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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 1 Mes to 4 Mes . Further studies past the formation of 4 Mes suggest that ketene complexes are formed en route to squaraine 2 Mes and iron carboxylate 3 Mes , 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., Competing Interests: There are no conflicts to declare., (This journal is © The Royal Society of Chemistry.)

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.

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.

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.

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., Competing Interests: The author(s) declared the following potential conflicts of interest with respect to the research, authorship, and/or publication of this article: The authors declare that there is no conflict of interest. Dr Le Foll has obtained funding from Pfizer (GRAND Awards, including salary support) for investigator-initiated projects. Dr Le Foll has some in-kind donation of cannabis product from Aurora and medication donation from Pfizer and Bioprojet and was provided a coil for TMS study from Brainsway. Dr Le Foll has obtained industry funding from Canopy (through research grants handled by CAMH or University of Toronto), Bioprojet, ACS and Alkermes. Dr Le Foll has received in kind donations of nabiximols from GW Pharma for past studies funded by CIHR and NIH. He has been consultant for Shionogi. He is supported by CAMH and a clinician-scientist award from the department of Family and Community Medicine of the University of Toronto and an Addiction Psychiatry Chair from the department of Psychiatry of the University of Toronto., (© The Author(s) 2023.)

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., Competing Interests: Financial Disclosure Debika Bhattacharya reports research support from the National Institutes of Health for the submitted work. She also reports research support from Gilead Sciences and clinical trial support from AbbVie and Regeneron, outside the submitted work. Marion G. Peters reports personal fees from Wainright, Silberback, Excision BioTherapeutics, Aligos, and Antios, as well as spousal employment with Roche, outside the submitted work. Camlin Tierney reports grants from the NIH during the conduct of the study. Mary Glenn Fowler reports IMPAACT Leadership LOC support for the present manuscript. Judith S. Currier reports research support from Resverologix and Merck and Company outside the submitted work. Vani Govender reports support from DAIDS. The other authors did not report any potential conflicts of interest., (Copyright © 2023 by the American College of Obstetricians and Gynecologists. Published by Wolters Kluwer Health, Inc. All rights reserved.)

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., (©Ranak Trivedi, Sierra Kawena Hirayama, Rashmi Risbud, Madhuvanthi Suresh, Marika Blair Humber, Kevin Butler, Alex Razze, Christine Timko, Karin Nelson, Donna M Zulman, Steven M Asch, Keith Humphreys, John D Piette. Originally published in JMIR Formative Research (https://formative.jmir.org), 16.06.2023.)

Herein, we report the synthesis and characterization of a new class of hybrid Wells-Dawson polyoxometalate (POM) containing a diphosphoryl group (P 2 O 6 X) of the general formula [P 2 W 17 O 57 (P 2 O 6 X)] 6- (X=O, NH, or CR 1 R 2 ). 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=CR 1 R 2 ) 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., (© 2023 The Authors. Angewandte Chemie International Edition published by Wiley-VCH GmbH.)

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., (©2022 AMIA - All rights reserved.)

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.

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., (Copyright © 2022 The Author(s). Published by Wolters Kluwer Health, Inc.)

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., (© 2022. The Author(s), under exclusive license to Springer Nature Switzerland AG.)

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., Competing Interests: D.B. and F.M. report research grant support from Gilead Sciences Inc, under award numbers IN-US-987-5950 and GPHA 07844 respectively). M.G.P. has been a consultant to Aligos and Antios. Overall support for the International Maternal Pediatric Adolescent AIDS Clinical Trials Network (IMPAACT) was provided by the National Institute of Allergy and Infectious Diseases (NIAID) with co-funding from the Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD) and the National Institute of Mental Health (NIMH), all components of the National Institutes of Health (NIH), under Award Numbers UM1AI068632 (IMPAACT LOC), UM1AI068616 (IMPAACT SDMC) and UM1AI106716 (IMPAACT LC), and by NICHD contract number HHSN275201800001I. Additional funding from NIAID UM1AI069465 to A.G., NIAID R01 01AI100748-01 and NICHD R01 HD085862 to D.B. Study products were provided free by AbbVie, Gilead Sciences, Boehringer Ingelheim, and ViiV/GlaxoSmithKline. Award Numbers UM1AI068632-15 (IMPAACT LOC), UM1AI068616-15 (IMPAACT SDMC) and UM1AI106716-15 (IMPAACT LC), and by NICHD contract number HHSN275201800001I. The content is solely the responsibility of the authors and does not necessarily represent the official views of the NIH. The other authors have no conflicts of interest to disclose., (Copyright © 2022 The Author(s). Published by Wolters Kluwer Health, Inc.)

