Evaluation of the effect of methamphetamine on traumatic injury complications and outcomes.

BACKGROUND: This study investigates the impact of methamphetamine use on trauma patient outcomes. METHODS: This retrospective study analyzed patients between 18 and 55 years old presenting to a single trauma center in San Bernardino County, CA who sustained traumatic injury during the 10-year study period (January 1st, 2005 to December 31st, 2015). Routine serum ethanol levels and urine drug screens (UDS) were completed on all trauma patients. Exclusion criteria included patients with an elevated serum ethanol level (> 0 mg/dL). Those who screened positive on UDS for only methamphetamine and negative for cocaine and cannabis (MA(+)) were compared to those with a triple negative UDS for methamphetamine, cocaine, and cannabis (MA(-)). The primary outcome studied was the impact of a methamphetamine positive drug screen on hospital mortality. Secondary outcomes included length of stay (LOS), heart rate, systolic and diastolic blood pressure (SBP and DBP, respectively), and total amount of blood products utilized during hospitalization. To analyze the effect of methamphetamine, age, gender, injury severity score, and mechanism of injury (blunt vs. penetrating) were matched between MA(-) and MA(+) through a propensity matching algorithm. RESULTS: After exclusion, 2538 patients were included in the final analysis; 449 were patients in the MA(+) group and 2089 patients in the MA(-) group. A selection of 449 MA(-) patients were matched with the MA(+) group based on age, gender, injury severity score, and mechanism of injury. This led to a final sample size of 898 patients with 449 patients in each group. No statistically significant change was observed in hospital mortality. Notably, a methamphetamine positive drug screen was associated with a longer LOS (median of 4 vs. 3 days in MA(+) and MA(-), respectively, p < 0.0001), an increased heart rate at the scene (103 vs. 94 bpm for MA(+) and MA(-), respectively, p = 0.0016), and an increased heart rate upon arrival to the trauma center (100 vs. 94 bpm for MA(+) and MA(-), respectively, p < 0.0001). Moreover, the MA(+) group had decreased SBP at the scene compared to the MA(-) group (127 vs. 132 bpm for MA(+) and MA(-), respectively, p = 0.0149), but SBP was no longer statistically different when patients arrived at the trauma center (p = 0.3823). There was no significant difference in DBP or in blood products used. CONCLUSION: Methamphetamine positive drug screens in trauma patients were not associated with an increase in hospital mortality; however, a methamphetamine positive drug screen was associated with a longer LOS and an increased heart rate.

Radiation dosimetry and biodistribution of the translocator protein radiotracer [(11)C]DAA1106 determined with PET/CT in healthy human volunteers.

INTRODUCTION: When microglia become activated (an integral part of neuroinflammation), cellular morphology changes and expression of translocator protein (TSPO) 18 kDa is increased. Over the past several years, [(11)C]DAA1106 has emerged as a reliable radiotracer for labeling TSPO with high affinity during positron emission tomography (PET) scanning. While [(11)C]DAA1106 PET scanning has been used in several research studies, a radiation dosimetry study of this radiotracer in humans has not yet been published. METHODS: Twelve healthy participants underwent full body dynamic [(11)C]DAA1106 PET scanning, with 8 sequential whole body scans (approximately 12 bed positions each), following a single injection. Regions of interest were drawn manually, and time activity curves (TACs) were obtained for 15 organs. OLINDA/EXM 1.1 was used to compute radiation absorbed doses to the target organs, as well as effective dose (ED) and effective dose equivalent (EDE). RESULTS: The ED and EDE were 4.06 ± 0.58 µSv/MBq and 5.89 ± 0.83 µSv/MBq, respectively. The highest absorbed doses were to the heart wall, kidney, liver, pancreas, and spleen. TACs revealed that peak dose rates are during the first scan (at 6 min) for all organs other than the urinary bladder wall, which had its peak dose rate during the fourth scan (at 30 min). CONCLUSIONS: The recently developed radiotracer [(11)C]DAA1106 has its EDE and target-organ absorbed dose such that, for a single administration, its radiation dosimetry is well within the U.S. FDA guidelines for basic research studies in adults. This dose level implies that the dosimetry for multiple [(11)C]DAA1106 scans within a given year also falls within FDA guidelines, and this favorable property makes this radiotracer suitable for examining microglial activation repeatedly over time, which may in the future be useful for longitudinal tracking of disease progression and monitoring of therapy response in conditions marked by neuroinflammation (e.g., head trauma and multiple sclerosis).

