Cannabis Use Characteristics Associated with Self-Reported Cognitive Function in a Nationally Representative U.S. sample.

BACKGROUND: With increases in cannabis use and potency, there is a need to improve our understanding of the impact of use on cognitive function. Previous research indicates long-term cannabis use may have a negative effect on executive function. Few studies have examined persistence of it in protracted abstinence, and there is limited evidence of predictors of worse cognitive function in current and former users. In this study, we aim to evaluate the associations between cannabis use status (current, former, and never use) and self-report cognition. Further, we investigate if cannabis use characteristics predict self-report cognitive function. METHODS: Cross-sectional cannabis use data from the National Epidemiological Survey on Alcohol and Related Conditions-III (NESARC-III), a national survey (N = 36,309) conducted in the USA between 2012 and 2013 were used alongside the Executive Function Index scales. The data were analyzed by using Ordinary Least Squares regression. RESULTS: Current (N = 3,681, Female = 37.7%) and former users (N = 7,448, Female = 45.4%) reported poorer cognition than never users (N = 24,956, Female = 56.6%). Self-reported cognition of former users was in-between that of current and never users. Several cannabis use characteristics were associated with self-reported cognition in current and former users. CONCLUSION: While prospective studies are required to confirm, findings suggest cannabis use is linked to worse cognition. There may be some limited recovery of cognition in former users and some cannabis use characteristics predict impairment. These findings add to our understanding of the cognitive impact of cannabis use. As worse cognitive function may impact relapse, findings have implications for personalization of cannabis use disorder treatment.

Diphosphoryl-functionalized Polyoxometalates: Structurally and Electronically Tunable Hybrid Molecular Materials.

Herein, we report the synthesis and characterization of a new class of hybrid Wells-Dawson polyoxometalate (POM) containing a diphosphoryl group (P2 O6 X) of the general formula [P2 W17 O57 (P2 O6 X)]6- (X=O, NH, or CR1 R2 ). Modifying the bridging unit X was found to impact the redox potentials of the POM. The ease with which a range of α-functionalized diphosphonic acids (X=CR1 R2 ) can be prepared provides possibilities to access diverse functionalized hybrid POMs. Compared to existing phosphonate hybrid Wells-Dawson POMs, diphosphoryl-substituted POMs offer a wider tunable redox window and enhanced hydrolytic stability. This study provides a basis for the rational design and synthesis of next-generation hybrid Wells-Dawson POMs.

Significant association of nicotine reinforcement and cue reactivity: a translational study in humans and rats.

Relapse is common amongst smokers attempting to quit and tobacco cue-induced craving is an important relapse mechanism. Preclinical studies commonly use cue-induced reinstatement of nicotine seeking to investigate relapse neurobiology. Previous research suggests dependence severity and nicotine intake history affect smoking resumption and cue-induced reinstatement of nicotine seeking. However, behavioural data may be interpreted in terms of nicotine reinforcement. This translational study investigated if individual differences in objectively assessed nicotine reinforcement strength were associated with cue-reactivity in both rats and human smokers, which to our knowledge has not been investigated before. Rats (n = 16) were trained to self-administer nicotine and were tested on a progressive ratio schedule of nicotine reinforcement, to assess reinforcer strength, and on a test of cue-induced reinstatement of nicotine seeking. Nicotine reinforcement strength was assessed in human smokers (n = 104) using a forced choice task (nicotine containing vs. denicotinised cigarettes) and self-reported cue-induced craving was assessed following exposure to smoking and neutral cues. Responding for nicotine under progressive ratio was strongly positively correlated with cue-induced reinstatement of nicotine seeking in rats. Nicotine choices in human smokers were significantly associated with cue-induced craving controlling for dependence severity, years of smoking, and urge to smoke following neutral cues. Findings suggest nicotine reinforcement strength is associated with both types of cue-induced behaviour, implying some translational commonality between cue-induced craving in human smokers and cue-induced reinstatement of nicotine seeking in rats. Findings are discussed in relation to clinical implications and whether these laboratory tasks assess drug 'wanting'.

Impact of CYP2A6 Activity on Nicotine Reinforcement and Cue-Reactivity in Daily Smokers.