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., Competing Interests: P.M.F. is a consultant for Merck. The remaining authors have no conflicts of interest to disclose., (Copyright © 2021 Wolters Kluwer Health, Inc. All rights reserved.)

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., (Published by Oxford University Press on behalf of the Society for Research on Nicotine and Tobacco 2021.)

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.

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'., (Copyright © 2021 Wolters Kluwer Health, Inc. All rights reserved.)

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., (Copyright © 2020 Wolters Kluwer Health, Inc. All rights reserved.)

Aim: We investigated morning cortisol, stress, rs1006737 and childhood trauma relationship with CACNA1C methylation. Materials & methods: Morning cortisol release, childhood trauma and perceived stress were collected and genotyping for rs1006737 conducted in 103 adult males. Genomic DNA extracted from saliva was bisulphite converted and using pyrosequencing methylation determined at 11 CpG sites within intron 3 of CACNA1C . Results: A significant negative correlation between waking cortisol and overall mean methylation was found and a positive correlation between CpG5 methylation and perceived stress. Conclusion: CACNA1C methylation levels may be related to cortisol release and stress perception. Future work should evaluate the influence of altered CACNA1C methylation on stress reactivity to investigate this as a potential mechanism for mental health vulnerability.

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.

Close human-wildlife interactions are rapidly growing, particularly due to wildlife tourism popularity. Using both laboratory and ecological observation studies we explored potential interspecies communication signalling mechanisms underpinning human-animal approach behaviour, which to date have been unclear. First impression ratings (n = 227) of Barbary macaques' social and health traits were related to the macaques' facial morphology and their observed behaviour supporting a shared facial signalling system in primates. These ratings significantly predicted intended approach to the macaques during hypothetical interactions. Finally, real-world interspecies proximity was observed and found to be best predicted by the interaction between human first impression perception and animal behaviour. Specifically, perceived macaque health in interaction with actual macaque dominance drives close interactions despite human proclivity to avoid dominant animals, raising safety concerns in interspecies interactions.

Background: In the Promoting Maternal and Infant Survival Everywhere (PROMISE) trial, tenofovir disoproxil fumarate (TDF) use was associated with moderate or severe adverse pregnancy/neonatal outcomes. This study characterized tenofovir diphosphate (TFV-DP) and emtricitabine triphosphate (FTC-TP) concentrations in dried blood spots (DBS) and assessed association between severe adverse pregnancy/neonatal outcomes and TFV-DP concentration., Methods: Retrospective case-control study of PROMISE trial arm-C women randomized to receive TDF, FTC, and ritonavir-boosted lopinavir (LPV/r), who took at least 1 dose of TDF + FTC and had week-4 postrandomization DBS drawn before delivery. Cases, defined as severe adverse pregnancy/neonatal outcomes (very preterm delivery before 34 weeks of gestation, stillbirth ≥20 weeks of gestation, or infant death before 14 days-of-age), were matched to controls (1:2 ratio) by site and gestational age at entry. Week 4 and week 8 DBS samples were assayed for TFV-DP and FTC-TP by liquid chromatography and tandem mass spectrometry. Associations were tested using Wilcoxon rank test and conditional logistic regression., Results: Of 447 PROMISE arm-C women, 33 met case definitions, and overall, 22 cases and 44 controls were analyzed. Median (interquartile range) concentrations of TFV-DP at weeks 4 and 8 were 706 (375-1023) fmol/punch and 806 (414-1265) fmol/punch, respectively. Odds ratio (95% confidence interval) for severe adverse pregnancy/neonatal outcome with natural log of TFV-DP concentrations as the predictor were 1.27 (0.74 to 2.18) and 1.74 (0.66 to 4.60) at weeks 4 and 8, respectively. Median (interquartile range) concentrations of FTC-TP at weeks 4 and 8 were 0.27 (0.05-0.36) pmol/punch and 0.29 (0.05-0.40) pmol/punch, respectively., Conclusions: TFV-DP concentrations in DBS appeared not to be associated with severe adverse pregnancy/neonatal outcomes, although sample size was limited.

