Effect of accel, sucrose and silver thiosulphate on substrate utilization in cut tuberose (Polianthes tuberosa L.) flowers

This study was undertaken to investigate the effect of Accel™, sucrose and silver thiosulphate (STS) on the dry weight, accumulation of sucrose and reducing sugars in cut tuberose (Polianthes tuberosa L) petals at various positions along the spike. Cut stems of Tuberose were held in optimum treatments that prolonged their vase life (Hutchinson et al., 2003): continuous holding in 25 mg/L BA equivalent of Accel; pulsing in 20% sucrose for 24 hrs and subsequently holding in either deionized water (DIW) or in 25 mg/L BA; pulsing in 2 mM STS for 1 hr and subsequent holding in DIW. The middle and bottom florets of cut flowers held in DIW were heavier than the top florets. Pulsing tuberose cut flowers in sucrose or in STS improved the dry weights of the middle and bottom florets in the 1st 3 days but up to 6 days of top florets. Florets of cut flowers pulsed in sucrose and subsequently held in Accel were heavier than those subsequently held in DIW or those held continuously in Accel. Sucrose, STS and Accel increased floret opening but had varied influence on the accumulation of sucrose and reducing sugars in petals of florets along the spike. Cut tuberose stems pulsed in sucrose and subsequently held in either DIW or 25 mg/L BA equivalent of Accel accumulated the largest amounts of sucrose and reducing sugars. Pulsing cut tuberose flowers in 10% sucrose and subsequently holding them in Accel or DIW or pulsing in STS, while having no influence on sucrose levels in bottom florets, significantly increased levels in top florets for the 1st 3 days before a sharp decline in petals pulsed in sucrose. The main difference was that while most of the sucrose accumulated in the middle florets, reducing sugars was concentrated on the bottom florets along the spike. Unexpectedly, pulsing stems in STS or holding them in Accel had no significant influence on levels of sucrose or reducing sugars within the 9 days of testing even though most florets had opened by this time. The results of the present study suggest that while sucrose had a direct influence on accumulating of sucrose and reducing sugars in florets, Accel and STS improved vase life and floret opening in cut tuberose stems either indirectly through substrate mobilization and increased metabolism or may have played another different role other than substrate mobilization

Risk Adjustment In Neurocritical care (RAIN)--prospective validation of risk prediction models for adult patients with acute traumatic brain injury to use to evaluate the optimum location and comparative costs of neurocritical care: a cohort study.

