What is the role of autoimmunity in type 1 diabetes? A clinical perspective

Despite tremendous research efforts, type 1 diabetes is one of the few remaining autoimmune diseases without any approved immunological treatment. This observation compels us to reconsider the role of autoimmunity in the pathogenesis of this disease. In this commentary, we will review solely human data in an attempt to appreciate, in an unbiased manner, the importance and relevance of the immunological alterations in patients with type 1 diabetes. The aim of this paper is to generate reflection on this topic, rather than a controversy

A prospective randomised trial comparing nasogastric with intravenous hydration in children with bronchiolitis (protocol) The comparative rehydration in bronchiolitis study (CRIB)

<p>Abstract</p> <p>Background</p> <p>Bronchiolitis is the most common reason for admission of infants to hospital in developed countries. Fluid replacement therapy is required in about 30% of children admitted with bronchiolitis. There are currently two techniques of fluid replacement therapy that are used with the same frequency-intravenous (IV) or nasogastric (NG).</p> <p>The evidence to determine the optimum route of hydration therapy for infants with bronchiolitis is inadequate. This randomised trial will be the first to provide good quality evidence of whether nasogastric rehydration (NGR) offers benefits over intravenous rehydration (IVR) using the clinically relevant continuous outcome measure of duration of hospital admission.</p> <p>Methods/Design</p> <p>A prospective randomised multi-centre trial in Australia and New Zealand where children between 2 and 12 months of age with bronchiolitis, needing non oral fluid replacement, are randomised to receive either intravenous (IV) or nasogastric (NG) rehydration.</p> <p>750 patients admitted to participating hospitals will be recruited, and will be followed daily during the admission and by telephone 1 week after discharge. Patients with chronic respiratory, cardiac, or neurological disease; choanal atresia; needing IV fluid resuscitation; needing an IV for other reasons, and those requiring CPAP or ventilation are excluded.</p> <p>The primary endpoint is duration of hospital admission. Secondary outcomes are complications, need for ICU admission, parental satisfaction, and an economic evaluation. Results will be analysed using t-test for continuous data, and chi squared for categorical data. Non parametric data will be log transformed.</p> <p>Discussion</p> <p>This trial will define the role of NGR and IVR in bronchiolitis</p> <p>Trail registration</p> <p>The trial is registered with the Australian and New Zealand Clinical Trials Registry - ACTRN12605000033640</p

Accuracy of PECARN, CATCH, and CHALICE head injury decision rules in children: a prospective cohort study

© 2017 Elsevier Ltd Background Clinical decision rules can help to determine the need for CT imaging in children with head injuries. We aimed to validate three clinical decision rules (PECARN, CATCH, and CHALICE) in a large sample of children. Methods In this prospective observational study, we included children and adolescents (age

A multicentre randomised controlled trial of levetiracetam versus phenytoin for convulsive status epilepticus in children (protocol): Convulsive Status Epilepticus Paediatric Trial (ConSEPT) - a PREDICT study

