We have established that the efficacy of a heterologous poxvirus vectored HIV vaccine, fowlpox virus (FPV)-HIV gag/pol prime followed by attenuated vaccinia virus (VV)-HIV gag/pol booster immunisation, is strongly influenced by the cytokine milieu at the priming vaccination site, with endogenous IL-13 detrimental to the quality of the HIV specific CD8+ T cell response induced. We have now developed a novel HIV vaccine that co-expresses a C-terminal deletion mutant of the mouse IL-4, deleted for the essential tyrosine (Y119) required for signalling. In our vaccine system, the mutant IL-4C118 can bind to IL-4 type I and II receptors with high affinity, and transiently prevent the signalling of both IL-4 and IL-13 at the vaccination site. When this IL-4C118 adjuvanted vaccine was used in an intranasal rFPV/intramuscular rVV prime-boost immunisation strategy, greatly enhanced mucosal/systemic HIV specific CD8+ T cells with higher functional avidity, expressing IFN-γ, TNF-α and IL-2 and greater protective efficacy were detected. Surprisingly, the IL-4C118 adjuvanted vaccines also induced robust long-lived HIV gag-specific serum antibody responses, specifically IgG1 and IgG2a. The p55-gag IgG2a responses induced were of a higher magnitude relative to the IL-13Rα2 adjuvant vaccine. More interestingly, our recently tested IL-13Rα2 adjuvanted vaccine which only inhibited IL-13 activity, even though induced excellent high avidity HIV-specific CD8+ T cells, had a detrimental impact on the induction of gag-specific IgG2a antibody immunity. Our observations suggest that (i) IL-4 cell-signalling in the absence of IL-13 retarded gag-specific antibody isotype class switching, or (ii) IL-13Rα2 signalling was involved in inducing good gag-specific B cell immunity. Thus, we believe our novel IL-4R antagonist adjuvant strategy offers great promise not only for HIV-1 vaccines, but also against a range of chronic infections where sustained high quality mucosal and systemic T and B cell immunity are required for protection.

The combination of prescription opioid dependence and chronic pain is increasingly prevalent and hazardous to public health. Variability in pain may explain poor prescription opioid addiction treatment outcomes in persons with chronic pain. This study examined pain trajectories and pain volatility in patients with chronic pain receiving treatment for prescription opioid addiction. We conducted secondary analyses of adults with chronic pain (N = 149) who received buprenorphine-naloxone (BUP-NLX) and counseling for 12 weeks in an outpatient, multi-site clinical trial. Good treatment outcome was defined as urine-verified abstinence from opioids at treatment endpoint (Week 12) and during at least two of the previous three weeks. Pain severity significantly declined over time during treatment (b = − 0.36, p < .001). Patients with greater pain volatility were less likely to have a good treatment outcome (OR = 0.55, p < .05), controlling for baseline pain severity and rate of change in pain over time. A one standard deviation increase in pain volatility was associated with a 44% reduction in the probability of endpoint abstinence. The significant reduction in subjective pain during treatment provides observational support for the analgesic effects of BUP-NLX in patients with chronic pain and opioid dependence. Patients with greater volatility in subjective pain during treatment have increased risk for returning to opioid use by the conclusion of an intensive treatment with BUP-NLX and counseling. Future research should examine underlying mechanisms of pain volatility and identify related therapeutic targets to optimize interventions for prescription opioid addiction and co-occurring chronic pain.