INTRODUCTION: Variation in CYP2A6, the primary enzyme responsible for nicotine metabolism, is associated with nicotine dependence, cigarette consumption, and abstinence outcomes in smokers. The impact of CYP2A6 activity on nicotine reinforcement and tobacco cue-reactivity, mechanisms that may contribute to these previous associations, has not been fully evaluated. AIMS AND METHODS: CYP2A6 activity was indexed using 3 genetic approaches in 104 daily smokers completing forced-choice and cue-induced craving tasks assessing nicotine reinforcement and tobacco cue-reactivity, respectively. First, smokers were stratified by the presence or absence of reduced/loss-of-function CYP2A6 gene variants (normal vs. reduced metabolizers). As nicotine metabolite ratio (NMR) is a reliable biomarker of CYP2A6 activity, our second and third approaches used additional genetic variants identified in genome-wide association studies of NMR to create a weighted genetic risk score (wGRS) to stratify smokers (fast vs. slow metabolizers) and calculate a wGRS-derived NMR. RESULTS: Controlling for race and sex, normal metabolizers (vs. reduced) selected a greater proportion of puffs from nicotine-containing cigarettes (vs. denicotinized) on the forced-choice task (p = .031). In confirmatory analyses, wGRS-based stratification (fast vs. slow metabolizers) produced similar findings. Additionally, wGRS-derived NMR, which correlated with actual NMR assessed in a subset of participants (n = 55), was positively associated with the proportion of puffs from nicotine-containing cigarettes controlling for race and sex (p = .015). None of the CYP2A6 indices were associated with tobacco cue-reactivity in minimally deprived smokers. CONCLUSIONS: Findings suggest increased nicotine reinforcement is exhibited by smokers with high CYP2A6 activity, which may contribute to heavier smoking and poorer cessation outcomes previously reported in faster metabolizers. IMPLICATIONS: CYP2A6 activity is a key determinant of smoking behavior and outcomes. Therefore, these findings support the targeting of CYP2A6 activity, either therapeutically or as a clinically relevant biomarker in a precision medicine approach, for tobacco use disorder treatment.

Elevated cortisol awakening response associated with early life stress and impaired executive function in healthy adult males.

Experiencing early life stress (ELS) and subsequent dysregulation of the hypothalamic-pituitary-adrenal (HPA) axis may play a role in the aetiology of mental health disorders. However, the exact mechanisms linking HPA-axis dysregulation with the development of psychopathology have not been fully delineated. Progress in this area is hampered by the complex and often conflicting associations found between markers of HPA-axis function and risk factors for mental health disorders such as impaired executive function (EF) and ELS. This study investigated the association of the cortisol awakening response (CAR) with ELS and EF in a healthy adult male population (n=109, aged 21-63). As previous inconsistencies in CAR and ELS association studies may be the result of not considering ELS-related factors such as cumulative exposure, type of stressor and developmental timing of ELS, these were also investigated. The main findings were that the CAR was significantly elevated in individuals reporting ELS compared to those reporting no ELS (p=0.007) and that an elevated CAR predicted poorer problem solving/planning (p=0.046). Cumulative exposure, type of stressor and developmental timing of ELS were also found to impact significantly on the CAR. These results suggest that ELS is associated with chronic changes in HPA-axis function and that these changes may be associated with impairments in problem solving/planning. Future work should investigate further the neurobiological mechanisms linking ELS, the CAR and EF and their role in conferring risk for the development of mental health disorders.

Big data in Earth science: Emerging practice and promise.

Improvements in the number and resolution of Earth- and satellite-based sensors coupled with finer-resolution models have resulted in an explosion in the volume of Earth science data. This data-rich environment is changing the practice of Earth science, extending it beyond discovery and applied science to new realms. This Review highlights recent big data applications in three subdisciplines-hydrology, oceanography, and atmospheric science. We illustrate how big data relate to contemporary challenges in science: replicability and reproducibility and the transition from raw data to information products. Big data provide unprecedented opportunities to enhance our understanding of Earth's complex patterns and interactions. The emergence of digital twins enables us to learn from the past, understand the current state, and improve the accuracy of future predictions.

Privacy-Preserving Gaze Data Streaming in Immersive Interactive Virtual Reality: Robustness and User Experience.

