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Background Increasing the availability of non-alcoholic options is a promising population-level intervention to reduce alcohol consumption, currently unassessed in naturalistic settings. This study in an online retail context aimed to estimate the impact of increasing the proportion of non-alcoholic (relative to alcoholic) drinks, on selection and purchasing of alcohol. Methods and results Adults (n = 737) residing in England and Wales who regularly purchased alcohol online were recruited between March and July 2021. Participants were randomly assigned to one of 3 groups: '25% non-alcoholic/75% alcoholic'; '50% non-alcoholic/50% alcoholic'; and '75% non-alcoholic/25% alcoholic,' then selected drinks in a simulated online supermarket, before purchasing them in an actual online supermarket. The primary outcome was the number of alcohol units selected (with intention to purchase); secondary outcomes included actual purchasing. A total of 607 participants (60% female, mean age = 38 years [range: 18 to 76]) completed the study and were included in the primary analysis. In the first part of a hurdle model, a greater proportion of participants in the '75% non-alcoholic' group did not select any alcohol (13.1%) compared to the '25% non-alcoholic' group (3.4%; 95% confidence interval [CI] -2.09, -0.63; p < 0.001). There was no evidence of a difference between the '75% non-alcoholic' and the '50% non-alcoholic' (7.2%) groups (95% CI 0.10, 1.34; p = 0.022) or between the '50% non-alcoholic' and the '25% non-alcoholic' groups (95% CI -1.44, 0.17; p = 0.121). In the second part of a hurdle model in participants (559/607) selecting any drinks containing alcohol, the '75% non-alcoholic' group selected fewer alcohol units compared to the '50% non-alcoholic' (95% CI -0.44, -0.14; p < 0.001) and '25% non-alcoholic' (95% CI -0.54, -0.24; p < 0.001) groups, with no evidence of a difference between the '50% non-alcoholic' and '25% non-alcoholic' groups (95% CI -0.24, 0.05; p = 0.178). Overall, across all participants, 17.46 units (95% CI 15.24, 19.68) were selected in the '75% non-alcoholic' group; 25.51 units (95% CI 22.60, 28.43) in the '50% non-alcoholic' group; and 29.40 units (95% CI 26.39, 32.42) in the '25% non-alcoholic' group. This corresponds to 8.1 fewer units (a 32% reduction) in the '75% non-alcoholic' compared to the '50% non-alcoholic' group, and 11.9 fewer alcohol units (41% reduction) compared to the '25% non-alcoholic' group; 3.9 fewer units (13% reduction) were selected in the '50% non-alcoholic' group than in the '25% non-alcoholic' group. For all other outcomes, alcohol selection and purchasing were consistently lowest in the '75% non-alcoholic' group. Study limitations include the setting not being entirely naturalistic due to using a simulated online supermarket as well as an actual online supermarket, and that there was substantial dropout between selection and purchasing. Conclusions This study provides evidence that substantially increasing the proportion of non-alcoholic drinks-from 25% to 50% or 75%-meaningfully reduces alcohol selection and purchasing. Further studies are warranted to assess whether these effects are realised in a range of real-world settings. Trial registration ISRCTN: 11004483; OSF: https://osf.io/qfupw., Author(s): Natasha Clarke 1,2,*, Anna K. M. Blackwell 3,4, Jennifer Ferrar 3, Katie De-Loyde 3, Mark A. Pilling 1, Marcus R. Munafò 3, Theresa M. Marteau 1,*, Gareth J. Hollands [...]