Background: Convulsive status epilepticus (CSE) is the most common life-threatening childhood neurological emergency. Despite this, there is a lack of high quality evidence supporting medication use after first line benzodiazepines, with current treatment protocols based solely on non-experimental evidence and expert opinion. The current standard of care, phenytoin, is only 60% effective, and associated with considerable adverse effects. A newer anti-convulsant, levetiracetam, can be given faster, is potentially more efficacious, with a more tolerable side effect profile. The primary aim of the study presented in this protocol is to determine whether intravenous (IV) levetiracetam or IV phenytoin is the better second line treatment for the emergency management of CSE in children. Methods/Design: 200 children aged between 3 months and 16 years presenting to 13 emergency departments in Australia and New Zealand with CSE, that has failed to stop with first line benzodiazepines, will be enrolled into this multicentre open randomised controlled trial. Participants will be randomised to 40 mg/kg IV levetiracetam infusion over 5 min or 20 mg/kg IV phenytoin infusion over 20 min. The primary outcome for the study is clinical cessation of seizure activity five minutes following the completion of the infusion of the study medication. Blinded confirmation of the primary outcome will occur with the primary outcome assessment being video recorded and assessed by a primary outcome assessment team blinded to treatment allocation. Secondary outcomes include: Clinical cessation of seizure activity at two hours; Time to clinical seizure cessation; Need for rapid sequence induction; Intensive care unit (ICU) admission; Serious adverse events; Length of Hospital/ICU stay; Health care costs; Seizure status/death at one-month post discharge. Discussion: This paper presents the background, rationale, and design for a randomised controlled trial comparing levetiracetam to phenytoin in children presenting with CSE in whom benzodiazepines have failed. This study will provide the first high quality evidence for management of paediatric CSE post first-line benzodiazepines. Trial registration: Prospectively registered with the Australian and New Zealand Clinical Trial Registry (ANZCTR): ACTRN12615000129583(11/2/2015). UTN U1111-1144-5272. ConSEPT protocol version 4 (12/12/2014).The study is funded by grants from the Health Research Council of New Zealand (HRC 12/525), Auckland, New Zealand; A+ Trust (Auckland District Health Board), Auckland, New Zealand; Queensland Emergency Medicine Research Foundation, Milton, Queensland, Australia (EMPJ-105R21–2014- FURYK); Private Practice Research and Education Trust Fund, The Townsville Hospital and Health Service, Douglas, Queensland, Australia; Eric Ormond Baker Charitable Fund, Equity Trustees, Clayton, Victoria, Australia; and Princess Margaret Hospital Foundation, Perth, Western Australia, Australia. The PREDICT network is supported as a Centre of Research Excellence for Paediatric Emergency Medicine by the National Health and Medical Research Council, Canberra, Australian Capital Territory, Australia (NHMRC GNT1058560). The Victorian sites were supported by the Victorian Government’s Infrastructure Support Program, Melbourne, Victoria, Australia. FEB’s time was part funded by a grant from the Murdoch Childrens Research Institute and the Royal Children’s Hospital Foundation, Melbourne, Victoria, Australia. SRD’s time was part funded by the Health Research Council of New Zealand (HRC13/556). The study sponsor is Starship Children’s Health, Private Bag 92,024, Auckland 1142, New Zealan

First histological observations on the incorporation of a novel nanocrystalline hydroxyapatite paste OSTIM(® )in human cancellous bone

BACKGROUND: A commercially available nanocrystalline hydroxyapatite paste Ostim(® )has been reported in few recent studies to surpass other synthetic bone substitutes with respect to the observed clinical results. However, the integration of this implantable material has been histologically evaluated only in animal experimental models up to now. This study aimed to evaluate the tissue incorporation of Ostim(® )in human cancellous bone after reconstructive bone surgery for trauma. METHODS: Biopsy specimens from 6 adult patients with a total of 7 tibial, calcaneal or distal radial fractures were obtained at the time of osteosynthesis removal. The median interval from initial operation to tissue sampling was 13 (range 3–15) months. Samples were stained with Masson-Goldner, von Kossa, and toluidine blue. Osteoid volume, trabecular width and bone volume, and cortical porosity were analyzed. Samples were immunolabeled with antibodies against CD68, CD56 and human prolyl 4-hydroxylase to detect macrophages, osteoblasts, and fibroblasts, respectively. TRAP stainings were used to identify osteoclasts. RESULTS: Histomorphometric data indicated good regeneration with normal bone turnover: mean osteoid volume was 1.93% of the trabecular bone mass, trabecular bone volume – 28.4%, trabecular width – 225.12 μm, and porosity index – 2.6%. Cortical and spongious bone tissue were well structured. Neither inflammatory reaction, nor osteofibrosis or osteonecrosis were observed. The implanted material was widely absorbed. CONCLUSION: The studied nanocrystalline hydroxyapatite paste showed good tissue incorporation. It is highly biocompatible and appears to be a suitable bone substitute for juxtaarticular comminuted fractures in combination with a stable screw-plate osteosynthesis