Eye tracking is routinely being incorporated into virtual reality (VR) systems. Prior research has shown that eye tracking data, if exposed, can be used for re-identification attacks [14]. The state of our knowledge about currently existing privacy mechanisms is limited to privacy-utility trade-off curves based on data-centric metrics of utility, such as prediction error, and black-box threat models. We propose that for interactive VR applications, it is essential to consider user-centric notions of utility and a variety of threat models. We develop a methodology to evaluate real-time privacy mechanisms for interactive VR applications that incorporate subjective user experience and task performance metrics. We evaluate selected privacy mechanisms using this methodology and find that re-identification accuracy can be decreased to as low as 14% while maintaining a high usability score and reasonable task performance. Finally, we elucidate three threat scenarios (black-box, black-box with exemplars, and white-box) and assess how well the different privacy mechanisms hold up to these adversarial scenarios. This work advances the state of the art in VR privacy by providing a methodology for end-to-end assessment of the risk of re-identification attacks and potential mitigating solutions. f.

Mechanistic investigations of the Fe(ii) mediated synthesis of squaraines.

The scission and homologation of CO is a fundamental process in the Fischer-Tropsch reaction. However, given the heterogeneous nature of the catalyst and forcing reaction conditions, it is difficult to determine the intermediates of this reaction. Here we report detailed mechanistic insight into the scission/homologation of CO by two-coordinate iron terphenyl complexes. Mechanistic investigations, conducted using in situ monitoring and reaction sampling techniques (IR, NMR, EPR and Mössbauer spectroscopy) and structural characterisation of isolable species, identify a number of proposed intermediates. Crystallographic and IR spectroscopic data reveal a series of migratory insertion reactions from 1Mes to 4Mes. Further studies past the formation of 4Mes suggest that ketene complexes are formed en route to squaraine 2Mes and iron carboxylate 3Mes, with a number of ketene containing structures being isolated, in addition to the formation of unbound, protonated ketene (8). The synthetic and mechanistic studies are supported by DFT calculations.

Privacy-preserving datasets of eye-tracking samples with applications in XR.

Virtual and mixed-reality (XR) technology has advanced significantly in the last few years and will enable the future of work, education, socialization, and entertainment. Eye-tracking data is required for supporting novel modes of interaction, animating virtual avatars, and implementing rendering or streaming optimizations. While eye tracking enables many beneficial applications in XR, it also introduces a risk to privacy by enabling re-identification of users. We applied privacy definitions of it-anonymity and plausible deniability (PD) to datasets of eye-tracking samples and evaluated them against the state-of-the-art differential privacy (DP) approach. Two VR datasets were processed to reduce identification rates while minimizing the impact on the performance of trained machine-learning models. Our results suggest that both PD and DP mechanisms produced practical privacy-utility trade-offs with respect to re-identification and activity classification accuracy, while k-anonymity performed best at retaining utility for gaze prediction.

The Role of Dopamine D3 Receptors in Tobacco Use Disorder: A Synthesis of the Preclinical and Clinical Literature.

Tobacco smoking is a significant cause of preventable morbidity and mortality globally. Current pharmacological approaches to treat tobacco use disorder (TUD) are only partly effective and novel approaches are needed. Dopamine has a well-established role in substance use disorders, including TUD, and there has been a long-standing interest in developing agents that target the dopaminergic system to treat substance use disorders. Dopamine has 5 receptor subtypes (DRD1 to DRD5). Given the localization and safety profile of the dopamine receptor D3 (DRD3), it is of therapeutic potential for TUD. In this chapter, the preclinical and clinical literature investigating the role of DRD3 in processes relevant to TUD will be reviewed, including in nicotine reinforcement, drug reinstatement, conditioned stimuli and cue-reactivity, executive function, and withdrawal. Similarities and differences in findings from the animal and human work will be synthesized and findings will be discussed in relation to the therapeutic potential of targeting DRD3 in TUD.

Implementation and Preliminary Evaluation of a 12-Week Cognitive Behavioural and Motivational Enhancement Group Therapy for Cannabis Use Disorder.

