Comparison of injury patterns and interventions between adolescent, adult and paediatric trauma cases: a cross-sectional review of TARN data.

OBJECTIVES: The aim is to compare adolescent (10-24.99 years) trauma patterns and interventions to adult (≥25) and paediatric cases (<10) and to identify any transition points. DESIGN AND SETTING: Data were collected from the Trauma and Audit Research Network (TARN) over a 10-year period. We conducted a retrospective cross-sectional analysis. PARTICIPANTS: After exclusions there were 505 162 TARN eligible cases. PRIMARY AND SECONDARY OUTCOME MEASURES: To compare adolescent trauma patterns and interventions to those in paediatric and adult cohorts. Identify transition points for mechanism of injury (MOI) and interventions by individual year over the adolescent age range (10-24.99). RESULTS: Road traffic accidents are the most common MOI in the adolescent group, in contrast to both the paediatric and adult group where falls <2 m are most common. Violence-related injury (shootings and stabbings) are more common in the adolescent group, 9.4% compared with 0.3% and 1.5% in the paediatric and adult groups, respectively. The adolescent grouping had the highest median Injury Severity Score (ISS) and the highest proportion of interventions. The proportion of cases due to stabbing peaked at age 17 (11.8%) becoming the second most common MOI. The median ISS peaked at 13 at age 18. The percentage of cases that fulfil the definition of polytrauma enters double figures (11.8%) at age 15 reaching a peak of 17.6% at age 18. The use of blood products within the first 6 hours remains around 2% (1.6%-2.8%) until age 15 (3.4%), increasing to 4.7% at age 16. CONCLUSIONS: Trauma patterns are more closely aligned between adult and paediatric cohorts than adolescence. The highest proportion of trauma interventions occur in the adolescent population. Analysing the adolescent cohort by year of age identified some common points for when descriptors or outcomes altered in frequency, predominantly between the ages of 15-17 years.

Fifteen-minute consultation: A guide to the paediatric primary survey.

It's 21:00 and you receive a stand-by call from the local ambulance service. Peter, a 9-year-old boy, was riding an electric scooter and has collided with a car. He has reduced consciousness, signs of shock and is hypoxic. How will you prepare your team? What are the possible injuries? Who will perform the primary survey? Injury is the leading cause of morbidity and mortality in the paediatric population accounting for approximately half of all attendances to paediatric emergency departments in the UK and Ireland. Major trauma can be distressing for patients, parents and physicians. Managing major trauma is challenging and it is vital to have a clear and organised approach. In this 15-minute guide we describe a structured approach to the primary survey that includes how to prepare before the child's arrival, the suggested roles of team members and the key components of the primary survey. We discuss life-threatening injuries, the life-saving bundle and the principles of resuscitation, and the role of imaging in the initial assessment of the injured child.

Self-harm and suicide during and after opioid agonist treatment among primary care patients in England: a cohort study.

