IntEgrating smoking cessation treAtment into usual online psychological care for people with common mEntal illness: Protocol for an online randomised feasibility and pilot study (ESCAPE digital).

BACKGROUND: In the UK, smoking prevalence in people with depression (34%) and anxiety (29%) is more than double that of the general population (13%). People who stop smoking improve their mental health with comparable effect sizes found for antidepressants. In England, online psychological therapy is a standard treatment for depression and anxiety. Online therapy is an acceptable setting for smoking cessation support; however, integrated smoking and mental health support is not available. This novel study aims to assess the acceptability and feasibility of an online smoking cessation intervention, and trial procedures, offered alongside online mental health treatment as it offers increased reach to people with common mental health difficulties who smoke. METHODS: A two-armed; Intervention (Integrated SilverCloud smoking cessation support) and control group (SilverCloud usual care), pragmatic, randomised controlled feasibility trial. We aim to recruit 500 adult smokers eligible for online mental health treatment. Follow-up will be conducted at 3-months and 6-months. We will assess the acceptability and feasibility of the trial procedures (i.e., recruitment, data completeness, self-reported acceptability and satisfaction) and the intervention (i.e., self-reported quit attempt, engagement with the smoking cessation and mental health programs, smoking cessation medicine and e-cigarette use, self-reported acceptability and satisfaction) and pilot clinical outcomes (i.e., biologically validated smoking abstinence, anxiety, depression, quality of health). CONCLUSION: If the Trial is successful, a randomised controlled effectiveness trial will follow to examine whether integrated smoking cessation and mental health treatment increases smoking abstinence and improves depression and anxiety compared to usual care. TRIAL REGISTRATION: ISRCTN10612149 (https://doi.org/10.1186/ISRCTN10612149), 02/02/2023.

The impact of introducing alcohol-free beer options in bars and public houses on alcohol sales and revenue: A randomised crossover field trial.

AIMS: The study aimed to estimate the impact of introducing a draught alcohol-free beer, thereby increasing the relative availability of these products, on alcohol sales and monetary takings in bars and pubs in England. DESIGN: Randomised crossover field trial. SETTING: England. PARTICIPANTS: Fourteen venues that did not previously sell draught alcohol-free beer. INTERVENTION AND COMPARATOR: Venues completed two intervention periods and two control periods in a randomised order over 8 weeks. Intervention periods involved replacing one draught alcoholic beer with an alcohol-free beer. Control periods operated business as usual. MEASUREMENTS: The primary outcome was mean weekly volume (in litres) of draught alcoholic beer sold. The secondary outcome was mean weekly revenue [in GBP (£)] from all drinks. Analyses adjusted for randomised order, special events, season and busyness. FINDINGS: The adjusted mean difference in weekly sales of draught alcoholic beer was -20 L [95% confidence interval (CI) = -41 to +0.4], equivalent to a 4% reduction (95% CI = 8% reduction to 0.1% increase) in the volume of alcoholic draught beer sold when draught alcohol-free beer was available. Excluding venues that failed at least one fidelity check resulted in an adjusted mean difference of -29 L per week (95% CI = -53 to -5), equivalent to a 5% reduction (95% CI = 8% reduction to 0.8% reduction). The adjusted mean difference in weekly revenue was +61 GBP per week (95% CI = -328 to +450), equivalent to a 1% increase (95% CI = 5% decrease to 7% increase) when draught alcohol-free beer was available. CONCLUSIONS: Introducing a draught alcohol-free beer in bars and pubs in England reduced the volume of draught alcoholic beer sold by 4% to 5%, with no evidence of the intervention impacting net revenue.

Do Flavour Descriptions Influence Subjective Ratings of Flavoured and Unflavoured E-Liquids among Non-Smoking and Non-Vaping UK Adolescents?