Background: Gambling is a behaviour engaged in by millions of people worldwide; for some, gambling can become a severely maladaptive behaviour, and previous research has identified a wide range of psychosocial risk factors that can be considered important for the development and maintenance of disordered gambling. Although risk factors have been identified, the homogeneity of risk factors across specific groups thought to be vulnerable to disordered gambling is to date, unexplored., Methods: To address this, the current review sought to conduct a systematic overview of literature relating to seven vulnerable groups: young people and adolescents, older adults, women, veterans, indigenous peoples, prisoners, and low socio-economic/income groups., Results: Multiple risk factors associated with disordered gambling were identified; some appeared consistently across most groups, including being male, co-morbid mental and physical health conditions, substance use disorders, accessibility and availability of gambling, form and mode of gambling, and experience of trauma. Further risk factors were identified that were specific to each vulnerable group., Conclusion: Within the general population, certain groups are more vulnerable to disordered gambling. Although some risk factors are consistent across groups, some risk factors appear to be group specific. It is clear that there is no homogenous pathway in to disordered gambling, and that social, developmental, environmental and demographic characteristics can all interact to influence an individual's relationship with gambling., (Copyright © 2019 Elsevier Ltd. All rights reserved.)

To design immune interventions that can synergize with antiretroviral therapy (ART) to reduce the rate of HIV mother-to-child transmission (MTCT), it is essential to characterize maternal immune responses in the setting of ART during pregnancy and breastfeeding and define their effect on MTCT. Prior studies reported an association between breast milk envelope (Env)-specific antibodies and antibody-dependent cell cytotoxicity (ADCC) activity with reduced postnatal transmission. In this study, we investigated whether these immune correlates were similarly associated with protection in a matched case-control study of mother-infant pairs receiving maternal ART or infant nevirapine prophylaxis during breastfeeding in the International Maternal-Pediatric-Adolescent AIDS Clinical Trials Network Promoting Maternal-Infant Survival Everywhere (PROMISE) trial, assessing postnatal transmission risk in 19 transmitting and 57 nontransmitting mothers using conditional logistic regression models adjusted for maternal plasma viral load. The odds ratios of postnatal MTCT for a 1-unit increase in an immune correlate were 3.61 (95% confidence interval [CI], 0.56, 23.14) for breast milk Env-specific secretory IgA (sIgA), 2.32 (95% CI, 0.43, 12.56) for breast milk and 2.16 (95% CI, 0.51, 9.14) for plasma Env-specific IgA, and 4.57 (95% CI, 0.68, 30.48) for breast milk and 0.96 (95% CI, 0.25, 3.67) for plasma ADCC activity, with all CIs spanning 1.0. Interestingly, although mucosal IgA responses are poor in untreated HIV-infected women, there was a strong correlation between the magnitudes of breast milk and plasma Env-specific IgA in this cohort. In this analysis of the small number of postnatal virus transmissions in the landmark PROMISE study, no single antibody response was associated with breast milk transmission risk. IMPORTANCE Each year, >150,000 infants become newly infected with HIV-1 through MTCT despite ART, with up to 42% of infections occurring during breastfeeding. Several factors contribute to continued pediatric infections, including ART nonadherence, the emergence of drug-resistant HIV strains, acute infection during breastfeeding, and poor access to ART in resource-limited areas. A better understanding of the maternal humoral immune responses that provide protection against postnatal transmission in the setting of ART is critical to guide the design of maternal vaccine strategies to further eliminate postnatal HIV transmission. In this study, we found that in women treated with antiretrovirals during pregnancy, there was a positive correlation between plasma viral load and breast milk and plasma IgA responses; however, conclusions regarding odds of MTCT risk were limited by the small sample size. These findings will inform future studies to investigate maternal immune interventions that can synergize with ART to eliminate MTCT during breastfeeding., (Copyright © 2019 Hompe et al.)