The detrimental health effects of smoking are well-known, but the impact of regular nicotine use without exposure to the other constituents of tobacco is less clear. Given the increasing daily use of alternative nicotine delivery systems, such as e-cigarettes, it is increasingly important to understand and separate the effects of nicotine use from the impact of tobacco smoke exposure. Using a multivariable Mendelian randomisation framework, we explored the direct effects of nicotine compared with the non-nicotine constituents of tobacco smoke on health outcomes (lung cancer, chronic obstructive pulmonary disease [COPD], forced expiratory volume in one second [FEV-1], forced vital capacity [FVC], coronary heart disease [CHD], and heart rate [HR]). We used Genome-Wide Association Study (GWAS) summary statistics from Buchwald and colleagues, the GWAS and Sequencing Consortium of Alcohol and Nicotine, the International Lung Cancer Consortium, and UK Biobank. Increased nicotine metabolism increased the risk of COPD, lung cancer, and lung function in the univariable analysis. However, when accounting for smoking heaviness in the multivariable analysis, we found that increased nicotine metabolite ratio (indicative of decreased nicotine exposure per cigarette smoked) decreases heart rate (b = -0.30, 95% CI -0.50 to -0.10) and lung function (b = -33.33, 95% CI -41.76 to -24.90). There was no clear evidence of an effect on the remaining outcomes. The results suggest that these smoking-related outcomes are not due to nicotine exposure but are caused by the other components of tobacco smoke; however, there are multiple potential sources of bias, and the results should be triangulated using evidence from a range of methodologies. Author summary: Although we know that smoking tobacco negatively impacts health, we know relatively little about whether nicotine plays a role in causing poor health outcomes. When used for short periods of time, nicotine appears to have little impact on health. However, until recently, nicotine has rarely been used for long periods without accompanying exposure to tobacco smoke, so it is hard to disentangle the effects of regular nicotine use from the effects of tobacco smoke exposure. In this study, we aimed to dissect the effects of nicotine versus non-nicotine constituents of tobacco smoke on heart and lung health using multivariable Mendelian randomisation and data from a range of sources (including UK Biobank). We found that nicotine does not appear to be an independent cause of poor lung function, lung cancer, chronic obstructive pulmonary disease, or coronary heart disease, but does increase heart rate. These results support previous evidence which suggests that nicotine on its own does not directly cause poor health outcomes, with the exception of increasing heart rate. [ABSTRACT FROM AUTHOR]

Background Tobacco smoking and e-cigarette use are strongly associated, but it is currently unclear whether this association is causal, or due to shared factors that influence both behaviours such as a shared genetic liability. The aim of this study was to investigate whether polygenic risk scores (PRS) for smoking initiation are associated with ever use of e-cigarettes. Methods and findings Smoking initiation PRS were calculated for young adults (N = 7,859, mean age = 24 years, 51% male) of European ancestry in the Avon Longitudinal Study of Parents and Children, a prospective birth cohort study initiated in 1991. PRS were calculated using the GWAS & Sequencing Consortium of Alcohol and Nicotine use (GSCAN) summary statistics. Five thresholds ranging from 5 x 10.sup.-8 to 0.5 were used to calculate 5 PRS for each individual. Using logistic regression, we investigated the association between smoking initiation PRS and the main outcome, self-reported e-cigarette use (n = 2,894, measured between 2016 and 2017), as well as self-reported smoking initiation and 8 negative control outcomes (socioeconomic position at birth, externalising disorders in childhood, and risk-taking in young adulthood). A total of 878 young adults (30%) had ever used e-cigarettes at 24 years, and 150 (5%) were regular e-cigarette users at 24 years. We observed positive associations of similar magnitude between smoking initiation PRS (created using the p < 5 x 10.sup.-8 threshold) and both smoking initiation (odds ratio (OR) = 1.29, 95% CI 1.19 to 1.39, p < 0.001) and ever e-cigarette use (OR = 1.24, 95% CI 1.14 to 1.34, p < 0.001) by the age of 24 years, indicating that a genetic predisposition to smoking initiation is associated with an increased risk of using e-cigarettes. At lower p-value thresholds, we observed an association between smoking initiation PRS and ever e-cigarette use among never smokers. We also found evidence of associations between smoking initiation PRS and some negative control outcomes, particularly when less stringent p-value thresholds were used to create the PRS, but also at the strictest threshold (e.g., gambling, number of sexual partners, conduct disorder at 7 years, and parental socioeconomic position at birth). However, this study is limited by the relatively small sample size and potential for collider bias. Conclusions Our results indicate that there may be a shared genetic aetiology between smoking and e-cigarette use, and also with socioeconomic position, externalising disorders in childhood, and risky behaviour more generally. This indicates that there may be a common genetic vulnerability to both smoking and e-cigarette use, which may reflect a broad risk-taking phenotype., Author(s): Jasmine N. Khouja 1,2,3,*, Robyn E. Wootton 1,2, Amy E. Taylor 2,4, George Davey Smith 1,2, Marcus R. Munafò 1,3,4 Introduction There are an estimated 3.6 million electronic cigarette [...]