INTRODUCTION: Youth use of electronic cigarettes (e-cigarettes) is rising globally and is associated with health harms. Flavour descriptions on e-liquid packaging may contribute to the appeal of e-cigarettes among youth. This study compared subjective ratings of e-liquid packaging flavour descriptions among non-smoking and non-vaping UK adolescents. METHODS: This was an online observational study in a UK sample of non-smoking and non-vaping adolescents aged 11-17 years. The primary analyses compared flavoured versus unflavoured descriptions and the secondary analyses compared candy/sweet flavour versus fruit flavour descriptions. Outcomes were packaging appraisal, packaging receptivity, perceived harm, and perceived audience. RESULTS: The survey was completed by 120 participants (74% female). Packaging appraisal ratings were higher for e-liquids with flavoured descriptions than unflavoured descriptions (mean difference 5.9, 95% CI 4.2 to 7.6, p<.001). Similarly, packaging receptivity ratings were higher for e-liquids with flavoured descriptions than unflavoured descriptions (mean difference 4.2, 95% CI 2.8 to 5.6, p<.001). Participants also perceived e-liquids with flavoured (versus unflavoured) descriptions as less 'grown-up' (mean difference -5.2, 95% CI -7.3 to -3.1, p<.001). However, ratings of perceived harm were similar for flavoured and unflavoured descriptions (mean difference -1.0, 95% CI -2.6 to 0.5, p=.189). CONCLUSIONS: Although this study found differences in subjective ratings of e-liquids with flavoured and unflavoured descriptions, non-smoking and non-vaping UK adolescents generally had low appraisal and receptivity for e-liquids and they perceived them as being 'grown-up' and harmful. IMPLICATIONS: Youth use of electronic cigarettes (e-cigarettes) is increasing globally, leading to concerns about health harms. This study compared adolescents' ratings of e-liquids with flavoured versus unflavoured descriptions and e-liquids with candy/sweet flavour versus fruit flavour descriptions. This study adds to previous studies that have compared adolescents' ratings of e-liquids with tobacco flavour versus non-tobacco flavour descriptions. Although packaging appraisal and receptivity ratings were higher (more positive) for e-liquids with flavoured versus unflavoured descriptions, overall, adolescents who do not smoke or vape had low appraisal and receptivity for e-liquids, and they perceived them as being 'grown-up' and harmful.

Estimating the health impact of nicotine exposure by dissecting the effects of nicotine versus non-nicotine constituents of tobacco smoke: A multivariable Mendelian randomisation study.

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.

MRSamePopTest: introducing a simple falsification test for the two-sample mendelian randomisation 'same population' assumption.

Two-sample MR is an increasingly popular method for strengthening causal inference in epidemiological studies. For the effect estimates to be meaningful, variant-exposure and variant-outcome associations must come from comparable populations. A recent systematic review of two-sample MR studies found that, if assessed at all, MR studies evaluated this assumption by checking that the genetic association studies had similar demographics. However, it is unclear if this is sufficient because less easily accessible factors may also be important. Here we propose an easy-to-implement falsification test. Since recent theoretical developments in causal inference suggest that a causal effect estimate can generalise from one study to another if there is exchangeability of effect modifiers, we suggest testing the homogeneity of variant-phenotype associations for a phenotype which has been measured in both genetic association studies as a method of exploring the 'same-population' test. This test could be used to facilitate designing MR studies with diverse populations. We developed a simple R package to facilitate the implementation of our proposed test. We hope that this research note will result in increased attention to the same-population assumption, and the development of better sensitivity analyses.

KEY MESSAGE: • Two-sample Mendelian randomisation (2SMR) can be used to estimate the lifetime effect of a modifiable exposure on an outcome of interest. • 2SMR point estimates are not interpretable if the exposure and outcome GWASs do not come from homogeneous populations, so called 'same population' assumption. However, this assumption is often not validated in applied studies. • We propose and validate a novel sensitivity analysis for this assumption, which checks if SNP effects for the same trait are homogeneous across the two populations.

Confirmation of COVID-19 infection status and reporting of Long COVID symptoms in a population-based birth cohort: No evidence of a nocebo effect.