BACKGROUND: The first 4 weeks after initiation and cessation of opioid agonist treatment for opioid dependence are associated with an increased risk of all-cause mortality and overdose. We aimed to investigate whether the rate of self-harm and suicide among people who were prescribed opioid agonist treatment differs during initiation, cessation, and the remainder of time on and off treatment. METHODS: We did a retrospective cohort study and used health-care records from UK Clinical Practice Research Datalink, linked to mortality and hospital admission data, for adults (age 18-75 years at cohort entry) who were prescribed opioid agonist treatment at least once in primary care in England between Jan 2, 1998, and Nov 30, 2018. We estimated rates and adjusted risk ratios (aRRs) of hospital admissions for self-harm and death by suicide, comparing time during and after treatment, as well as comparing stable periods of time on treatment with treatment initiation, cessation, and the remaining time off treatment. FINDINGS: Between Jan 2, 1998, and Nov 30, 2018, 8070 patients (5594 [69·3%] men and 2476 [30·7%] women) received 17 004 episodes of opioid agonist treatment over 40 599 person-years. Patients were mostly of White ethnicity (7006 [86·8%] patients). 807 episodes of self-harm (1·99 per 100 person-years) and 46 suicides (0·11 per 100 person-years) occurred during the study period. The overall age-standardised and sex-standardised mortality ratio for suicide was 7·5 times (95% CI 5·5-10·0) higher in the study cohort than in the general population. Opioid agonist treatment was associated with a reduced risk of self-harm (aRR in periods off treatment 1·50 [95% CI 1·21-1·88]), but was not significantly associated with suicide risk (aRR in periods off treatment 1·21 [0·64-2·28]). Risk of self-harm (aRR 2·60 [95% CI 1·83-3·70]) and suicide (4·68 [1·63-13·42]) were both elevated in the first 4 weeks after stopping opioid agonist treatment compared with stable periods on treatment. INTERPRETATION: Stable periods of opioid agonist treatment are associated with reduced risk of self-harm, emphasising the importance of improving retention of patients in treatment. The first month following cessation of opioid agonist treatment is a period of increased risk of suicide and self-harm, during which additional psychosocial support is required. FUNDING: Medical Research Council.

Kinetic and structural parameters governing Fic-mediated adenylylation/AMPylation of the Hsp70 chaperone, BiP/GRP78.

Fic (filamentation induced by cAMP) proteins regulate diverse cell signaling events by post-translationally modifying their protein targets, predominantly by the addition of an AMP (adenosine monophosphate). This modification is called Fic-mediated adenylylation or AMPylation. We previously reported that the human Fic protein, HYPE/FicD, is a novel regulator of the unfolded protein response (UPR) that maintains homeostasis in the endoplasmic reticulum (ER) in response to stress from misfolded proteins. Specifically, HYPE regulates UPR by adenylylating the ER chaperone, BiP/GRP78, which serves as a sentinel for UPR activation. Maintaining ER homeostasis is critical for determining cell fate, thus highlighting the importance of the HYPE-BiP interaction. Here, we study the kinetic and structural parameters that determine the HYPE-BiP interaction. By measuring the binding and kinetic efficiencies of HYPE in its activated (Adenylylation-competent) and wild type (de-AMPylation-competent) forms for BiP in its wild type and ATP-bound conformations, we determine that HYPE displays a nearly identical preference for the wild type and ATP-bound forms of BiP in vitro and preferentially de-AMPylates the wild type form of adenylylated BiP. We also show that AMPylation at BiP's Thr366 versus Thr518 sites differentially affect its ATPase activity, and that HYPE does not adenylylate UPR accessory proteins like J-protein ERdJ6. Using molecular docking models, we explain how HYPE is able to adenylylate Thr366 and Thr518 sites in vitro. While a physiological role for AMPylation at both the Thr366 and Thr518 sites has been reported, our molecular docking model supports Thr518 as the structurally preferred modification site. This is the first such analysis of the HYPE-BiP interaction and offers critical insights into substrate specificity and target recognition.

Calcein Release Assay to Measure Membrane Permeabilization by Recombinant Alpha-Synuclein.

Lipid membranes are involved in regulating biochemical and biological processes and in modulating the selective permeability of cells, organelles, and vesicles. Membrane composition, charge, curvature, and fluidity all have concerted effects on cellular signaling and homeostasis. The ability to prepare artificial lipid assemblies that mimic biological membranes has enabled investigators to obtain considerable insight into biomolecule-membrane interactions. Lipid nanoscale assemblies can vary greatly in size and composition and can consist of a single lipid monolayer, a bilayer, or other more complex assemblies. This structural diversity makes liposomes suitable for a wide variety of biochemical and clinical applications. Here, we describe a calcein dye leakage assay that we have developed to monitor phospholipid vesicle disruption by alpha-synuclein (αSyn), a presynaptic protein that plays a central role in Parkinson's disease (PD). We present data showing the effect of adenylylation of αSyn on αSyn-mediated vesicle disruption as an example. This assay can be used to study the effect of mutations or post-translational modifications on αSyn-membrane interactions, to identify protein binding partners or chemical entities that perturb these interactions, and to study the effects of different lipids on the permeabilization activity of αSyn or any other protein.