Background: The purpose of this paper is to provide a preliminary evaluation of treatment outcomes, retention and client satisfaction following a 12-week combined cognitive behavioural therapy (CBT) and motivational enhancement therapy (MET) group treatment for cannabis use disorder (CUD) delivered in an outpatient setting. Implementation of the program is also described. Methods: A retrospective observational cohort study was conducted using data collected from medical records and self-report assessments. Participants were treatment-seeking cannabis users at the Centre for Addiction and Mental Health, Toronto. Cannabis use, cannabis-related problems, craving, withdrawal symptoms, self-efficacy for remaining abstinent, depression and anxiety were assessed pre- and post-treatment. Treatment retention was calculated by inspecting clinic attendance records, and client satisfaction was evaluated using an anonymous feedback survey. Potential predictors of treatment outcomes and retention were investigated in exploratory analyses. Results: Cannabis use was lower and days of abstinence higher post-treatment (vs pre-treatment). Post-treatment improvements in cannabis-related problems, craving, withdrawal symptoms, self-efficacy and mood were also observed. Completion of group treatment (⩾75% of sessions attended) was 57% and moderate levels of treatment satisfaction were reported. Conclusions: This study provides preliminary evidence that a 12-week combined CBT and MET treatment for cannabis use disorder delivered in a novel group setting improves cannabis use outcomes. Potential predictors of reduced cannabis use and retention were identified. Future controlled studies are warranted, and strategies for increasing retention should be explored.

Comparison of Antiretroviral Therapies in Pregnant Women Living With Human Immunodeficiency Virus and Hepatitis B Virus: A Randomized Controlled Trial.

OBJECTIVE: To describe the anti-hepatitis B virus (HBV) efficacy, HBeAg serologic changes, HBV perinatal transmission, and safety in pregnant women who are living with human immunodeficiency virus (HIV) and HBV co-infection who were randomized to various antiretroviral therapy (ART) regimens. METHODS: The PROMISE (Promoting Maternal and Infant Survival Everywhere) trial was a multicenter randomized trial for ART-naive pregnant women with HIV infection. Women with HIV and HBV co-infection at 14 or more weeks of gestation were randomized to one of three ART arms: one without HBV treatment (group 1) and two HBV treatment arms with single (group 2) or dual anti-HBV activity (group 3). The primary HBV outcome was HBV viral load antepartum change from baseline (enrollment) to 8 weeks; safety assessments included alanine aminotransferase (ALT) level, aspartate aminotransferase (AST) level, and anemia (hemoglobin less than 10 g/dL). Primary comparison was for the HBV-active treatment arms. Pairwise comparisons applied t test and the Fisher exact tests. RESULTS: Of 3,543 women, 3.9% were HBsAg-positive; 42 were randomized to group 1, 48 to group 2, and 48 to group 3. Median gestational age at enrollment was 27 weeks. Among HBV-viremic women, mean antepartum HBV viral load change at week 8 was -0.26 log 10 international units/mL in group 1, -1.86 in group 2, and -1.89 in group 3. In those who were HBeAg-positive, HBeAg loss occurred in 44.4% at delivery. Two perinatal HBV transmissions occurred in group 2. During the antepartum period, one woman (2.4%) in group 1 had grade 3 or 4 ALT or AST elevations, two women (4.2%) in group 2, and three women (6.3%) in group 3. CONCLUSION: Over a short period of time, HBV DNA suppression was not different with one or two HBV-active agents. HbeAg loss occurred in a substantial proportion of participants. Perinatal transmission of HBV infection was low. Hepatitis B virus-active ART was well-tolerated in pregnancy, with few grade 3 or 4 ALT or AST elevations. CLINICAL TRIAL REGISTRATION: ClinicalTrials.gov , NCT01061151.

Adapting a Telephone-Based, Dyadic Self-management Program to Be Delivered Over the Web: Methodology and Usability Testing.