Research in healthy adults suggests that C957T polymorphism of the dopamine D2 receptor encoding DRD2 and the Taq1A polymorphism of the neighbouring gene ankyrin repeat and kinase domain containing 1 (ANKK1) alter dopaminergic signalling and may influence prefrontally-mediated executive functions. A systematic review and meta-analysis was carried out on the evidence for the association of DRD2 C957T and ANKK1 Taq1A polymorphisms in performance on tasks relating to the three core domains of executive function: working memory, response inhibition and cognitive flexibility in healthy adults. CINAHL, MEDLINE, PsycARTICLES and PsychINFO databases were searched for predefined key search terms associated with the two polymorphisms and executive function. Studies were included if they investigated a healthy adult population with the mean age of 18-65 years, no psychiatric or neurological disorder and only the healthy adult arm were included in studies with any case-control design. Data from 17 independent studies were included in meta-analysis, separated by the Taq1A and C957T polymorphisms and by executive function tests: working memory (Taq1A, 6 samples, n = 1270; C957 T, 6 samples, n = 977), cognitive flexibility (C957 T, 3 samples, n = 620), and response inhibition (C957 T, 3 samples, n = 598). The meta-analyses did not establish significant associations between these gene polymorphisms of interest and any of the executive function domains. Theoretical implications and methodological considerations of these findings are discussed., (Copyright © 2019 Elsevier Ltd. All rights reserved.)

Substance use disorders are chronic, relapsing, and harmful conditions characterized by executive dysfunction. While there are currently no approved pharmacotherapy options for stimulant and cannabis use disorders, there are several evidence-based options available to help reduce symptoms during detoxification and aid long-term cessation for those with tobacco, alcohol and opioid use disorders. While these medication options have shown clinical efficacy, less is known regarding their potential to enhance executive function. This narrative review aims to provide a brief overview of research that has investigated whether commonly used pharmacotherapies for these substance use disorders (nicotine, bupropion, varenicline, disulfiram, acamprosate, nalmefene, naltrexone, methadone, buprenorphine, and lofexidine) effect three core executive function components (working memory, inhibitory control and cognitive flexibility). While pharmacotherapy-induced enhancement of executive function may improve cessation outcomes in dependent populations, there are limited and inconsistent findings regarding the effects of these medications on executive function. We discuss possible reasons for the mixed findings and suggest some future avenues of work that may enhance the understanding of addiction pharmacotherapy and cognitive training interventions and lead to improved patient outcomes.

Background: No randomized trial has directly compared the efficacy of prolonged infant antiretroviral prophylaxis versus maternal antiretroviral therapy (mART) for prevention of mother-to-child transmission throughout the breastfeeding period., Setting: Fourteen sites in Sub-Saharan Africa and India., Methods: A randomized, open-label strategy trial was conducted in HIV-1-infected women with CD4 counts ≥350 cells/mm (or ≥country-specific ART threshold if higher) and their breastfeeding HIV-1-uninfected newborns. Randomization at 6-14 days postpartum was to mART or infant nevirapine (iNVP) prophylaxis continued until 18 months after delivery or breastfeeding cessation, infant HIV-1 infection, or toxicity, whichever occurred first. The primary efficacy outcome was confirmed infant HIV-1 infection. Efficacy analyses included all randomized mother-infant pairs except those with infant HIV-1 infection at entry., Results: Between June 2011 and October 2014, 2431 mother-infant pairs were enrolled; 97% of women were World Health Organization Clinical Stage I, median screening CD4 count 686 cells/mm. Median infant gestational age/birth weight was 39 weeks/2.9 kilograms. Seven of 1219 (0.57%) and 7 of 1211 (0.58%) analyzed infants in the mART and iNVP arms, respectively, were HIV-infected (hazard ratio 1.0, 96% repeated confidence interval 0.3-3.1); infant HIV-free survival was high (97.1%, mART and 97.7%, iNVP, at 24 months). There were no significant differences between arms in median time to breastfeeding cessation (16 months) or incidence of severe, life-threatening, or fatal adverse events for mothers or infants (14 and 42 per 100 person-years, respectively)., Conclusions: Both mART and iNVP prophylaxis strategies were safe and associated with very low breastfeeding HIV-1 transmission and high infant HIV-1-free survival at 24 months.