OBJECTIVES: To validate risk prediction models for acute traumatic brain injury (TBI) and to use the best model to evaluate the optimum location and comparative costs of neurocritical care in the NHS. DESIGN: Cohort study. SETTING: Sixty-seven adult critical care units. PARTICIPANTS: Adult patients admitted to critical care following actual/suspected TBI with a Glasgow Coma Scale (GCS) score of < 15. INTERVENTIONS: Critical care delivered in a dedicated neurocritical care unit, a combined neuro/general critical care unit within a neuroscience centre or a general critical care unit outside a neuroscience centre. MAIN OUTCOME MEASURES: Mortality, Glasgow Outcome Scale - Extended (GOSE) questionnaire and European Quality of Life-5 Dimensions, 3-level version (EQ-5D-3L) questionnaire at 6 months following TBI. RESULTS: The final Risk Adjustment In Neurocritical care (RAIN) study data set contained 3626 admissions. After exclusions, 3210 patients with acute TBI were included. Overall follow-up rate at 6 months was 81%. Of 3210 patients, 101 (3.1%) had no GCS score recorded and 134 (4.2%) had a last pre-sedation GCS score of 15, resulting in 2975 patients for analysis. The most common causes of TBI were road traffic accidents (RTAs) (33%), falls (47%) and assault (12%). Patients were predominantly young (mean age 45 years overall) and male (76% overall). Six-month mortality was 22% for RTAs, 32% for falls and 17% for assault. Of survivors at 6 months with a known GOSE category, 44% had severe disability, 30% moderate disability and 26% made a good recovery. Overall, 61% of patients with known outcome had an unfavourable outcome (death or severe disability) at 6 months. Between 35% and 70% of survivors reported problems across the five domains of the EQ-5D-3L. Of the 10 risk models selected for validation, the best discrimination overall was from the International Mission for Prognosis and Analysis of Clinical Trials in TBI Lab model (IMPACT) (c-index 0.779 for mortality, 0.713 for unfavourable outcome). The model was well calibrated for 6-month mortality but substantially underpredicted the risk of unfavourable outcome at 6 months. Baseline patient characteristics were similar between dedicated neurocritical care units and combined neuro/general critical care units. In lifetime cost-effectiveness analysis, dedicated neurocritical care units had higher mean lifetime quality-adjusted life-years (QALYs) at small additional mean costs with an incremental cost-effectiveness ratio (ICER) of £14,000 per QALY and incremental net monetary benefit (INB) of £17,000. The cost-effectiveness acceptability curve suggested that the probability that dedicated compared with combined neurocritical care units are cost-effective is around 60%. There were substantial differences in case mix between the 'early' (within 18 hours of presentation) and 'no or late' (after 24 hours) transfer groups. After adjustment, the 'early' transfer group reported higher lifetime QALYs at an additional cost with an ICER of £11,000 and INB of £17,000. CONCLUSIONS: The risk models demonstrated sufficient statistical performance to support their use in research but fell below the level required to guide individual patient decision-making. The results suggest that management in a dedicated neurocritical care unit may be cost-effective compared with a combined neuro/general critical care unit (although there is considerable statistical uncertainty) and support current recommendations that all patients with severe TBI would benefit from transfer to a neurosciences centre, regardless of the need for surgery. We recommend further research to improve risk prediction models; consider alternative approaches for handling unobserved confounding; better understand long-term outcomes and alternative pathways of care; and explore equity of access to postcritical care support for patients following acute TBI. FUNDING: The National Institute for Health Research Health Technology Assessment programme

Survival with disability. Whose life is it, anyway?

Editor—We read with interest the editorial by Dr Lönnqvist entitled “Medical Research and the Ethics of Medical Treatments: Disability-free Survival”.1 The editorial refers to our study, RESCUEicp, that interrogated the effect of secondary decompressive craniectomy in traumatic brain injury (TBI) patients with refractory intracranial hypertension.2 The editorial states ‘the conclusion to draw is instead that, despite reducing overall mortality, surgery is not associated with any true long-term benefits in this setting; it only increases the number of patients in a vegetative state or suffering serious disability, and should therefore not be used’. We have major concerns about this statement with reference to our study, and with the wider premise that underpins the editorial, and we will address each of these in turn.The RESCUEicp and RESCUE-ASDH projects were funded by the National Institute for Health Research (NIHR; EME 09/800/16 and HTA 12/35/57 respectively)

Are we ready for Optimal CPP-oriented management of TBI patients?