The causes of multiple sclerosis (MS) remain unknown. Smoking has been associated with MS in observational studies and is often thought of as an environmental risk factor. We used two-sample mendelian randomization (MR) to examine whether this association is causal using genetic variants identified in genome-wide association studies (GWASs) as associated with smoking. We assessed both smoking initiation and lifetime smoking behaviour (which captures smoking duration, heaviness, and cessation). There was very limited evidence for a meaningful effect of smoking on MS susceptibility as measured using summary statistics from the International Multiple Sclerosis Genetics Consortium (IMSGC) meta-analysis, including 14,802 cases and 26,703 controls. There was no clear evidence for an effect of smoking on the risk of developing MS (smoking initiation: odds ratio [OR] 1.03, 95% confidence interval [CI] 0.92–1.61; lifetime smoking: OR 1.10, 95% CI 0.87–1.40). These findings suggest that smoking does not have a detrimental consequence on MS susceptibility. Further work is needed to determine the causal effect of smoking on MS progression. Smoking is associated as an environmental risk factor with multiple sclerosis (MS). This study used genetic variants in a Mendelian Randomization framework to examine whether this relationship is causal, finding very limited evidence for a meaningful effect of smoking on MS susceptibility. [ABSTRACT FROM AUTHOR]

Biomarkers can be used to assess smoking behaviour more accurately and objectively than self-report. This study assessed the association between cotinine (a biomarker of smoke exposure) and later e-cigarette use among a population who were unexposed to e-cigarettes in youth. Young people in the Avon Longitudinal Study of Parents and Children took part in the study. We observed associations between cotinine at 15 years (measured between 2006 and 2008 before the wide availability of e-cigarettes) and self-reported ever use of e-cigarettes at 22 (measured between 2014 and 2015 when e-cigarettes were widely available) using logistic regression. A range of potential confounders were adjusted for (age, sex, body mass index, alcohol use and passive smoke exposure). Additionally, we adjusted for the young people's self-reported smoking status/history to explore potential misreporting and measurement error. In a sample of N = 1,194 young people, cotinine levels consistent with active smoking at 15 years were associated with increased odds of e-cigarette ever use at 22 years (Odds Ratio [OR] = 7.24, 95% CI 3.29 to 15.93) even when self-reported active smoking status at age 16 (OR = 3.14, 95% CI 1.32 to 7.48) and latent classes of smoking behaviour from 14 to 16 (OR = 2.70, 95% CI 0.98 to 7.44) were included in the model. Cotinine levels consistent with smoking in adolescence were strongly associated with increased odds of later e-cigarette use, even after adjusting for reported smoking behaviour at age 16 and smoking transitions from 14 to 16. [ABSTRACT FROM AUTHOR]

There is substantial variation in the timing of significant reproductive life events such as menarche and first sexual intercourse. Life history theory explains this variation as an adaptive response to an individual's environment and it is important to examine how traits within life history strategies affect each other. Here we applied Mendelian randomization (MR) methods to investigate whether there is a causal effect of variation in age at menarche and age at first sexual intercourse (markers or results of exposure to early life adversity) on outcomes related to reproduction, education and risky behaviour in UK Biobank (N = 114 883–181 255). Our results suggest that earlier age at menarche affects some traits that characterize life history strategies including earlier age at first and last birth, decreased educational attainment, and decreased age at leaving education (for example, we found evidence for a 0.26 year decrease in age at first birth per year decrease in age at menarche, 95% confidence interval: -0.34 to -0.17; p < 0.001). We find no clear evidence of effects of age at menarche on other outcomes, such as risk taking behaviour. Age at first sexual intercourse was also related to many life history outcomes, although there was evidence of horizontal pleiotropy which violates an assumption of MR and we therefore cannot infer causality from this analysis. Taken together, these results highlight how MR can be applied to test predictions of life history theory and to better understand determinants of health and social behaviour. [ABSTRACT FROM AUTHOR]