BACKGROUND: The COVID-19 pandemic has amplified the need for web-based behavioral interventions to support individuals who are diagnosed with chronic conditions and their informal caregivers. However, most interventions focus on patient outcomes. Dyadic technology-enabled interventions that simultaneously improve outcomes for patients and caregivers are needed. OBJECTIVE: This study aimed to describe the methodology used to adapt a telephone-based, facilitated, and dyadic self-management program called Self-care Using Collaborative Coping Enhancement in Diseases (SUCCEED) into a self-guided, web-based version (web-SUCCEED) and to conduct usability testing for web-SUCCEED. METHODS: We developed web-SUCCEED in 6 steps: ideation-determine the intervention content areas; prototyping-develop the wireframes, illustrating the look and feel of the website; prototype refinement via feedback from focus groups; finalizing the module content; programming web-SUCCEED; and usability testing. A diverse team of stakeholders including content experts, web designers, patients, and caregivers provided input at various stages of development. Costs, including full-time equivalent employee, were summarized. RESULTS: At the ideation stage, we determined the content of web-SUCCEED based on feedback from the program's original pilot study. At the prototyping stage, the principal investigator and web designers iteratively developed prototypes that included inclusive design elements (eg, large font size). Feedback about these prototypes was elicited through 2 focus groups of veterans with chronic conditions (n=13). Rapid thematic analysis identified two themes: (1) web-based interventions can be useful for many but should include ways to connect with other users and (2) prototypes were sufficient to elicit feedback about the esthetics, but a live website allowing for continual feedback and updating would be better. Focus group feedback was incorporated into building a functional website. In parallel, the content experts worked in small groups to adapt SUCCEED's content, so that it could be delivered in a didactic, self-guided format. Usability testing was completed by veterans (8/16, 50%) and caregivers (8/16, 50%). Veterans and caregivers gave web-SUCCEED high usability scores, noting that it was easy to understand, easy to use, and not overly burdensome. Notable negative feedback included "slightly agreeing" that the site was confusing and awkward. All veterans (8/8, 100%) agreed that they would choose this type of program in the future to access an intervention that aims to improve their health. Developing and maintaining the software and hosting together cost approximately US $100,000, excluding salary and fringe benefits for project personnel (steps 1-3: US $25,000; steps 4-6: US $75,000). CONCLUSIONS: Adapting an existing, facilitated self-management support program for delivery via the web is feasible, and such programs can remotely deliver content. Input from a multidisciplinary team of experts and stakeholders can ensure the program's success. Those interested in adapting programs should have a realistic estimate of the budget and staffing requirements.

Self-reported Antiretroviral Adherence: Association With Maternal Viral Load Suppression in Postpartum Women Living With HIV-1 From Promoting Maternal and Infant Survival Everywhere, a Randomized Controlled Trial in Sub-Saharan Africa and India.

INTRODUCTION: Optimal adherence to antiretroviral therapy (ART) is crucial to promoting maternal-infant health. SETTING: Fourteen sites in 7 countries within sub-Saharan Africa and India. METHODS: The multicomponent, open-label strategy PROMISE trial enrolled breastfeeding mother-infant pairs not meeting in-country criteria for maternal ART (mART) initiation in the postpartum component within 5 days of delivery. Randomization was to mART versus infant NVP (iNVP) prophylaxis. Infants in the mART arm also received 6 weeks of iNVP. Self-reported adherence was assessed in a secondary analysis. Time-to-event analyses were performed to explore the association between adherence and maternal viral load (mVL) in the mART arm. RESULTS: Two thousand four hundred thirty-one mother-infant pairs were enrolled between 2011 and 2014; the baseline maternal median CD4 was 686 (IQR 553-869), and the median mVL was 322 copies/mL (IQR 40-1422). Self-reported adherence was lower in the mART arm compared with the iNVP arm (no missed doses within 4 weeks of all study visits: 66% vs 83%; within 2 weeks: 71% vs 85%; P < 0.0001). The iNVP adherence at week 6 was high in both arms: 97% in mART arm; 95% in iNVP arm. Time-to-event analyses showed that adherence to mART was associated with time to first mVL ≥400 copies/mL ( P < 0.0001). Missing 1 full day of doses over 3 days was associated with a 66% risk of mVL ≥1000 copies/mL (HR: 1.66; 95% CI: 1.37, 1.99). CONCLUSIONS: Postpartum women were less adherent to their own ART than mothers providing their infant's nevirapine prophylaxis. The self-reported missed mART doses were associated with high mVL. Strategies to optimize postpartum mART adherence are urgently needed. CLINICAL TRIAL NUMBER: ClinicalTrials.gov: NCT01061151; closed to follow-up.

DR-VIDAL - Doubly Robust Variational Information-theoretic Deep Adversarial Learning for Counterfactual Prediction and Treatment Effect Estimation on Real World Data.

Determining causal effects of interventions onto outcomes from real-world, observational (non-randomized) data, e.g., treatment repurposing using electronic health records, is challenging due to underlying bias. Causal deep learning has improved over traditional techniques for estimating individualized treatment effects (ITE). We present the Doubly Robust Variational Information-theoretic Deep Adversarial Learning (DR-VIDAL), a novel generative framework that combines two joint models of treatment and outcome, ensuring an unbiased ITE estimation even when one of the two is misspecified. DR-VIDAL integrates: (i) a variational autoencoder (VAE) to factorize confounders into latent variables according to causal assumptions; (ii) an information-theoretic generative adversarial network (Info-GAN) to generate counterfactuals; (iii) a doubly robust block incorporating treatment propensities for outcome predictions. On synthetic and real-world datasets (Infant Health and Development Program, Twin Birth Registry, and National Supported Work Program), DR-VIDAL achieves better performance than other non-generative and generative methods. In conclusion, DR-VIDAL uniquely fuses causal assumptions, VAE, Info-GAN, and doubly robustness into a comprehensive, per- formant framework. Code is available at: https://github.com/Shantanu48114860/DR-VIDAL-AMIA-22 under MIT license.