Objective: Monitoring cerebral autoregulation (CA) is important for TBI patients, 1 as impaired CA correlates with poor outcome. 2 3 Today, automated algorithms allow to assess CPP for which autoregulation is best preserved (CPPopt) continuously and present it at the bedside 5 6 . Individualising CPP treatment using CPPopt is attractive and this has been recognised in published guidelines. However there are no specifications for its use clinically and it has therefore never been prospectively evaluated 1 . Numerous logistic, technical, feasibility and safety questions remain before the idea of selecting individual CPP treatment targets based on the state of CA 4 can be incorporated into clinical practice. How far are we from strict guidelines on the incorporation of this methodology into TBI protocols? Design: Literature review Subjects: Methods: Systematic review Results: The feasibility of CPPot-guided therapy has only been evaluated retrospectively and in non-clinical ways, whereas no studies exist on its safety. A prospective investigation of CPPopt-guided therapy has been initiated with ‘CppOpt Guided Therapy: Assessment of Target Effectiveness’ (COGiTATE), a multicenter randomized trial assessing feasibility and safety of a continuous CA monitoring-based therapy in adult TBI patients. Conclusions: COGiTATE seems to be the first step to define the physiological effect of targeting CPPopt and should pave the way toward establishing the exact protocol of CPPopt-oriented therapy and the phase III study. References: 1. Carney N, Totten AM, OʼReilly C, et al. Guidelines for the Management of Severe Traumatic Brain Injury, Fourth Edition. Neurosurgery. 2016;80(1):1. doi:10.1227/NEU.0000000000001432. 2. Hlatky R, Furuya Y, Valadka AB, et al. Dynamic autoregulatory response after severe head injury. J Neurosurg. 2002;97(5):1054-1061. doi:10.3171/jns.2002.97.5.1054. 3. Czosnyka M, Czosnyka Z, Smielewski P. Pressure reactivity index: journey through the past 20 years. doi:10.1007/s00701-017-3310-1. 4. Steiner LA, Czosnyka M, Piechnik SK, et al. Continuous monitoring of cerebrovascular pressure reactivity allows determination of optimal cerebral perfusion pressure in patients with traumatic brain injury. Crit Care Med. 2002;30(4):733-738. http://www.ncbi.nlm.nih.gov/pubmed/11940737. Accessed December 28, 2017. 5. Aries MJH, Czosnyka M, Budohoski KP, et al. Continuous determination of optimal cerebral perfusion pressure in traumatic brain injury*. Crit Care Med. 2012. doi:10.1097/CCM.0b013e3182514eb6. 6. Liu X, Maurits NM, Aries MJH, et al. Monitoring of Optimal Cerebral Perfusion Pressure in Traumatic Brain Injured Patients Using a Multi-Window Weighting Algorithm. J Neurotrauma. 2017;34(22):3081-3088. doi:10.1089/neu.2017.5003. 7. Depreitere B, Güiza F, Berghe G Van Den, et al. Pressure autoregulation monitoring and cerebral perfusion pressure target recommendation in patients with severe traumatic brain injury based on minute-by-minute monitoring data. J Neurosurg. 2014;120(120):1451-1457. doi:10.3171/2014.3.JNS131500. 8. Güiza F, Meyfroidt G, Piper I, et al. Cerebral Perfusion Pressure Insults and Associations with Outcome in Adult Traumatic Brain Injury. doi:10.1089/neu.2016.4807. 9. Oshorov A V, Savin IA, Goriachev AS, Popugaev KA, Potapov AA, Gavrilov AG. [The first experience in monitoring the cerebral vascular autoregulation in the acute period of severe brain injury]. Anesteziol Reanimatol. (2):61-64. http://www.ncbi.nlm.nih.gov/pubmed/18540464. Accessed January 1, 2018. 10. Donnelly J, Czosnyka M, Adams H, et al. Individualizing Thresholds of Cerebral Perfusion Pressure Using Estimated Limits of Autoregulation. Crit Care Med. 2017;45(9):1464-1471. doi:10.1097/CCM.0000000000002575. 11. Dias C, Silva MJ, Pereira E, et al. Optimal Cerebral Perfusion Pressure Management at Bedside: A Single-Center Pilot Study. Neurocrit Care. 2015;23(1):92-102. doi:10.1007/s12028-014-0103-8. 12. Jaeger M, Dengl M, J&#252, Schuhmann MU. Effects of cerebrovascular pressure reactivity-guided optimization of cerebral perfusion pressure on brain tissue oxygenation after traumatic brain injury*. Crit Care Med. 2010;38(5):1343-1347. doi:10.1097/ccm.0b013e3181d45530

Cerebrospinal Fluid and Microdialysis Cytokines in Severe Traumatic Brain Injury: A Scoping Systematic Review.