Neuroinflammation, Mast Cells, and Glia: Dangerous Liaisons

The perspective of neuroinflammation as an epiphenomenon following neuron damage is being replaced by the awareness of glia and their importance in neural functions and disorders. Systemic inflammation generates signals that communicate with the brain and leads to changes in metabolism and behavior, with microglia assuming a pro-inflammatory phenotype. Identification of potential peripheral-to-central cellular links is thus a critical step in designing effective therapeutics. Mast cells may fulfill such a role. These resident immune cells are found close to and within peripheral nerves and in brain parenchyma/meninges, where they exercise a key role in orchestrating the inflammatory process from initiation through chronic activation. Mast cells and glia engage in crosstalk that contributes to accelerate disease progression; such interactions become exaggerated with aging and increased cell sensitivity to stress. Emerging evidence for oligodendrocytes, independent of myelin and support of axonal integrity, points to their having strong immune functions, innate immune receptor expression, and production/response to chemokines and cytokines that modulate immune responses in the central nervous system while engaging in crosstalk with microglia and astrocytes. In this review, we summarize the findings related to our understanding of the biology and cellular signaling mechanisms of neuroinflammation, with emphasis on mast cell-glia interactions

The progress of early phase bone healing using porous granules produced from calcium phosphate cement

<p>Abstract</p> <p>Objective</p> <p>Bone grafting is a vital component in many surgical procedures to facilitate the repair of bone defects or fusions. Autologous bone has been the gold standard to date in spite of associated donor-site morbidity and the limited amount of available donor bone. The aim of this study was to investigate the progress of bone regeneration and material degradation of calcium phosphate granules (CPG) produced from a calcium phosphate self-setting cement powder compared to the use of autologous bone grafting in the treatment of "critical size defects" on load-bearing long bones of minipigs.</p> <p>Methods</p> <p>A critical size defect in the tibial metaphysis of 16 mini-pigs was filled either with autologous cancellous graft or with micro- and macroporous carbonated, apatic calcium phosphate granules (CPG) produced from a calcium phosphate self-setting cement powder. After 6 weeks, the specimens were assessed by X-ray and histological evaluation. The amount of new bone formation was analysed histomorphometrically.</p> <p>Results</p> <p>The semi-quantitative analysis of the radiological results showed a complete osseous bridging of the defect in three cases for the autograft group. In the same group five animals showed a beginning, but still incomplete bridging of the defect, whereas in the CPG group just two animals developed this. All other animals of the CPG group showed only a still discontinuous new bone formation. Altogether, radiologically a better osseous bridging was observed in the autograft group compared to the CPG group.</p> <p>Histomorphometrical analysis after six weeks of healing revealed that the area of new bone was significantly greater in the autograft group concerning the central area of the defect zone (p < 0.001) as well as the cortical defect zone (p < 0.002). All defects showed new bone formation, but only in the autograft group defects regenerated entirely</p> <p>Conclusions</p> <p>Within the limits of the present study it could be demonstrated that autologous cancellous grafts lead to a significantly better bone regeneration compared to the application of calcium phosphate granules (CPG) produced from a calcium phosphate self-setting cement powder after 6 weeks. In the early phase of bone-healing, the sole application of CPG appears to be inferior to the autologous cancellous grafts in an <it>in vivo </it>critical size defect on load-bearing long bones of mini-pigs.</p

Performance of two head injury decision rules evaluated on an external cohort of 18,913 children

The Pediatric Emergency Care Applied Research Network (PECARN) decision rule demonstrates high sensitivity for identifying children at low risk for clinically important traumatic brain injury (ciTBI). As with the PECARN rule, the Israeli Decision Algorithm for Identifying TBI in Children (IDITBIC) recommends proceeding directly to computed tomography (CT) in children with Glasgow Coma Score (GCS) lower than 15. The aim was to assess the diagnostic accuracy of two clinical rules that assign children with GCS lower than 15 at presentation directly to CT