Mendelian randomization (MR) is an established approach to evaluate the effect of an exposure on an outcome. The gene-by-environment (GxE) study design can be used to determine whether the genetic instrument affects the outcome through pathways other than via the exposure of interest (horizontal pleiotropy). MR phenome-wide association studies (MR-pheWAS) search for the effects of an exposure, and can be conducted in UK Biobank using the PHESANT package. In this proof-of-principle study, we introduce the novel GxE MR-pheWAS approach, that combines MR-pheWAS with the use of GxE interactions. This method aims to identify the presence of effects of an exposure while simultaneously investigating horizontal pleiotropy. We systematically test for the presence of causal effects of smoking heaviness–stratifying on smoking status (ever versus never)–as an exemplar. If a genetic variant is associated with smoking heaviness (but not smoking initiation), and this variant affects an outcome (at least partially) via tobacco intake, we would expect the effect of the variant on the outcome to differ in ever versus never smokers. We used PHESANT to test for the presence of effects of smoking heaviness, instrumented by genetic variant rs16969968, among never and ever smokers respectively, in UK Biobank. We ranked results by the strength of interaction between ever and never smokers. We replicated previously established effects of smoking heaviness, including detrimental effects on lung function. Novel results included a detrimental effect of heavier smoking on facial aging. We have demonstrated how GxE MR-pheWAS can be used to identify potential effects of an exposure, while simultaneously assessing whether results may be biased by horizontal pleiotropy. Mendelian randomization uses genetic variants associated with an exposure to investigate causality. For instance, a genetic variant that relates to how heavily a person smokes, has been used to test whether smoking causally affects health outcomes. Mendelian randomization is biased if the genetic variant also affects the outcome via other pathways. We exploit additional information–that the effect of heavy smoking only occurs in people who actually smoke–to overcome this problem. By testing associations in ever and never smokers separately we can assess whether the genetic variant affects an outcome via smoking or another pathway. If the effect is at least partially via smoking heaviness, we would expect the effect to differ in ever versus never smokers, and this would suggest that smoking causally influences the outcome. Previous Mendelian randomization studies of smoking heaviness focused on specific outcomes–here we searched for the presence of causal effects of smoking heaviness across over 18 000 traits. We identified previously established effects (e.g. a detrimental effect on lung function) and novel results including a detrimental effect of heavier smoking on facial aging. Our approach can be used to test for the presence of causal effects of other exposures, where the exposure only occurs in known subsets of the population. [ABSTRACT FROM AUTHOR]

Background: The shape of glassware may exacerbate or counteract biases in perceived volume, which may lead people to misjudge the pouring of alcoholic drinks. The aim of these studies was to investigate the effect of glass shape on the pouring accuracy of liquid volume. Methods: In Study 1, using an online computerised task, participants (n = 211) were asked to pour liquid in glasses in a within-subjects design with factors of glass shape (straight, curved) and requested percentage fullness (10, 20, 25, 30, 40, 50, 60, 70, 75, 80, 90%). Curve estimations were carried out to determine if errors followed a linear or non-linear relationship. In Study 2, in a real world experimental study, participants (n = 96) were asked to pour water to the midpoint of pint glasses in a within-subjects design with one factor of glass shape (straight, curved, tulip, inverted). Differences between poured amounts were analysed using one-way repeated measures ANOVA. Results: In Study 1, participants under-poured in curved glasses compared to straight glasses at all requested amounts. In Study 2, participants under-poured in curved (p < 0.001, dz = 1.51) and tulip (p < 0.001, dz = 0.59) glasses compared to straight glasses. Findings were inconclusive as to whether or not a difference was present between pourings in inverted and straight glasses. Participants displayed a tendency to under-pour in all glasses relative to requested amounts in both studies. Conclusions: The shape of glassware appears to influence the pouring accuracy of liquid. Pouring in tulip and curved glasses was more inaccurate compared to straight glasses, possibly due to the height of liquid within the glass and volume changing in a non-linear relationship. [ABSTRACT FROM AUTHOR]

Biologists determine experimental effects by perturbing biological entities or units. When done appropriately, independent replication of the entity–intervention pair contributes to the sample size (N) and forms the basis of statistical inference. If the wrong entity–intervention pair is chosen, an experiment cannot address the question of interest. We surveyed a random sample of published animal experiments from 2011 to 2016 where interventions were applied to parents and effects examined in the offspring, as regulatory authorities provide clear guidelines on replication with such designs. We found that only 22% of studies (95% CI = 17%–29%) replicated the correct entity–intervention pair and thus made valid statistical inferences. Nearly half of the studies (46%, 95% CI = 38%–53%) had pseudoreplication while 32% (95% CI = 26%–39%) provided insufficient information to make a judgement. Pseudoreplication artificially inflates the sample size, and thus the evidence for a scientific claim, resulting in false positives. We argue that distinguishing between biological units, experimental units, and observational units clarifies where replication should occur, describe the criteria for genuine replication, and provide concrete examples of in vitro, ex vivo, and in vivo experimental designs. [ABSTRACT FROM AUTHOR]