OBJECTIVE: To perform two scoping systematic reviews of the literature on cytokine measurement in: 1. cerebral microdialysis (CMD) and 2. cerebrospinal fluid (CSF) in severe traumatic brain injury (TBI) patients. METHODS: Two separate systematic reviews were conducted: one for CMD cytokines and the second for CSF cytokines. Both were conducted in severe TBI (sTBI) patients only. DATA SOURCES: Articles from MEDLINE, BIOSIS, EMBASE, Global Health, Scopus, Cochrane Library (inception to October 2016), reference lists of relevant articles, and gray literature were searched. STUDY SELECTION: Two reviewers independently identified all manuscripts utilizing predefined inclusion/exclusion criteria. A two-tier filter of references was conducted. DATA EXTRACTION: Patient demographic and study data were extracted to tables. RESULTS: There were 19 studies identified describing the analysis of cytokines via CMD in 267 sTBI patients. Similarly, there were 32 studies identified describing the analysis of CSF cytokines in 1,363 sTBI patients. The two systematic reviews demonstrated: 1. limited literature available on CMD cytokine measurement in sTBI, with some preliminary data supporting feasibility of measurement and associations between cytokines and patient outcome. 2. Various CSF measured cytokines may be associated with patient outcome at 6-12 months, including interleukin (IL)-1b, IL-1ra, IL-6, IL-8, IL-10, and tumor necrosis factor 3. There is little to no literature in support of an association between CSF cytokines and neurophysiologic or tissue outcomes. CONCLUSION: The evaluation of CMD and CSF cytokines is an emerging area of the literature in sTBI. Further, large prospective multicenter studies on cytokines in CMD and CSF need to be conducted.This work was made possible through salary support through: the Cambridge Commonwealth Trust Scholarship, the Royal College of Surgeons of Canada—Harry S. Morton Traveling Fellowship in Surgery, the University of Manitoba Clinician Investigator Program, R. Samuel McLaughlin Research and Education Award, the Manitoba Medical Service Foundation, and the University of Manitoba Faculty of Medicine Dean’s Fellowship Fund. These studies were supported by National Institute for Healthcare Research (NIHR, UK) through the Acute Brain Injury and Repair theme of the Cambridge NIHR Biomedical Research Center, an NIHR Senior Investigator Award to DM, and an NIHR Research Professorship to PH. Authors were also supported by a European Union Framework Program 7 grant (CENTER-TBI; Grant Agreement No. 602150). ET has received funding support from Swedish Society of Medicine (Grant no. SLS-587221). AH is supported by an MRC Studentship for Neuro-inflammation following Human Traumatic Brain injury (G0802251)

Cerebrospinal fluid and microdialysis cytokines in aneurysmal subarachnoid hemorrhage: A scoping systematic review