Research Note: Vocal Attack Time-Extended Analysis.

Normative data for vocal attack time (VAT) have previously been presented, but descriptive statistics and assessments of statistical significance of differences have previously been based on a data corpus that included both negative- and positive-valued VATs. Negative VAT values denote a glottal vocal attack, but, at the present time, the signification of the magnitude of a negative VAT value is unknown. The magnitude of a positive VAT value, on the other hand, conveys useful information about glottal behavior at the time of voice onset and is much more likely to be of use, especially in the clinical domain. We present descriptive statistics for the set of positive-valued VATs and demonstrate that the VAT differences between genders and among tone categories in Cantonese remain valid.

Alpha-Synuclein Is a Target of Fic-Mediated Adenylylation/AMPylation: Possible Implications for Parkinson's Disease.

During disease, cells experience various stresses that manifest as an accumulation of misfolded proteins and eventually lead to cell death. To combat this stress, cells activate a pathway called unfolded protein response that functions to maintain endoplasmic reticulum (ER) homeostasis and determines cell fate. We recently reported a hitherto unknown mechanism of regulating ER stress via a novel post-translational modification called Fic-mediatedadenylylation/AMPylation. Specifically, we showed that the human Fic (filamentation induced by cAMP) protein, HYPE/FicD, catalyzes the addition of an adenosine monophosphate (AMP) to the ER chaperone, BiP, to alter the cell's unfolded protein response-mediated response to misfolded proteins. Here, we report that we have now identified a second target for HYPE-alpha-synuclein (αSyn), a presynaptic protein involved in Parkinson's disease. Aggregated αSyn has been shown to induce ER stress and elicit neurotoxicity in Parkinson's disease models. We show that HYPE adenylylates αSyn and reduces phenotypes associated with αSyn aggregation invitro, suggesting a possible mechanism by which cells cope with αSyn toxicity.

Using [(11)C]Ro15 4513 PET to characterise GABA-benzodiazepine receptors in opiate addiction: Similarities and differences with alcoholism.

The importance of the GABA-benzodiazepine receptor complex and its subtypes are increasingly recognised in addiction. Using the α1/α5 benzodiazepine receptor PET radioligand [(11)C]Ro15 4513, we previously showed reduced binding in the nucleus accumbens and hippocampus in abstinent alcohol dependence. We proposed that reduced [(11)C]Ro15 4513 binding in the nucleus accumbens was a marker of addiction whilst the reduction in hippocampus and positive relationship with memory was a consequence of chronic alcohol abuse. To examine this further we assessed [(11)C]Ro15 4513 binding in another addiction, opiate dependence, and used spectral analysis to estimate contributions of α1 and α5 subtypes to [(11)C]Ro15 4513 binding in opiate and previously acquired alcohol-dependent groups. Opiate substitute maintained opiate-dependent men (n=12) underwent an [(11)C]Ro15 4513 PET scan and compared with matched healthy controls (n=13). We found a significant reduction in [(11)C]Ro15 4513 binding in the nucleus accumbens in the opiate-dependent compared with the healthy control group. There was no relationship between [(11)C]Ro15 4513 binding in the hippocampus with memory. We found that reduced [(11)C]Ro15 4513 binding was associated with reduced α5 but not α1 subtypes in the opiate-dependent group. This was also seen in an alcohol-dependent group where an association between memory performance and [(11)C]Ro15 4513 binding was primarily driven by α5 and not α1 subtype. We suggest that reduced α5 levels in the nucleus accumbens are associated with addiction since we have now shown this in dependence to two pharmacologically different substances, alcohol and opiates.