Brain nicotinic acetylcholine receptor availability and response to smoking cessation treatment: a randomized trial.

IMPORTANCE: Cigarette smoking leads to upregulation of nicotinic acetylcholine receptors (nAChRs) in the human brain, including the common α4ß2* nAChR subtype. While subjective aspects of tobacco dependence have been extensively examined as predictors of quitting smoking with treatment, no studies to our knowledge have yet reported the relationship between the extent of pretreatment upregulation of nAChRs and smoking cessation. OBJECTIVE: To determine whether the degree of nAChR upregulation in smokers predicts quitting with a standard course of treatment. DESIGN, SETTING, AND PARTICIPANTS: Eighty-one tobacco-dependent cigarette smokers (volunteer sample) underwent positron emission tomographic (PET) scanning of the brain with the radiotracer 2-FA followed by 10 weeks of double-blind, placebo-controlled treatment with nicotine patch (random assignment). Pretreatment specific binding volume of distribution (VS/fP) on PET images (a value that is proportional to α4ß2* nAChR availability) was determined for 8 brain regions of interest, and participant-reported ratings of nicotine dependence, craving, and self-efficacy were collected. Relationships between these pretreatment measures, treatment type, and outcome were then determined. The study took place at academic PET and clinical research centers. MAIN OUTCOMES AND MEASURES: Posttreatment quit status after treatment, defined as a participant report of 7 or more days of continuous abstinence and an exhaled carbon monoxide level of 3 ppm or less. RESULTS: Smokers with lower pretreatment VS/fP values (a potential marker of less severe nAChR upregulation) across all brain regions studied were more likely to quit smoking (multivariate analysis of covariance, F8,69 = 4.5; P < .001), regardless of treatment group assignment. Furthermore, pretreatment average VS/fP values provided additional predictive power for likelihood of quitting beyond the self-report measures (stepwise binary logistic regression, likelihood ratio χ21 = 19.8; P < .001). CONCLUSIONS AND RELEVANCE: Smokers with less upregulation of available α4ß2* nAChRs have a greater likelihood of quitting with treatment than smokers with more upregulation. In addition, the biological marker studied here provided additional predictive power beyond subjectively rated measures known to be associated with smoking cessation outcome. While the costly, time-consuming PET procedure used here is not likely to be used clinically, simpler methods for examining α4ß2* nAChR upregulation could be tested and applied in the future to help determine which smokers need more intensive and/or lengthier treatment. TRIAL REGISTRATION: clinicaltrials.gov Identifier: NCT01526005.

The anti-interferon activity of conserved viral dUTPase ORF54 is essential for an effective MHV-68 infection.

Gammaherpesviruses such as KSHV and EBV establish lifelong persistent infections through latency in lymphocytes. These viruses have evolved several strategies to counteract the various components of the innate and adaptive immune systems. We conducted an unbiased screen using the genetically and biologically related virus, MHV-68, to find viral ORFs involved in the inhibition of type I interferon signaling and identified a conserved viral dUTPase, ORF54. Here we define the contribution of ORF54 in type I interferon inhibition by ectopic expression and through the use of genetically modified MHV-68. ORF54 and an ORF54 lacking dUTPase enzymatic activity efficiently inhibit type I interferon signaling by inducing the degradation of the type I interferon receptor protein IFNAR1. Subsequently, we show in vitro that the lack of ORF54 causes a reduction in lytic replication in the presence of type I interferon signaling. Investigation of the physiological consequence of IFNAR1 degradation and importance of ORF54 during MHV-68 in vivo infection demonstrates that ORF54 has an even greater impact on persistent infection than on lytic replication. MHV-68 lacking ORF54 expression is unable to efficiently establish latent infection in lymphocytes, although it replicates relatively normally in lung tissues. However, infection of IFNAR-/- mice alleviates this phenotype, emphasizing the specific role of ORF54 in type I interferon inhibition. Infection of mice and cells by a recombinant MHV-68 virus harboring a site specific mutation in ORF54 rendering the dUTPase inactive demonstrates that dUTPase enzymatic activity is not required for anti-interferon function of ORF54. Moreover, we find that dUTPase activity is dispensable at all stages of MHV-68 infection analyzed. Overall, our data suggest that ORF54 has evolved anti-interferon activity in addition to its dUTPase enzymatic activity, and that it is actually the anti-interferon role that renders ORF54 critical for establishing an effective persistent infection of MHV-68.