External validation of the Scandinavian guidelines for management of minimal, mild and moderate head injuries in children

© 2018 The Author(s). Background: Clinical decision rules (CDRs) aid in the management of children with traumatic brain injury (TBI). Recently, the Scandinavian Neurotrauma Committee (SNC) has published practical, evidence-based guidelines for children with Glasgow Coma Scale (GCS) scores of 9-15. This study aims to validate these guidelines and to compare them with other CDRs. Methods: A large prospective cohort of children (< 18 years) with TBI of all severities, from ten Australian and New Zealand hospitals, was used to assess the SNC guidelines. Firstly, a validation study was performed according to the inclusion and exclusion criteria of the SNC guideline. Secondly, we compared the accuracy of SNC, CATCH, CHALICE and PECARN CDRs in patients with GCS 13-15 only. Diagnostic accuracy was calculated for outcome measures of need for neurosurgery, clinically important TBI (ciTBI) and brain injury on CT. Results: The SNC guideline could be applied to 19,007/20,137 of patients (94.4%) in the validation process. The frequency of ciTBI decreased significantly with stratification by decreasing risk according to the SNC guideline. Sensitivities for the detection of neurosurgery, ciTBI and brain injury on CT were 100.0% (95% CI 89.1-100.0; 32/32), 97.8% (94.5-99.4; 179/183) and 95% (95% CI 91.6-97.2; 262/276), respectively, with a CT/admission rate of 42% (mandatory CT rate of 5%, 18% CT or admission and 19% only admission). Four patients with ciTBI were missed; none needed specific intervention. In the homogenous comparison cohort of 18,913 children, the SNC guideline performed similar to the PECARN CDR, when compared with the other CDRs. Conclusion: The SNC guideline showed a high accuracy in a large external validation cohort and compares well with published CDRs for the management of paediatric TBI

A prospective observational study to assess the diagnostic accuracy of clinical decision rules for children presenting to emergency departments after head injuries (protocol): The Australasian Paediatric Head Injury Rules Study (APHIRST)

Background: Head injuries in children are responsible for a large number of emergency department visits. Failure to identify a clinically significant intracranial injury in a timely fashion may result in long term neurodisability and death. Whilst cranial computed tomography (CT) provides rapid and definitive identification of intracranial injuries, it is resource intensive and associated with radiation induced cancer. Evidence based head injury clinical decision rules have been derived to aid physicians in identifying patients at risk of having a clinically significant intracranial injury. Three rules have been identified as being of high quality and accuracy: the Canadian Assessment of Tomography for Childhood Head Injury (CATCH) from Canada, the Children's Head Injury Algorithm for the Prediction of Important Clinical Events (CHALICE) from the UK, and the prediction rule for the identification of children at very low risk of clinically important traumatic brain injury developed by the Pediatric Emergency Care Applied Research Network (PECARN) from the USA. This study aims to prospectively validate and compare the performance accuracy of these three clinical decision rules when applied outside the derivation setting.Methods/design: This study is a prospective observational study of children aged 0 to less than 18 years presenting to 10 emergency departments within the Paediatric Research in Emergency Departments International Collaborative (PREDICT) research network in Australia and New Zealand after head injuries of any severity. Predictor variables identified in CATCH, CHALICE and PECARN clinical decision rules will be collected. Patients will be managed as per the treating clinicians at the participating hospitals. All patients not undergoing cranial CT will receive a follow up call 14 to 90 days after the injury. Outcome data collected will include results of cranial CTs (if performed) and details of admission, intubation, neurosurgery and death. The performance accuracy of each of the rules will be assessed using rule specific outcomes and inclusion and exclusion criteria.Discussion: This study will allow the simultaneous comparative application and validation of three major paediatric head injury clinical decision rules outside their derivation setting.Trial registration: The study is registered with the Australian New Zealand Clinical Trials Registry (ANZCTR)- ACTRN12614000463673 (registered 2 May 2014). © 2014 Babl et al.; licensee BioMed Central Ltd