Zinc is a transmembrane agonist that induces platelet activation in a tyrosine phosphorylation-dependent manner.

Following platelet adhesion and primary activation at sites of vascular injury, secondary platelet activation is induced by soluble platelet agonists, such as ADP, ATP, thrombin and thromboxane. Zinc ions are also released from platelets and damaged cells and have been shown to act as a platelet agonist. However, the mechanism of zinc-induced platelet activation is not well understood. Here we show that exogenous zinc gains access to the platelet cytosol and induces full platelet aggregation that is dependent on platelet protein tyrosine phosphorylation, PKC and integrin αIIbß3 activity and is mediated by granule release and secondary signalling. ZnSO4 increased the binding affinity of GpVI, but not integrin α2ß1. Low concentrations of ZnSO4 potentiated platelet aggregation by collagen-related peptide (CRP-XL), thrombin and adrenaline. Chelation of intracellular zinc reduced platelet aggregation induced by a number of different agonists, inhibited zinc-induced tyrosine phosphorylation and inhibited platelet activation in whole blood under physiologically relevant flow conditions. Our data are consistent with a transmembrane signalling role for zinc in platelet activation during thrombus formation.

Effect of Voice Onset Type on Vocal Attack Time.

Vocal attack time (VAT) is the time lag between the growth of sound pressure (SP) and electroglottographic (EGG) signals at vocal initiation. The characteristics of voice initiation are associated with issues of vocal hygiene, efficiency, and quality. Vocal onsets have commonly been qualitatively characterized into three types: hard, simultaneous, and breathy. This study examines the effect of voice onset type on VAT values in normal speakers. SP and EGG recordings were obtained for 55 female and 57 male subjects while producing multiple tokens of three tasks (sustained /ɑ/ and "always" as unaspirated onsets, and "hallways" as an aspirated onset). Results revealed a significant effect of onset type on VAT, with the mean VAT for the "hallways" (aspirated) task greater than the mean VAT for the sustained /ɑ/ and "always" (unaspirated) tasks. There was no significant VAT difference between the sustained /ɑ/ and "always" tasks. Findings confirm the sensitivity of the VAT measure to vocal onset type and suggest its potential application as an objective and quantitative clinical measure of the type of vocal onset.

Performance of a pilot-scale nitrifying trickling filter treating municipal aerated lagoon effluent.

Colfax, WA, operates an aerated lagoon to achieve compliance with its National Pollutant Discharge Elimination System (NPDES) permit, which currently requires biochemical oxygen demand (BOD) and total suspended solids (TSS) removal. However, ammonia removal may soon be required, and Colfax is considering a nitrifying trickling filter (NTF) that would allow them to also maintain the lagoons. To obtain data from which to ultimately design a full-scale system, a four-year NTF pilot study was performed. Results demonstrated that an NTF would be an effective, reliable NH3 removal method and could produce effluent NH3 concentrations < 1.0 mg/L. NTF performance was characterized by zero- and first-order kinetics; zero-order rates correlated with influent NH3 concentrations and mass load. Utilizing data from these investigations it was determined that the pilot NTF could be reduced by 19%, which demonstrates the value of pilot testing. Finally, pilot data was evaluated to provide a data set that will be useful to engineers designing full-scale NTFs.

Acute increases in synaptic GABA detectable in the living human brain: a [¹¹C]Ro15-4513 PET study.