Brief Report: Impact of Antiretroviral Regimen on Pregnancy and Infant Outcomes in Women With HIV/ HBV Coinfection.

BACKGROUND: There are limited data on the impact of antenatal antiretroviral regimens (ARV) on pregnancy and infant outcomes in HIV/HBV coinfection. We compared outcomes among 3 antenatal antiretroviral regimens for pregnant women with HIV/HBV. METHODS: The PROMISE study enrolled ARV-naive pregnant women with HIV. Women with HBV were randomized to (no anti-HBV)-zidovudine (ZDV) + intrapartum nevirapine and 1 week of tenofovir disoproxil fumarate and emtricitabine (TDF-FTC); (3TC)-3TC + ZDV + LPV/r; or (FTC-TDF)-FTC + TDF + LPV/r. Pairwise group comparisons were performed with Fisher exact, t , or log rank tests. Adverse pregnancy outcome (APO) was a composite of low birth weight, preterm delivery, spontaneous abortion, stillbirth, or congenital anomaly. RESULTS: Of 138 women with HIV/HBV, 42, 48, and 48 were analyzed in the no anti-HBV, 3TC, and FTC-TDF arms. Median age was 27 years. APOs trended lower in the no anti-HBV (26%) vs 3TC (38%), and FTC-TDF arms (35%), P ≥ 0.25). More infant deaths occurred among the FTC-TDF [6 (13%)] vs no anti-HBV [2 (5%)] and 3TC [3 (7%)] arms. There were no differences in time-to-death, HIV-free survival, birth or one-year WHO Z-score length-for-age, and head circumference. Hepatitis B e antigen (HBeAg) was associated with an increased risk of APO, 48% vs 27% (odds ratio 2.79, 95% confidence interval: 1.19 to 6.67, post hoc ). CONCLUSION: With HBV/HIV coinfection, the risk of an APO was increased with maternal ARV compared with ZDV alone, although the differences were not statistically significant. Maternal HBeAg was associated with a significantly increased risk of APO. Infant mortality was highest with FTC + TDF + LPV/r. Early assessment of HBeAg could assist in identifying high-risk pregnancies for close monitoring.

A privacy-preserving approach to streaming eye-tracking data.

Eye-tracking technology is being increasingly integrated into mixed reality devices. Although critical applications are being enabled, there are significant possibilities for violating user privacy expectations. We show that there is an appreciable risk of unique user identification even under natural viewing conditions in virtual reality. This identification would allow an app to connect a user's personal ID with their work ID without needing their consent, for example. To mitigate such risks we propose a framework that incorporates gatekeeping via the design of the application programming interface and via software-implemented privacy mechanisms. Our results indicate that these mechanisms can reduce the rate of identification from as much as 85% to as low as 30%. The impact of introducing these mechanisms is less than 1.5° error in gaze position for gaze prediction. Gaze data streams can thus be made private while still allowing for gaze prediction, for example, during foveated rendering. Our approach is the first to support privacy-by-design in the flow of eye-tracking data within mixed reality use cases.

Pharmacokinetics and safety of maraviroc in neonates.