Objective: To perform two scoping systematic reviews of the literature on cytokine measurement in cerebral microdialysis (CMD) and cerebrospinal fluid (CSF) in aneurysmal subarachnoid hemorrhage (SAH) patients, aiming to summarize the evidence relating cytokine levels to pathophysiology, disease progression, and outcome. Methods: Two separate systematic reviews were conducted: one for CMD cytokines and the second for CSF cytokines. Data sources: Articles from MEDLINE, BIOSIS, EMBASE, Global Health, Scopus, Cochrane Library (inception to October 2016), reference lists of relevant articles, and gray literature were searched. Study selection: Two reviewers independently identified all manuscripts utilizing predefined inclusion/exclusion criteria. A two-tier filter of references was conducted. Data extraction: Patient demographic and study data were extracted to tables. Results: There were 9 studies identified describing the analysis of cytokines via CMD in 246 aneurysmal SAH patients. Similarly, 20 studies were identified describing the analysis of CSF cytokines in 630 patients. The two scoping systematic reviews demonstrated the following: (1) limited literature available on CMD cytokine measurement in aneurysmal SAH with some preliminary data supporting feasibility of measurement and potential association between interleukin (IL)-6 and patient outcome. (2) Various CSF measured cytokines may be associated with patient outcome at 3-6 months, including IL-1ra, IL-6, IL-8, and tumor necrosis factor-alpha. (3) There is a small literature body supporting an association between acute/subacute CSF transforming growth factor levels and the development of chronic hydrocephalus at 2-3 months. Conclusion: The evaluation of CMD and CSF cytokines is an emerging area of the literature in aneurysmal SAH. Further large prospective multicenter studies on cytokines in CMD and CSF need to be conducted.This work was made possible through salary support through the Cambridge Commonwealth Trust Scholarship, the Royal College of Surgeons of Canada—Harry S. Morton Travelling Fellowship in Surgery, the University of Manitoba Clinician Investigator Program, R. Samuel McLaughlin Research and Education Award, the Manitoba Medical Service Foundation, and the University of Manitoba Faculty of Medicine Dean’s Fellowship Fund. ET has received funding support from Swedish Society of Medicine (grant no. SLS-587221). AH receives support from the Medical Research Council (MRC) (Studentship for Neuro-inflammation following Human Traumatic Brain Injury - G0802251), Cambridge Biomedical Research Centre, and Royal College of Surgeons of England. These studies were supported by National Institute for Healthcare Research (NIHR, UK) through the Acute Brain Injury and Repair theme of the Cambridge NIHR Biomedical Research Centre, an NIHR Senior Investigator Award to DKM, and an NIHR Research Professorship to PH. Authors were also supported by a European Union Framework Program 7 grant (CENTER-TBI; grant agreement no. 602150). PH receives support from the National Institute of Health Research, Cambridge Biomedical Research Centre

An evaluation of the clinical and cost-effectiveness of alternative care locations for critically ill adult patients with acute traumatic brain injury.

BACKGROUND: For critically ill adult patients with acute traumatic brain injury (TBI), we assessed the clinical and cost-effectiveness of: (a) Management in dedicated neurocritical care units versus combined neuro/general critical care units within neuroscience centres. (b) 'Early' transfer to a neuroscience centre versus 'no or late' transfer for those who present at a non-neuroscience centre. METHODS: The Risk Adjustment In Neurocritical care (RAIN) Study included prospective admissions following acute TBI to 67 UK adult critical care units during 2009-11. Data were collected on baseline case-mix, mortality, resource use, and at six months, Glasgow Outcome Scale Extended (GOSE), and quality of life (QOL) (EuroQol 5D-3L). We report incremental effectiveness, costs and cost per Quality-Adjusted Life Year (QALY) of the alternative care locations, adjusting for baseline differences with validated risk prediction models. We tested the robustness of results in sensitivity analyses. FINDINGS: Dedicated neurocritical care unit patients (N = 1324) had similar six-month mortality, higher QOL (mean gain 0.048, 95% CI -0.002 to 0.099) and increased average costs compared with those managed in combined neuro/general units (N = 1341), with a lifetime cost per QALY gained of £14,000. 'Early' transfer to a neuroscience centre (N = 584) was associated with lower mortality (odds ratio 0.52, 0.34-0.80), higher QOL for survivors (mean gain 0.13, 0.032-0.225), but positive incremental costs (£15,001, £11,123 to £18,880) compared with 'late or no transfer' (N = 263). The lifetime cost per QALY gained for 'early' transfer was £11,000. CONCLUSIONS: For critically ill adult patients with acute TBI, within neuroscience centres management in dedicated neurocritical care units versus combined neuro/general units led to improved QoL and higher costs, on average, but these differences were not statistically significant. This study finds that 'early' transfer to a neuroscience centre is associated with reduced mortality, improvement in QOL and is cost-effective

Temporal profile of intracranial pressure and cerebrovascular reactivity in severe traumatic brain injury and association with fatal outcome: An observational study