The inhibitory γ-aminobutyric acid (GABA) neurotransmitter system is associated with the regulation of normal cognitive functions and dysregulation has been reported in a number of neuropsychiatric disorders including anxiety disorders, schizophrenia and addictions. Investigating the role of GABA in both health and disease has been constrained by difficulties in measuring acute changes in synaptic GABA using neurochemical imaging. The aim of this study was to investigate whether acute increases in synaptic GABA are detectable in the living human brain using the inverse agonist GABA-benzodiazepine receptor (GABA-BZR) positron emission tomography (PET) tracer, [(11)C]Ro15-4513. We examined the effect of 15 mg oral tiagabine, which increases synaptic GABA by inhibiting the GAT1 GABA uptake transporter, on [(11)C]Ro15-4513 binding in 12 male participants using a paired, double blind, placebo-controlled protocol. Spectral analysis was used to examine synaptic α1 and extrasynaptic α5 GABA-BZR subtype availability in brain regions with high levels of [(11)C]Ro15-4513 binding. We also examined the test-retest reliability of α1 and a5-specific [(11)C]Ro15-4513 binding in a separate cohort of 4 participants using the same spectral analysis protocol. Tiagabine administration produced significant reductions in hippocampal, parahippocampal, amygdala and anterior cingulate synaptic α1 [(11)C]Ro15-4513 binding, and a trend significance reduction in the nucleus accumbens. These reductions were greater than test-retest reliability, indicating that they are not the result of chance observations. Our results suggest that acute increases in endogenous synaptic GABA are detectable in the living human brain using [(11)C]Ro15-4513 PET. These findings have potentially major implications for the investigation of GABA function in brain disorders and in the development of new treatments targeting this neurotransmitter system.

Investigating expectation and reward in human opioid addiction with [(11) C]raclopride PET.

The rewarding properties of some abused drugs are thought to reside in their ability to increase striatal dopamine levels. Similar increases have been shown in response to expectation of a positive drug effect. The actions of opioid drugs on striatal dopamine release are less well characterized. We examined whether heroin and the expectation of heroin reward increases striatal dopamine levels in human opioid addiction. Ten opioid-dependent participants maintained on either methadone or buprenorphine underwent [(11) C]raclopride positron emission tomography imaging. Opioid-dependent participants were scanned three times, receiving reward from 50-mg intravenous heroin (diamorphine; pharmaceutical heroin) during the first scan to generate expectation of the same reward at the second scan, during which they only received 0.1-mg intravenous heroin. There was no heroin injection during the third scan. Intravenous 50-mg heroin during the first scan induced pronounced effects leading to high levels of expectation at the second scan. There was no detectable increase in striatal dopamine levels to either heroin reward or expectation of reward. We believe this is the first human study to examine whether expectation of heroin reward increases striatal dopamine levels in opioid addiction. The absence of detectable increased dopamine levels to both the expectation and delivery of a heroin-related reward may have been due to the impact of substitute medication. It does however contrast with the changes seen in abstinent stimulant users, suggesting that striatal dopamine release alone may not play such a pivotal role in opioid-maintained individuals.

Effect of fundamental frequency at voice onset on vocal attack time.

OBJECTIVE: To examine vocal attack time (VAT) values associated with the production of low, mid, and high rates of vocal fold vibration in normal speakers. STUDY DESIGN: Sound pressure (SP) and electroglottographic (EGG) recordings were obtained for eight female and five male subjects while producing multiple tokens of the sustained vowels /ɑ/, /i/, and /u/ at comfortable loudness and at mid, low (-3 semitones), and high (+6 semitones) rates of vocal fold vibration. METHODS: Generalized sinusoidal models of the SP and EGG signals were computed to compare rates of amplitude change. VAT was computed from the time lag of the cross-correlation function. RESULTS: Adjusted mean VAT for the high frequency condition was smaller than the adjusted mean VAT values for the low- and mid-frequency conditions. There was no significant difference between the mid and low frequency conditions. CONCLUSIONS: Findings reveal an association of the VAT measure with increases in vocal fold tension associated with the production of high rates of vocal fold vibration.

History of cigarette smoking is associated with higher limbic GABAA receptor availability.