OBJECTIVE: The aim of this study was to evaluate safety and pharmacokinetics of maraviroc administered with standard antiretroviral prophylaxis to HIV-1 exposed infants and to determine the appropriate dose of maraviroc during the first 6 weeks of life. DESIGN: A phase I, multicentre, open-label study enrolling two sequential cohorts. METHODS: IMPAACT 2007 participants enrolled by day 3 of life and were stratified by exposure to maternal efavirenz. Cohort 1 participants received two single 8 mg/kg maraviroc doses 1 week apart with pharmacokinetic sampling after each dose. Cohort 2 participants received 8 mg/kg maraviroc twice daily through 6 weeks of life with pharmacokinetic sampling at weeks 1 and 4. Maraviroc exposure target was Cavg at least 75 ng/ml. Laboratory and clinical evaluations assessed safety. RESULTS: Fifteen Cohort 1 and 32 Cohort 2 HIV-exposed neonates were enrolled (median gestational age 39 weeks, 51% male). All 13 evaluable Cohort 1 infants met the pharmacokinetic target. Median exposure for the 25 evaluable Cohort 2 infants met the pharmacokinetic target but variability was high, with 17-33% of infants below target at Weeks 1 and 4. Pharmacokinetic target achievement was similar between efavirenz exposure strata. No Grade 3+ toxicities, early study or treatment discontinuations due to maraviroc occurred. CONCLUSION: Median maraviroc exposure met the Cavg target in neonates receiving 8 mg/kg twice daily, although exposures were variable. Maternal efavirenz use did not impact maraviroc exposure and no discontinuations were due to maraviroc toxicity/intolerance. No infants acquired HIV-1 infection during follow-up. Maraviroc 8 mg/kg twice daily appears well tolerated during the first 6 weeks of life.

Association of Maternal Viral Load and CD4 Count With Perinatal HIV-1 Transmission Risk During Breastfeeding in the PROMISE Postpartum Component.

BACKGROUND: Breastfeeding mothers with HIV infection not qualifying for antiretroviral therapy (ART) based on country-specific guidelines at the time of the Promoting Maternal-Infant Survival Everywhere trial and their uninfected neonates were randomized to maternal ART (mART) or infant nevirapine prophylaxis (iNVP) postpartum. HIV transmission proportions were similar (<1%) in the 2 arms. We assessed whether maternal viral load (MVL) and CD4 cell counts were associated with breastfeeding HIV transmission. METHODS: MVL was collected at entry (7-14 days postpartum) and at weeks 6, 14, 26, and 50 postpartum. CD4 cell counts were collected at entry and weeks 14, 26, 38, and 50 postpartum. Infant HIV-1 nucleic acid test was performed at weeks 1 and 6, every 4 weeks until week 26, and then every 12 weeks. The associations of baseline and time-varying MVL and CD4 cell counts with transmission risk were assessed using time-to-event analyses by randomized treatment arm. RESULTS: Two thousand four hundred thirty-one mother-infant pairs were enrolled in the study. Baseline MVL (P = 0.11) and CD4 cell counts (P = 0.51) were not significantly associated with infant HIV-1 infection. Time-varying MVL was significantly associated with infant HIV-1 infection {hazard ratio [95% confidence interval (CI)]: 13.96 (3.12 to 62.45)} in the mART arm but not in the iNVP arm [hazard ratio (95% CI): 1.04 (0.20 to 5.39)]. Time-varying CD4 cell counts were also significantly associated with infant HIV-1 infection [hazard ratio (95% CI): 0.18 (0.03 to 0.93)] in the mART arm but not in the iNVP arm [hazard ratio (95% CI): 0.38 (0.08 to 1.77)]. CONCLUSIONS: In women receiving mART, increased MVL and decreased CD4 cell counts during breastfeeding were associated with increased risk of infant HIV-1 infection.

Novel therapeutic and drug development strategies for tobacco use disorder: endocannabinoid modulation.

INTRODUCTION: Tobacco use disorder (TUD) is a chronic relapsing condition. Existing pharmacotherapy can assist smokers to initiate smoking cessation, but relapse rates remain high. Novel therapeutics are required to help people quit and also to prevent relapse. The endocannabinoid system has been increasingly implicated in reward and addiction processes and the cannabinoid CB1 receptor inverse agonist rimonabant has been shown to be effective at promoting smoking cessation but has been associated with adverse psychiatric side effects. AREAS COVERED: Multiple converging factors likely contribute to the maintenance of smoking and cause relapse including nicotine reinforcement, propensity to reinstate drug seeking (induced by nicotine priming, nicotine-associated cues, and stress), the severity of withdrawal signs and executive function status. Studies assessing the impact of endocannabinoid (CB1 receptor, CB2 receptor, anandamide, and 2-arachidonoylglycerol) modulation on these addiction-related factors are reviewed. Future research avenues are also discussed. EXPERT OPINION: Endocannabinoid research in TUD is at a relatively early stage. Based on current evidence, CB1 receptor neutral antagonists and fatty acid amide hydrolase inhibitors demonstrate positive effects in studies assessing several addiction-related factors. This suggests they offer the greatest promise as novel cessation and anti-relapse agents.