for the phenotypic changes to the vascular endothelium in inflammation, which allows fluid and inflammatory cells to pass from the vascular space into the interstitial tissues. Specifically, EphA2/ephrin-A1 signaling in the lung may be responsible for pulmonary inflammation in acute lung injury. A role in T-cell maturation and chronic inflammation (heart failure, inflammatory bowel disease, and rheumatoid arthritis) is also reported. Although there remains much to learn about Eph/ephrin signaling in human disease, and specifically in injury and inflammation, this area of research raises the exciting prospect that novel therapies will be developed that precisely target these pathways.