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., (Copyright © 2017 Elsevier Inc. All rights reserved.)

Introduction: Impaired monitoring of errors and conflict (performance monitoring; PM) is well documented in substance dependence (SD) including nicotine dependence and may contribute to continued drug use. Contemporary models of PM and complementary behavioural evidence suggest that PM works by integrating recent reinforcement history rather than evaluating individual behaviours. Despite this, studies of PM in SD have typically used indices derived from reaction to task error or conflict on individual trials. Consequently impaired integration of reinforcement history during action selection tasks requiring behavioural control in SD populations has been underexplored., Methods: A reinforcement learning task assessed the ability of abstinent, satiated, former and never smokers (N=60) to integrate recent reinforcement history alongside a more typical behavioural index of PM reflecting the degree of reaction time slowing following an error (post-punishment slowing; PPS)., Results: On both indices there was a consistent pattern in PM data: Former smokers had the greatest and satiated smokers the poorest PM. Specifically satiated smokers had poorer reinforcement integration than former (p=0.005) and never smokers (p=0.041) and had less post-punishment slowing than former (p<0.001), never (p=0.003) and abstinent smokers (p=0.026)., Conclusions: These are the first data examining the effects of smoking status on PM that use an integration of reinforcement history metric. The concordance of the reinforcement integration and PPS data suggest that this could be a promising method to interrogate PM in future studies. PM is influenced by smoking status. As PM is associated with adapting behaviour, poor PM in satiated smokers may contribute towards continued smoking despite negative consequences. Former smokers show elevated PM suggesting this may be a good relapse prevention target for individuals struggling to remain abstinent however prospective and intervention studies are needed. A better understanding of PM deficits in terms of reinforcement integration failure may stimulate development of novel treatment approaches., (Copyright © 2017 Elsevier Inc. All rights reserved.)

Introduction: Previous research has indicated that variation in genes encoding catechol-O-methyltransferase ( COMT ) and dopamine receptor D2 ( DRD2 ) may influence cognitive function and that this may confer vulnerability to the development of mental health disorders such as schizophrenia. However, increasing evidence suggests environmental factors such as early life stress may interact with genetic variants in affecting these cognitive outcomes. This study investigated the effect of COMT Val158Met and DRD2 C957T polymorphisms on executive function and the impact of early life stress in healthy adults., Methods: One hundred and twenty-two healthy adult males (mean age 35.2 years, range 21-63) were enrolled in the study. Cognitive function was assessed using Cambridge Neuropsychological Test Automated Battery and early life stress was assessed using the Childhood Traumatic Events Scale (Pennebaker & Susman, 1988)., Results: DRD2 C957T was significantly associated with executive function, with CC homozygotes having significantly reduced performance in spatial working memory and spatial planning. A significant genotype-trauma interaction was found in Rapid Visual Information Processing test, a measure of sustained attention, with CC carriers who had experienced early life stress exhibiting impaired performance compared to the CC carriers without early life stressful experiences. There were no significant findings for COMT Val158Met ., Conclusions: This study supports previous findings that DRD2 C957T significantly affects performance on executive function related tasks in healthy individuals and shows for the first time that some of these effects may be mediated through the impact of childhood traumatic events. Future work should aim to clarify further the effect of stress on neuronal systems that are known to be vulnerable in mental health disorders and more specifically what the impact of this might be on cognitive function.