BACKGROUND: Both intracranial pressure (ICP) and the cerebrovascular pressure reactivity represent the dysregulation of pathways directly involved in traumatic brain injury (TBI) pathogenesis and have been used to inform clinical management. However, how these parameters evolve over time following injury and whether this evolution has any prognostic importance have not been studied. METHODS AND FINDINGS: We analysed the temporal profile of ICP and pressure reactivity index (PRx), examined their relation to TBI-specific mortality, and determined if the prognostic relevance of these parameters was affected by their temporal profile using mixed models for repeated measures of ICP and PRx for the first 240 hours from the time of injury. A total of 601 adults with TBI, admitted between September 2002 to January 2016, and with high-resolution continuous monitoring from a single centre, were studied. At 6 months postinjury, 133 (19%) patients had a fatal outcome; of those, 88 (78%) died from nonsurvivable TBI or brain death. The difference in mean ICP between those with a fatal outcome and functional survivors was only significant for the first 168 hours after injury (all p < 0.05). For PRx, those patients with a fatal outcome also had a higher (more impaired) PRx throughout the first 120 hours after injury (all p < 0.05). The separation of ICP and PRx was greatest in the first 72 hours after injury. Mixed models demonstrated that the explanatory power of the PRx decreases over time; therefore, the prognostic weight assigned to PRx should similarly decrease. However, the ability of ICP to predict a fatal outcome remained relatively stable over time. As control of ICP is the central purpose of TBI management, it is likely that some of the information that is reflected in the natural history of ICP changes is no longer apparent because of therapeutic intervention. CONCLUSIONS: We demonstrated the temporal evolution of ICP and PRx and their relationship with fatal outcome, indicating a potential early prognostic and therapeutic window. The combination of dynamic monitoring variables and their time profile improved prediction of outcome. Therefore, time-driven dynamic modelling of outcome in patients with severe TBI may allow for more accurate and clinically useful prediction models. Further research is needed to confirm and expand on these findings.DKM is supported by a Senior Investigator award from the NIHR and a European Union Seventh Framework Program grant (CENTER-TBI; grant no. 602150). PJH is supported by a Research Professorship from the NIHR, the NIHR Cambridge Biomedical Research Centre

Monitoring the Neuroinflammatory Response Following Acute Brain injury

Traumatic brain injury (TBI) and subarachnoid hemorrhage (SAH) are major contributors to morbidity and mortality. Following the initial insult, patients may deteriorate due to secondary brain damage. The underlying molecular and cellular cascades incorporate components of the innate immune system. There are different approaches to assess and monitor cerebral inflammation in the neuro intensive care unit. The aim of this narrative review is to describe techniques to monitor inflammatory activity in patients with TBI and SAH in the acute setting. The analysis of pro- and anti-inflammatory cytokines in compartments of the central nervous system (CNS), including the cerebrospinal fluid and the extracellular fluid, represent the most common approaches to monitor surrogate markers of cerebral inflammatory activity. Each of these compartments has a distinct biology that reflects local processes and the cross-talk between systemic and CNS inflammation. Cytokines have been correlated to outcomes as well as ongoing, secondary injury progression. Alongside the dynamic, focal assay of humoral mediators, imaging, through positron emission tomography, can provide a global in vivo measurement of inflammatory cell activity, which reveals long-lasting processes following the initial injury. Compared to the innate immune system activated acutely after brain injury, the adaptive immune system is likely to play a greater role in the chronic phase as evidenced by T-cell-mediated autoreactivity toward brain-specific proteins. The most difficult aspect of assessing neuroinflammation is to determine whether the processes monitored are harmful or beneficial to the brain as accumulating data indicate a dual role for these inflammatory cascades following injury. In summary, the inflammatory component of the complex injury cascade following brain injury may be monitored using different modalities. Using a multimodal monitoring approach can potentially aid in the development of therapeutics targeting different aspects of the inflammatory cascade and improve the outcome following TBI and SAH