Research into the causal and perpetuating factors influencing aggression has partly focused on the general tendency of aggression-prone individuals to infer hostile intent in others, even in ambiguous circumstances. This is referred to as the ‘hostile interpretation bias’. Whether this hostile interpretation bias also exists in basal information processing, such as perception of facial emotion, is not yet known, especially with respect to the perception of ambiguous expressions. In addition, little is known about how this potential bias in facial emotion perception is related to specific characteristics of aggression. In the present study, conducted in a penitentiary setting with detained male adults, we investigated if violent offenders (n = 71) show a stronger tendency to interpret ambiguous facial expressions on a computer task as angry rather than happy, compared to non-violent offenders (n = 14) and to a control group of healthy volunteers (n = 32). We also investigated if hostile perception of facial expressions is related to specific characteristics of aggression, such as proactive and reactive aggression. No clear statistical evidence was found that violent offenders perceived facial emotional expressions as more angry than non-violent offenders or healthy volunteers. A regression analysis in the violent offender group showed that only age and a self-report measure of hostility predicted outcome on the emotion perception task. Other traits, such as psychopathic traits, intelligence, attention and a tendency to jump to conclusions were not associated with interpretation of anger in facial emotional expressions. We discuss the possible impact of the study design and population studied on our results, as well as implications for future studies. [ABSTRACT FROM AUTHOR]

We can regard the wider incentive structures that operate across science, such as the priority given to novel findings, as an ecosystem within which scientists strive to maximise their fitness (i.e., publication record and career success). Here, we develop an optimality model that predicts the most rational research strategy, in terms of the proportion of research effort spent on seeking novel results rather than on confirmatory studies, and the amount of research effort per exploratory study. We show that, for parameter values derived from the scientific literature, researchers acting to maximise their fitness should spend most of their effort seeking novel results and conduct small studies that have only 10%–40% statistical power. As a result, half of the studies they publish will report erroneous conclusions. Current incentive structures are in conflict with maximising the scientific value of research; we suggest ways that the scientific ecosystem could be improved. [ABSTRACT FROM AUTHOR]

Static high contrast (‘dazzle’) patterns, such as zigzags, have been shown to reduce the perceived speed of an object. It has not escaped our notice that this effect has possible military applications and here we report a series of experiments on humans, designed to establish whether dynamic dazzle patterns can cause distortions of perceived speed sufficient to provide effective defence in the field, and the extent to which these effects are robust to a battery of manipulations. Dynamic stripe patterns moving in the same direction as the target are found to increase the perceived speed of that target, whilst dynamic stripes moving in the opposite direction to the target reduce the perceived speed. We establish the optimum position for such dazzle patches; confirm that reduced contrast and the addition of colour do not affect the performance of the dynamic dazzle, and finally, using the CO2 challenge, show that the effect is robust to stressful conditions. [ABSTRACT FROM AUTHOR]

Psychotic Experiences (PEs) during adolescence index increased risk for psychotic disorders and schizophrenia in adult life. Working memory (WM) deficits are a core feature of these disorders. Our objective was to examine the relationship between PEs and WM in a general population sample of young people in a case control study. 4744 individuals of age 17–18 from Bristol and surrounding areas (UK) were analyzed in a cross-sectional study nested within the Avon Longitudinal Study of Parents and Children (ALSPAC) birth cohort study. The dependent variable was PEs, assessed using the semi-structured Psychosis-Like Symptom Interview (PLIKSi). The independent variable was performance on a computerized numerical n-back working memory task. Signal-Detection Theory indices, including standardized hits rate, false alarms rate, discriminability index (d’) and response bias (c) from 2-Back and 3-Back tasks were calculated. 3576 and 3527 individuals had complete data for 2-Back and 3-Back respectively. Suspected/definite PEs prevalence was 7.9% (N = 374). Strongest evidence of association was seen between PEs and false alarms on the 2-Back, (odds ratio (OR) = 1.17 [95% confidence intervals (CI) 1.01, 1.35]) and 3-back (OR = 1.35 [1.18, 1.54]) and with c (OR = 1.59 [1.09, 2.34]), and lower d’ (OR = 0.76 [0.65, 0.89]), on the 3-Back. Adjustment for several potential confounders, including general IQ, drug exposure and different psycho-social factors, and subsequent multiple imputation of missing data did not materially alter the results. WM is impaired in young people with PEs in the general population. False alarms, rather than poor accuracy, are more closely related to PEs. Such impairment is consistent with different neuropsychological models of psychosis focusing on signal-to-noise discrimination, probabilistic reasoning and impaired reality monitoring as a basis of psychotic symptoms. [ABSTRACT FROM AUTHOR]