Cigarette smoking presents a significant worldwide healthcare challenge. Preclinical, genetic association and clinical trials studies provide considerable evidence for the involvement of the human γ-aminobutyric acid (GABA) system in the neurobiology of nicotine addiction. However there are few human GABA neurochemical imaging studies of nicotine addiction. We investigated limbic GABA(A) receptor availability in volunteers with a history of cigarette smoking using [(11)C]Ro15 4513 positron emission tomography (PET). Eight [(11)C]Ro15 4513 PET scans from volunteers with a history of cigarette smoking were compared to twelve scans from volunteers who were non-smokers. Total, α1 and α5 GABA(A) receptor subtype [(11)C]Ro15 4513 V(T) values were quantified using spectral analysis of limbic regions implicated in nicotine addiction. Spectral analysis allows quantification of the overall [(11)C]Ro15 4513 spectral frequency as well as α1 and α5 GABA(A) receptor subtype specific spectral frequency components. Volunteers with a history of cigarette smoking showed significantly higher total [(11)C]Ro15 4513 V(T) values in the presubgenual cingulate and parahippocampal gyrus, and at a trend level in the insula, nucleus accumbens and subgenual cingulate. In six abstinent previous smokers ('ex-smokers'), total [(11)C]Ro15 4513 binding was significantly higher in all limbic regions studied, with higher α5 availability in the amygdala, anterior cingulate, nucleus accumbens and presubgenual cingulate. These results suggest that limbic GABA(A) receptor availability is higher in volunteers with a history of cigarette smoking which may reflect either higher expression of GABA(A) receptors or lower endogenous GABA levels. The findings in ex-smokers suggest that higher GABA(A) receptor availability continues with abstinence indicating that this may be a trait marker for nicotine addiction or that alterations in GABA function associated with cigarette smoking persist.

Striatal dopamine D2/D3 receptor binding in pathological gambling is correlated with mood-related impulsivity.

Pathological gambling (PG) is a behavioural addiction associated with elevated impulsivity and suspected dopamine dysregulation. Reduced striatal dopamine D(2)/D(3) receptor availability has been reported in drug addiction, and may constitute a premorbid vulnerability marker for addictive disorders. The aim of the present study was to assess striatal dopamine D(2)/D(3) receptor availability in PG, and its association with trait impulsivity. Males with PG (n=9) and male healthy controls (n=9) underwent [11C]-raclopride positron emission tomography imaging and completed the UPPS-P impulsivity scale. There was no significant difference between groups in striatal dopamine D(2)/D(3) receptor availability, in contrast to previous reports in drug addiction. However, mood-related impulsivity ('Urgency') was negatively correlated with [11C]-raclopride binding potentials in the PG group. The absence of a group difference in striatal dopamine binding implies a distinction between behavioural addictions and drug addictions. Nevertheless, our data indicate heterogeneity in dopamine receptor availability in disordered gambling, such that individuals with high mood-related impulsivity may show differential benefits from dopamine-based medications.

Vocal release time: a quantification of vocal offset.

OBJECTIVE: To determine the vocal release time (VRT) for linguistically unconstrained voice offsets in a healthy young adult population. STUDY DESIGN: Sound pressure (SP) and electroglottographic (EGG) recordings were obtained for 57 female and 55 male subjects while producing multiple tokens of three tasks (sustained /ɑ:/, "always," and "hallways") at comfortable pitch and loudness. METHODS: SP and EGG signals were digitally time reversed and generalized sinusoidal models of the SP and EGG signals were obtained to compare rates of amplitude change. VRT was computed from the time lag of the cross-correlation function. RESULTS: Adjusted mean VRT values were significantly greater for females than for males. There was no systematic effect of age on VRT. However, 25-29-year old and >40 year old females showed shorter VRT values than the youngest female age group. CONCLUSIONS: Normative data are presented for a new measure of the duration of vocal offset, VRT. Acquisition of this measure requires little user intervention, thereby minimizing effects of subjective decision making. Comparison with previously reported vocal attack time (VAT) values for the same population suggests phenomenological differences between linguistically and physiologically constrained voice onsets and unconstrained voice offsets.