Some patients with COVID-19 develop symptoms after the acute infection, known as 'Long COVID'. We examined whether or not confirmation of COVID-19 infection status could act as a nocebo, using data from questionnaires distributed to the Avon Longitudinal Study of Parents and Children cohort. We examined associations between confirmation of COVID-19 infection status (confirmed by a positive test vs unconfirmed) and reporting of Long COVID symptoms. We explored the roles of sex and anxiety as potential moderators. There was no clear evidence of a strong association between confirmation of COVID-19 infection status and the Long COVID composite score, physical or psychological symptoms or duration of symptoms. There was no clear evidence of moderation by sex or anxiety. We therefore found no evidence of a nocebo effect. Our data suggest that this psychological mechanism does not play a role in the medical symptomatology experienced by patients with Long COVID.

Exploring the dimensions of responsible research systems and cultures: a scoping review.

The responsible conduct of research is foundational to the production of valid and trustworthy research. Despite this, our grasp of what dimensions responsible conduct of research (RCR) might contain-and how it differs across disciplines (i.e. how it is conceptualized and operationalized)-is tenuous. Moreover, many initiatives related to developing and maintaining RCR are developed within disciplinary and institutional silos which naturally limits the benefits that RCR practice can have. To this end, we are working to develop a better understanding of how RCR is conceived and realized, both across disciplines and across institutions in Europe. The first step in doing this is to scope existing knowledge on the topic, of which this scoping review is a part. We searched several electronic databases for relevant published and grey literature. An initial sample of 715 articles was identified, with 75 articles included in the final sample for qualitative analysis. We find several dimensions of RCR that are underemphasized or are excluded from the well-established World Conferences on Research Integrity (WCRI) Singapore Statement on Research Integrity and explore facets of these dimensions that find special relevance in a range of research disciplines.

The potential role of gray matter volume differences in the association between smoking and depression: A narrative review.

Tobacco use and major depression are both leading contributors to the global burden of disease and are also highly comorbid. Previous research indicates bi-directional causality between tobacco use and depression, but the mechanisms that underlie this causality are unclear, especially for the causality from tobacco use to depression. Here we narratively review the available evidence for a potential causal role of gray matter volume in the association. We summarize the findings of large existing neuroimaging meta-analyses, studies in UK Biobank, and the Enhancing NeuroImaging Genetics through MetaAnalysis (ENIGMA) consortium and assess the overlap in implicated brain areas. In addition, we review two types of methods that allow us more insight into the causal nature of associations between brain volume and depression/smoking: longitudinal studies and Mendelian Randomization studies. While the available evidence suggests overlap in the alterations in brain volumes implicated in tobacco use and depression, there is a lack of research examining the underlying pathophysiology. We conclude with recommendations on (genetically-informed) causal inference methods useful for studying these associations.

Maternal caffeine consumption during pregnancy and offspring cord blood DNA methylation: an epigenome-wide association study meta-analysis.

Background: Prenatal caffeine exposure may influence offspring health via DNA methylation, but no large studies have tested this. Materials & methods: Epigenome-wide association studies and differentially methylated regions in cord blood (450k or EPIC Illumina arrays) were meta-analyzed across six European cohorts (n = 3725). Differential methylation related to self-reported caffeine intake (mg/day) from coffee, tea and cola was compared with assess whether caffeine is driving effects. Results: One CpG site (cg19370043, PRRX1) was associated with caffeine and another (cg14591243, STAG1) with cola intake. A total of 12-22 differentially methylated regions were detected with limited overlap across caffeinated beverages. Conclusion: We found little evidence to support an intrauterine effect of caffeine on offspring DNA methylation. Statistical power limitations may have impacted our findings.