Growing evidence implicates impairment of autophagy as a candidate pathogenic mechanism in the spectrum of neurodegenerative disorders which includes amyotrophic lateral sclerosis and frontotemporal lobar degeneration (ALS-FTLD). SQSTM1, which encodes the autophagy receptor SQSTM1/p62, is genetically associated with ALS-FTLD, although to date autophagy-relevant functional defects in disease-associated variants have not been described. A key protein-protein interaction in autophagy is the recognition of a lipid-anchored form of LC3 (LC3-II) within the phagophore membrane by SQSTM1, mediated through its LC3-interacting region (LIR), and notably some ALS-FTLD mutations map to this region. Here we show that although representing a conservative substitution and predicted to be benign, the ALS-associated L341V mutation of SQSTM1 is defective in recognition of LC3B. We place our observations on a firm quantitative footing by showing the L341V-mutant LIR is associated with a ∼3-fold reduction in LC3B binding affinity and using protein NMR we rationalize the structural basis for the effect. This functional deficit is realized in motor neuron-like cells, with the L341V mutant EGFP-mCherry-SQSTM1 less readily incorporated into acidic autophagic vesicles than the wild type. Our data supports a model in which the L341V mutation limits the critical step of SQSTM1 recruitment to the phagophore. The oligomeric nature of SQSTM1, which presents multiple LIRs to template growth of the phagophore, potentially gives rise to avidity effects which amplify the relatively modest impact of any single mutation on LC3B binding. Over the lifetime of a neuron, impaired autophagy could expose a vulnerability, which ultimately tips the balance from cell survival toward cell death.

Background: Collection of genetic biospecimens as part of critical illness investigations is increasingly commonplace. Oversight bodies vary in restrictions imposed on genetic research, introducing inconsistencies in study design, potential for sampling bias, and the possibility of being overly prohibitive of this type of research altogether. We undertook this study to better understand whether restrictions on genetic data collection beyond those governing research on cognitively intact subjects reflect the concerns of surrogates for critically ill patients., Methods: We analyzed survey data collected from 1,176 patients in nonurgent settings and 437 surrogates representing critically ill adults. Attitudes pertaining to genetic data (familiarity, perceptions, interest in participation, concerns) and demographic information were examined using univariate and multivariate techniques., Results: We explored differences among respondents who were receptive (1,333) and nonreceptive (280) to genetic sample collection. Whereas factors positively associated with receptivity to research participation were "complete trust" in health-care providers (OR, 2.091; 95% CI, 1.544-2.833), upper income strata (OR, 2.319; 95% CI, 1.308-4.114), viewing genetic research "very positively" (OR, 3.524; 95% CI, 2.122-5.852), and expressing "no worry at all" regarding disclosure of results (OR, 2.505; 95% CI, 1.436-4.369), black race was negatively associated with research participation (OR, 0.410; 95% CI, 0.288-0.585). We could detect no difference in receptivity to genetic sample collection comparing ambulatory patients and surrogates (OR, 0.738; 95% CI, 0.511-1.066)., Conclusions: Expressing trust in health-care providers and viewing genetic research favorably were associated with increased willingness for study enrollment, while concern regarding breach of confidentiality and black race had the opposite effect. Study setting had no bearing on willingness to participate.

The fitness effects of mutations are context specific and depend on both external (e.g., environment) and internal (e.g., cellular stress, genetic background) factors. The influence of population size and density on fitness effects are unknown, despite the central role population size plays in the supply and fixation of mutations. We addressed this issue by comparing the fitness of 92 Keio strains (Escherichia coli K12 single gene knockouts) at comparatively high (1.2×10(7) CFUs/mL) and low (2.5×10(2) CFUs/mL) densities, which also differed in population size (high: 1.2×10(8); low: 1.25×10(3)). Twenty-eight gene deletions (30%) exhibited a fitness difference, ranging from 5 to 174% (median: 35%), between the high and low densities. Our analyses suggest this variation among gene deletions in fitness responses reflected in part both gene orientation and function, of the gene properties we examined (genomic position, length, orientation, and function). Although we could not determine the relative effects of population density and size, our results suggest fitness effects of mutations vary with these two factors, and this variation is gene-specific. Besides being a mechanism for density-dependent selection (r-K selection), the dependence of fitness effects on population density and size has implications for any population that varies in size over time, including populations undergoing evolutionary rescue, species invasions into novel habitats, and cancer progression and metastasis. Further, combined with recent advances in understanding the roles of other context-specific factors in the fitness effects of mutations, our results will help address theoretical and applied biological questions more realistically.