As our understanding of genetics has improved, genome-wide association studies (GWAS) have identified numerous variants associated with lifestyle behaviours and health outcomes. However, what is sometimes overlooked is the possibility that genetic variants identified in GWAS of disease might reflect the effect of modifiable risk factors as well as direct genetic effects. We discuss this possibility with illustrative examples from tobacco and alcohol research, in which genetic variants that predict behavioural phenotypes have been seen in GWAS of diseases known to be causally related to these behaviours. This consideration has implications for the interpretation of GWAS findings. [ABSTRACT FROM AUTHOR]

There is increasing public and scientific concern regarding the long-term behavioural effects of video game use in children, but currently little consensus as to the nature of any such relationships. We investigated the relationship between video game use in children, degree of violence in games, and measures of depression and a 6-level banded measure of conduct disorder. Data from the Avon Longitudinal Study of Parents and Children were used. A 3-level measure of game use at age 8/9 years was developed, taking into account degree of violence based on game genre. Associations with conduct disorder and depression, measured at age 15, were investigated using ordinal logistic regression, adjusted for a number of potential confounders. Shoot-em-up games were associated with conduct disorder bands, and with a binary measure of conduct disorder, although the strength of evidence for these associations was weak. A sensitivity analysis comparing those who play competitive games to those who play shoot-em-ups found weak evidence supporting the hypothesis that it is violence rather than competitiveness that is associated with conduct disorder. However this analysis was underpowered, and we cannot rule out the possibility that increasing levels of competition in games may be just as likely to account for the observed associations as violent content. Overall game exposure as indicated by number of games in a household was not related to conduct disorder, nor was any association found between shoot-em-up video game use and depression. [ABSTRACT FROM AUTHOR]

Background: Judgements of volume may influence the rate of consumption of alcohol and, in turn, the amount consumed. The aim of the current study was to examine the impact of the size and shape of wine glasses on perceptions of wine volume. Methods: Online experiment: Participants (n = 360; recruited via Mechanical Turk) were asked to match the volume of wine in two wine glasses, specifically: 1. the Reference glass holding a fixed reference volume, and 2. the Comparison glass, for which the volume could be altered until participants perceived it matched the reference volume. One of three comparison glasses was shown in each trial: ‘wider’ (20% wider but same capacity); ‘larger’ (same width but 25% greater capacity); or ‘wider-and-larger’ (20% wider and 25% greater capacity). Reference volumes were 125ml, 175ml and 250ml, in a fully factorial within-subjects design: 3 (comparison glass) x 3 (reference volume). Non-zero differences between the volumes with which participants filled comparison glasses and the corresponding reference volumes were identified using sign-rank tests. Results: Participants under-filled the wider glass relative to the reference glass for larger reference volumes, and over-filled the larger glass relative to the reference glass for all reference volumes. Results for the wider-and-larger glass showed a mixed pattern across reference volume. For all comparison glasses, in trials with larger reference volumes participants tended to fill the comparison glass less, relative to trials with smaller reference volumes for the same comparison glass. Conclusions: These results are broadly consistent with people using the relative fullness of glasses to judge volume, and suggest both the shape and capacity of wine glasses may influence perceived volume. Perceptions that smaller glasses contain more than larger ones (despite containing the same volume), could slow drinking speed and overall consumption by serving standard portions in smaller glasses. This hypothesis awaits testing. [ABSTRACT FROM AUTHOR]

Background: Possession of the ε4 allele of the Apolipoprotein E (APOE) gene is associated with an increased risk of Alzheimer’s disease. Early adult life effects of ε4 are less well understood. Working memory has been relatively little studied (compared to episodic memory) in relation to APOE genotype despite its importance in cognitive functioning. Our hypothesis was that ε4 would lead to an impairment in working memory in young adults. Methods: We studied working memory using a computerised n-back task in the Avon Longitudinal Study of Parents and Children (ALSPAC) at age 18. Data was available for 1049–1927 participants and for the 2- and 3-back versions of the task. Using multiple and multi-level regression controlling for important confounders we examined the association between APOE genotype on accuracy and reaction times. Results: There was no evidence of a genotype effect on accuracy when the two difficulty levels were examined separately. There was some evidence to support a deleterious effect of the ε4 allele on n-back accuracy in the multi-level regression. There was weak evidence that the ε22 group were less accurate but the numbers were very low in this group. The ε34 group had faster reaction times than the reference ε33 group in all adjusted analyses but the ε44 group were only faster in the 3-back condition in multi-level analyses. Conclusions: There was no evidence of benefit in ε4 carriers, but there was some evidence of a detrimental effect on working memory in this large study. [ABSTRACT FROM AUTHOR]

