Examining the validity of the Delis-Kaplan Executive Function System (D-KEFS) in traumatic brain injury.

This study examines the validity of the Delis-Kaplan Executive Function System (D-KEFS) in a traumatic brain injury (TBI) population compared to participants with orthopaedic injuries and normative controls. The utility of the D-KEFS was examined using a between groups design. One hundred patients with mild uncomplicated to severe TBI were recruited from a consecutive cohort of patients admitted as inpatients to a UK Major Trauma Centre and compared to 823 participants from the D-KEFS normative sample and 26 participants with orthopaedic injuries. Data were filtered for performance validity. Sample discrimination was calculated from D-KEFS subtest scores and derived index scores. Sensitivity to TBI severity was established. The TBI participants performed significantly lower on the D-KEFS Trail Making Test, Colour Word Interference, Colour Word Switching, Letter Fluency and Verbal Fluency Category Switching Total Words Correct. The D-KEFS index scores discriminated between TBI, orthopaedic and normative participants with large and moderate effect sizes, respectively. The D-KEFS demonstrated a dose-response relationship with TBI severity. These effects were robust to differences in premorbid intellectual functioning; however, D-KEFS performance was sensitive to performance on tests of mental processing speed. The use of a D-KEFS index score provides a robust and reliable discrimination of TBI patients from healthy control participants. This discrimination is not accounted for by premorbid intellect or the non-specific effects of trauma. The clinical and conceptual implications of these findings are considered.

Cognitive Outcome After Complicated Mild Traumatic Brain Injury: A Literature Review and Meta-Analysis.

Cognitive outcome for mild traumatic brain injury (mTBI) with positive brain imaging (complicated mTBI) was compared with that for mTBI with normal imaging (uncomplicated mTBI) and with moderate to severe TBI, using meta-analysis. Twenty-three studies utilizing objective neurocognitive tests were included in the analysis. At less than 3 months post-injury, complicated mTBI was associated with poorer cognitive outcomes than uncomplicated mTBI, but deficits were not comparable to those with moderate-severe TBI. After 3 months post-injury, a similar pattern was detected. Beyond 3 months, deficits in complicated mTBI relative to those with uncomplicated mTBI were present in processing speed, memory, executive function, and language, although the latter may be the result of reduced semantic fluency. The effect size of deficits in these domains was more marked in moderate-severe TBI. The available data support the use of complicated mTBI as a distinct classification in the prediction of cognitive outcome. The extent of cognitive deficit in complicated mTBI was small and unlikely to cause significant disability. However, patients with complicated mTBI constitute a broad category encompassing individuals who may differ markedly in the nature and extent of intracranial imaging abnormality, and further studies are warranted. Limitations of the available studies include small, selected samples; variations in TBI severity classification; absence of validity ("effort") testing; differing imaging methodology; and lack of long-term follow-up.

BRAF Modulates Lipid Use and Accumulation.

There is increasing evidence that oxidative metabolism and fatty acids play an important role in BRAF-driven tumorigenesis, yet the effect of BRAF mutation and expression on metabolism is poorly understood. We examined how BRAF mutation and expression modulates metabolite abundance. Using the non-transformed NIH3T3 cell line, we generated cells that stably overexpressed BRAF V600E or BRAF WT. We found that cells expressing BRAF V600E were enriched with immunomodulatory lipids. Further, we found a unique transcriptional signature that was exclusive to BRAF V600E expression. We also report that BRAF V600E mutation promoted accumulation of long chain polyunsaturated fatty acids (PUFAs) and rewired metabolic flux for non-Warburg behavior. This cancer promoting mutation further induced the formation of tunneling nanotube (TNT)-like protrusions in NIH3T3 cells that preferentially accumulated lipid droplets. In the plasma of melanoma patients harboring the BRAF V600E mutation, levels of lysophosphatidic acid, sphingomyelin, and long chain fatty acids were significantly increased in the cohort of patients that did not respond to BRAF inhibitor therapy. Our findings show BRAF V600 status plays an important role in regulating immunomodulatory lipid profiles and lipid trafficking, which may inform future therapy across cancers.

An arithmetic correction for the effect of lipid on carbon stable isotope ratios in muscle and digestive glands of the American lobster (Homarus americanus).