Children's alcohol expectancies shift in late childhood/early adolescence in ways thought to lead to increased risk for adolescent alcohol use. The precise nature of this shift and the maturational processes that may influence it remain to be clarified. To these ends, we compared expectancy endorsement by grade across four expectancy domains: positive, negative, arousal and sedation, in a cross-sectional sample of 3rd-6th grade children attending afterschool programs (n = 299). Structural equation modeling (SEM) then was used to describe the relationships between expectancies and differences in: (a) cognitive ability and concept formation, (b) risk-taking personality traits, and (c) social exposure or values regarding alcohol-related information. Results showed those children in higher grades endorsed significantly more positive, negative and sedating expectancies for alcohol than their younger peers. Concept formation partially and fully mediated the relationships between grade and both positive and sedating expectancies, respectively, but not the relationship between grade and negative expectancies. Sensation seeking did not increase across grades in this sample, and the relationship between sensation seeking and positive expectancies was fully mediated by reported alcohol exposure and values. This study provides a basis for future exploration of developmental influences on alcohol expectancies, an understanding of which may be helpful in the design of prevention efforts targeting high risk youth prior to adolescence.

Background Despite numerous clinical trials no efficacious medications for methamphetamine (MA) have been identified. Neuroinflammation, which has a role in MA-related reward and neurodegeneration, is a novel MA pharmacotherapy target. Ibudilast inhibits activation of microglia and pro-inflammatory cytokines and has reduced MA self-administration in preclinical research. This study examined whether ibudilast would reduce subjective effects of MA in humans. Methods Adult, non-treatment seeking, MA-dependent volunteers (N = 11) received oral placebo, moderate ibudilast (40 mg), and high-dose ibudilast (100 mg) via twice-daily dosing for 7 days each in an inpatient setting. Following infusions of saline, MA 15mg, and MA 30mg participants rated 12 subjective drug effects on a visual analog scale (VAS). Results As demonstrated by statistically-significant ibudilast×MA condition interactions (p < .05), ibudilast reduced several MA-related subjective effects including High, Effect (i.e., any drug effect), Good, Stimulated and Like. The ibudilast-related reductions were most pronounced in the MA 30mg infusions, with ibudilast 100 mg significantly reducing Effect (97.5% CI [- 12.54, -2.27]), High (97.5% CI [-12.01, -1.65]), and Good (97.5% CI [-11.20, -0.21]), compared to placebo. Conclusions Ibudilast appeared to reduce reward-related subjective effects of MA in this early-stage study, possibly due to altering the processes of neuroinflammation involved in MA reward. Given this novel mechanism of action and the absence of an efficacious medication for MA dependence, ibudilast warrants further study to evaluate its clinical efficacy.

Adolescence is a period marked by increases in risk taking, sensation seeking, and emotion dysregulation. Neurobiological models of adolescent development propose that lagging development in brain regions associated with affect and behavior control compared to regions associated with reward and emotion processing may underlie these behavioral manifestations. Cross-sectional studies have identified several functional brain networks that may contribute to risk for substance use and psychopathology in adolescents. Determining brain structure measures that prospectively predict substance use and psychopathology could refine our understanding of the mechanisms that contribute to these problems, and lead to improved prevention efforts. Participants (N = 265) were healthy substance-naïve adolescents (ages 12–14) who underwent magnetic resonance imaging and then were followed annually for up to 13 years. Cortical thickness and surface area measures for three prefrontal regions (dorsolateral prefrontal cortex, inferior frontal gyrus, and orbitofrontal cortex) and three cortical regions from identified functional networks (anterior cingulate cortex, insular cortex, and parietal cortex) were used to predict subsequent binge drinking, externalizing symptoms, and internalizing symptoms. Thinner dorsolateral prefrontal cortex and inferior frontal cortex in early adolescence predicted more binge drinking and externalizing symptoms, respectively, in late adolescence (ps < .05). Having a family history of alcohol use disorder predicted more subsequent binge drinking and externalizing symptoms. Thinner parietal cortex, but not family history, predicted more subsequent internalizing symptoms (p < .05). This study emphasizes the temporal association between maturation of the salience, inhibition, and executive control networks in early adolescence and late adolescent behavior outcomes. Our findings indicate that developmental variations in these brain regions predate behavioral outcomes of substance use and psychopathology, and may therefore serve as prospective biomarkers of vulnerability.