Background: Fear of negative evaluation (FNE) defines social anxiety yet the process of inferring social evaluation, and its potential role in maintaining social anxiety, is poorly understood. We developed an instrumental learning task to model social evaluation learning, predicting that FNE would specifically bias learning about the self but not others. Methods: During six test blocks (3 self-referential, 3 other-referential), participants (n = 100) met six personas and selected a word from a positive/negative pair to finish their social evaluation sentences “I think [you are / George is]…”. Feedback contingencies corresponded to 3 rules, liked, neutral and disliked, with P[positive word correct] = 0.8, 0.5 and 0.2, respectively. Results: As FNE increased participants selected fewer positive words (β = −0.4, 95% CI −0.7, −0.2, p = 0.001), which was strongest in the self-referential condition (FNE × condition 0.28, 95% CI 0.01, 0.54, p = 0.04), and the neutral and dislike rules (FNE × condition × rule, p = 0.07). At low FNE the proportion of positive words selected for self-neutral and self-disliked greatly exceeded the feedback contingency, indicating poor learning, which improved as FNE increased. Conclusions: FNE is associated with differences in processing social-evaluative information specifically about the self. At low FNE this manifests as insensitivity to learning negative self-referential evaluation. High FNE individuals are equally sensitive to learning positive or negative evaluation, which although objectively more accurate, may have detrimental effects on mental health. [ABSTRACT FROM AUTHOR]

Two genetic loci, one in the cytochrome P450 1A1 (CYP1A1) and 1A2 (CYP1A2) gene region (rs2472297) and one near the aryl-hydrocarbon receptor (AHR) gene (rs6968865), have been associated with habitual caffeine consumption. We sought to establish whether a more refined and comprehensive assessment of caffeine consumption would provide stronger evidence of association, and whether a combined allelic score comprising these two variants would further strengthen the association. We used data from between 4,460 and 7,520 women in the Avon Longitudinal Study of Parents and Children, a longitudinal birth cohort based in the United Kingdom. Self-report data on coffee, tea and cola consumption (including consumption of decaffeinated drinks) were available at multiple time points. Both genotypes were individually associated with total caffeine consumption, and with coffee and tea consumption. There was no association with cola consumption, possibly due to low levels of consumption in this sample. There was also no association with measures of decaffeinated drink consumption, indicating that the observed association is most likely mediated via caffeine. The association was strengthened when a combined allelic score was used, accounting for up to 1.28% of phenotypic variance. This was not associated with potential confounders of observational association. A combined allelic score accounts for sufficient phenotypic variance in caffeine consumption that this may be useful in Mendelian randomization studies. Future studies may therefore be able to use this combined allelic score to explore causal effects of habitual caffeine consumption on health outcomes. [ABSTRACT FROM AUTHOR]

Background: Functional magnetic resonance imaging (fMRI) studies have reported multiple activation foci associated with a variety of conditions, stimuli or tasks. However, most of these studies used fewer than 40 participants. Methodology: After extracting data (number of subjects, condition studied, number of foci identified and threshold) from 94 brain fMRI meta-analyses (k = 1,788 unique datasets) published through December of 2011, we analyzed the correlation between individual study sample sizes and number of significant foci reported. We also performed an analysis where we evaluated each meta-analysis to test whether there was a correlation between the sample size of the meta-analysis and the number of foci that it had identified. Correlation coefficients were then combined across all meta-analyses to obtain a summary correlation coefficient with a fixed effects model and we combine correlation coefficients, using a Fisher’s z transformation. Principal Findings: There was no correlation between sample size and the number of foci reported in single studies (r = 0.0050) but there was a strong correlation between sample size and number of foci in meta-analyses (r = 0.62, p<0.001). Only studies with sample sizes <45 identified larger (>40) numbers of foci and claimed as many discovered foci as studies with sample sizes ≥45, whereas meta-analyses yielded a limited number of foci relative to the yield that would be anticipated from smaller single studies. Conclusions: These results are consistent with possible reporting biases affecting small fMRI studies and suggest the need to promote standardized large-scale evidence in this field. It may also be that small studies may be analyzed and reported in ways that may generate a larger number of claimed foci or that small fMRI studies with inconclusive, null, or not very promising results may not be published at all. [ABSTRACT FROM AUTHOR]