RATIONALE: Lipid correction models use elemental carbon-to-nitrogen ratios to estimate the effect of lipids on δ13 C values and provide a fast and inexpensive alternative to chemically removing lipids. However, the performance of these models varies, especially in whole-body invertebrate samples. The generation of tissue-specific lipid correction models for American lobsters, both an ecologically and an economically important species in eastern North America, will aid ecological research of this species and our understanding of the function of these models in invertebrates. METHOD: We determined the δ13 C and δ15 N values before and after lipid extraction in muscle and digestive glands of juvenile and adult lobster. We assessed the performance of four commonly used models (nonlinear, linear, natural logarithm (LN) and generalized linear model (GLM)) at estimating lipid-free δ13 C values based on the non-lipid-extracted δ13 C values and elemental C:N ratios. The accuracy of model predictions was tested using paired t-tests, and the performance of the different models was compared using the Akaike information criterion score. RESULTS: Lipid correction models accurately estimated post-lipid-extraction δ13 C values in both tissues. The nonlinear model was the least accurate for both tissues. In muscle, the three other models performed well, and in digestive glands, the LN model provided the most accurate estimates throughout the range of C:N values. In both tissues, the GLM estimates were not independent of the post-lipid-extraction δ13 C values, thus reducing their transferability to other datasets. CONCLUSIONS: Whereas previous work found that whole-body models poorly estimated the effect of lipids in invertebrates, we show that tissue-specific lipid correction models can generate accurate and precise estimates of lipid-free δ13 C values in lobster. We suggest that the tissue-specific logarithmic models presented here are the preferred models for accounting for the effect of lipid on lobster isotope ratios.

Overcoming Resistance to Therapies Targeting the MAPK Pathway in BRAF-Mutated Tumours.

Overactivation of the mitogen-activated protein kinase (MAPK) pathway is an important driver of many human cancers. First line, FDA-approved therapies targeting MAPK signalling, which include BRAF and MEK inhibitors, have variable success across cancers, and a significant number of patients quickly develop resistance. In recent years, a number of preclinical studies have reported alternative methods of overcoming resistance, which include promoting apoptosis, modulating autophagy, and targeting mitochondrial metabolism. This review summarizes mechanisms of resistance to approved MAPK-targeted therapies in BRAF-mutated cancers and discusses novel preclinical approaches to overcoming resistance.

Intensive care nurses' self-reported practice of intravenous fluid bolus therapy.

OBJECTIVE: To describe self-reported practice of fluid bolus therapy by intensive care nurses. RESEARCH METHODOLOGY: Multi-choice questionnaire of intensive care nurses conducted in July, 2014. SETTING: Major university tertiary referral centre. FINDINGS: 141 (64%) intensive care nurses responded. The majority of respondents identified 4% albumin as the commonest fluid bolus type and stated a fluid bolus was 250ml; however fluid bolus volume varied from 100ml to 1000ml. Hypotension was identified as the primary physiological trigger for a fluid bolus. In the hour following a fluid bolus for hypotension almost half of respondents expected an 'increase in mean arterial pressure of 0-10mmHg'; for oliguria, >60% expected an 'increase in urinary output of '0.5-1ml/kg/hour'; for low CVP, 50% expected 'an increase in CVP of 3-4mmHg'; and, for tachycardia, 45% expected a 'decrease in heart rate of 11-20beats/minute'. Finally, 7-10% of respondents were 'unsure' about the physiological response to a fluid bolus. CONCLUSION: Most respondents identified fluid bolus therapy to be at least 250ml of 4% albumin given as quickly as possible; however, volumes from 100 to 1000ml were also accepted. There was much uncertainty about the expected physiological response to fluid bolus therapy according to indication.

Plasma exchange in the intensive care unit: a 10 year retrospective audit.

BACKGROUND AND AIMS: Plasma exchange (PE) is a therapeutic technique for the removal of illness-associated antibodies and toxins. Little is currently known about the prescription and technique for PE in the Intensive Care setting. In addition, different illnesses require specific PE regimens to optimise the clinical outcome for the patient. We sought to audit our use of PE for: number of treatments, clinical indications, treatments prescribed and administered, any procedural or patient complications, and adherence to current best practice recommendations. METHOD: A retrospective audit involving all patients who were admitted to our tertiary 20 bed Intensive Care Unit (ICU) and received PE therapy between 1 January 2002 and 31 December 2011. Data was collected from identified patient medical records using a specifically designed case report form. RESULTS: Thirty unique patients were identified in this audit. There was an incidence of 0.15% use of PE during this period. Eighteen female patients (60%) were indentified, median age 59.5 (48-70) years. These 30 patients were prescribed 135 PE treatments, requiring 156 membranes in total with a 15.5% incidence of premature circuit clotting. Thrombotic Thrombocytopenic Purpura (TTP) was the most common indication for PE (37%) with 10 other clinical indications. Median length of ICU admission was 9.5 (3-17) days. The PE regimens received by patients in this ICU were not always prescribed in accordance with current best practice recommendations. No patient complications were identified with these PE treatments. CONCLUSION: PE is a valuable treatment option for critically ill patients suffering antibody-mediated illness. The findings of this audit have identified differences between the current prescription recommendations for PE and those applied. TTP was the most common indication for PE, and no patient complications were identified, however a 15.5% incidence of circuit clotting occurred. The infrequency of the therapy and the different indications present a challenge for Intensive Care clinicians to provide best care in all cases. Improving the prescription of PE through the implementation of a new protocol and clinical education may result in better outcomes for our patients.