Background: High levels of alcohol consumption and increases in heavy episodic drinking (binge drinking) are a growing public concern, due to their association with increased risk of personal and societal harm. Alcohol consumption has been shown to be sensitive to factors such as price and availability. The aim of this study was to explore the influence of glass shape on the rate of consumption of alcoholic and non-alcoholic beverages. Methods: This was an experimental design with beverage (lager, soft drink), glass (straight, curved) and quantity (6 fl oz, 12 fl oz) as between-subjects factors. Social male and female alcohol consumers (n = 159) attended two experimental sessions, and were randomised to drink either lager or a soft drink from either a curved or straight-sided glass, and complete a computerised task identifying perceived midpoint of the two glasses (order counterbalanced). Ethical approval was granted by the Faculty of Science Research Ethics Committee at the University of Bristol. The primary outcome measures were total drinking time of an alcoholic or non-alcoholic beverage, and perceptual judgement of the half-way point of a straight and curved glass. Results: Participants were 60% slower to consume an alcoholic beverage from a straight glass compared to a curved glass. This effect was only observed for a full glass and not a half-full glass, and was not observed for a non-alcoholic beverage. Participants also misjudged the half-way point of a curved glass to a greater degree than that of a straight glass, and there was a trend towards a positive association between the degree of error and total drinking time. Conclusions: Glass shape appears to influence the rate of drinking of alcoholic beverages. This may represent a modifiable target for public health interventions. [ABSTRACT FROM AUTHOR]

This Formal Comment responds to Jordan et al., and stresses that if scientific findings are to be robust, training in experimental design and statistics is critical to ensure that research questions, design considerations, and analyses are aligned. [ABSTRACT FROM AUTHOR]

A correction to the article "G = E: What GWAS Can Tell Us about the Environment" by Suzanne H. Gage and colleagues that was published in the previous issue is presented.

We previously used a single nucleotide polymorphism (SNP) in the CHRNA5-A3-B4 gene cluster associated with heaviness of smoking within smokers to confirm the causal effect of smoking in reducing body mass index (BMI) in a Mendelian randomisation analysis. While seeking to extend these findings in a larger sample we found that this SNP is associated with 0.74% lower body mass index (BMI) per minor allele in current smokers (95% CI -0.97 to -0.51, P = 2.00 × 10(-10)), but also unexpectedly found that it was associated with 0.35% higher BMI in never smokers (95% CI +0.18 to +0.52, P = 6.38 × 10(-5)). An interaction test confirmed that these estimates differed from each other (P = 4.95 × 10(-13)). This difference in effects suggests the variant influences BMI both via pathways unrelated to smoking, and via the weight-reducing effects of smoking. It would therefore be essentially undetectable in an unstratified genome-wide association study of BMI, given the opposite association with BMI in never and current smokers. This demonstrates that novel associations may be obscured by hidden population sub-structure. Stratification on well-characterized environmental factors known to impact on health outcomes may therefore reveal novel genetic associations.

Background: The behavioural impact of pharmacogenomics is untested. We tested two hypotheses concerning the behavioural impact of informing smokers their oral dose of NRT is tailored to analysis of DNA., Methods and Findings: We conducted an RCT with smokers in smoking cessation clinics (N = 633). In combination with NRT patch, participants were informed that their doses of oral NRT were based either on their mu-opioid receptor (OPRM1) genotype, or their nicotine dependence questionnaire score (phenotype). The proportion of prescribed NRT consumed in the first 28 days following quitting was not significantly different between groups: (68.5% of prescribed NRT consumed in genotype vs 63.6%, phenotype group, difference = 5.0%, 95% CI -0.9,10.8, p = 0.098). Motivation to make another quit attempt among those (n = 331) not abstinent at six months was not significantly different between groups (p = 0.23). Abstinence at 28 days was not different between groups (p = 0.67); at six months was greater in genotype than phenotype group (13.7% vs 7.9%, difference = 5.8%, 95% CI 1.0,10.7, p = 0.018)., Conclusions: Informing smokers their oral dose of NRT was tailored to genotype not phenotype had a small, statistically non-significant effect on 28-day adherence to NRT. Among those still smoking at six months, there was no evidence that saying NRT was tailored to genotype adversely affected motivation to make another quit attempt. Higher abstinence rate at six months in the genotype arm requires investigation., Trial Registration: Controlled-Trials.com ISRCTN14352545.