Current guidelines recommend pregnant women to limit caffeine intake to less than 200 mg daily, even though there is no clear proof of its effects on human development. A biological explanation for how exposure to caffeine during pregnancy influences development would help clarify if recommended limits are justified. An epigenetic mechanism, called DNA methylation (DNAm), has been suggested as a potential biological explanation for how caffeine intake during pregnancy influences health development. DNAm can switch genes 'on' or 'off' in response to environmental influences and therefore act as a bridge between genes and the environment. Studies have found that smoking during pregnancy is connected to over 6000 changes in DNAm at birth, with lasting effects into adulthood. To explore the link between caffeine intake during pregnancy and DNAm at birth, we analyzed data from 3725 mother­child pairs living in different European countries. We looked at effects from coffee, tea and cola intake during pregnancy on children's DNAm at birth. We found one change in DNAm to be connected to total caffeine and another to cola consumption during pregnancy. These few connections do not provide convincing evidence that caffeine intake during pregnancy impacts children's DNAm at birth. However, because mothers in our study consumed little caffeine, it is possible that results would be different in studies with participants consuming high amounts of caffeine during pregnancy. Potentially, our study did not include enough people to find very small changes in DNAm that are connected to caffeine consumption during pregnancy.

Reducing bias in secondary data analysis via an Explore and Confirm Analysis Workflow (ECAW): a proposal and survey of observational researchers.

Background. Although preregistration can reduce researcher bias and increase transparency in primary research settings, it is less applicable to secondary data analysis. An alternative method that affords additional protection from researcher bias, which cannot be gained from conventional forms of preregistration alone, is an Explore and Confirm Analysis Workflow (ECAW). In this workflow, a data management organization initially provides access to only a subset of their dataset to researchers who request it. The researchers then prepare an analysis script based on the subset of data, upload the analysis script to a registry, and then receive access to the full dataset. ECAWs aim to achieve similar goals to preregistration, but make access to the full dataset contingent on compliance. The present survey aimed to garner information from the research community where ECAWs could be applied-employing the Avon Longitudinal Study of Parents and Children (ALSPAC) as a case example. Methods. We emailed a Web-based survey to researchers who had previously applied for access to ALSPAC's transgenerational observational dataset. Results. We received 103 responses, for a 9% response rate. The results suggest that-at least among our sample of respondents-ECAWs hold the potential to serve their intended purpose and appear relatively acceptable. For example, only 10% of respondents disagreed that ALSPAC should run a study on ECAWs (versus 55% who agreed). However, as many as 26% of respondents agreed that they would be less willing to use ALSPAC data if they were required to use an ECAW (versus 45% who disagreed). Conclusion. Our data and findings provide information for organizations and individuals interested in implementing ECAWs and related interventions. Preregistration. https://osf.io/g2fw5 Deviations from the preregistration are outlined in electronic supplementary material A.

The providential randomisation of genotypes.

When building causal knowledge in behavioural genetics, the natural randomisation of genotypes at conception (approximately analogous to the artificial randomisation occurring in randomised controlled trials) facilitates the discovery of genetic causes. More importantly, the randomisation of genetic material within families also enables a better identification of (environmental) risk factors and aetiological pathways to diseases and behaviours.

Exploring the bidirectional causal pathways between smoking behaviours and headache: A Mendelian randomisation study.

INTRODUCTION: Although observational data suggests a relationship between headache and smoking, there remain questions about causality. Smoking may increase headache risk, individuals may smoke to alleviate headaches, or smoking and headache may share common risk factors. Mendelian randomisation (MR) is a method that uses genetic variants as instruments for making causal inferences about an exposure and an outcome. METHODS: First, we conducted logistic regression of observational data in UK Biobank assessing the association between smoking behaviours (smoking status, cigarettes per day amongst daily smokers and lifetime smoking score) on risk of self-reported headache (in the last month and for more than 3 months). Second, we used genetic instruments for smoking behaviours and headache (identified in independent genome-wide association studies) to perform bidirectional MR analysis. RESULTS: Observationally, there is a weak association between smoking behaviour and experiencing headache, with increased cigarettes per day associated with increased headache risk. In the MR analysis, genetic liability to smoking initiation and lifetime smoking increased odds of headache in the last month but not odds of headaches lasting more than three months. In the opposite direction there was weak evidence for higher genetic liability to headaches decreasing the chance of quitting. CONCLUSION: There was weak evidence for a partially bidirectional causal relationship between smoking behaviours and headache in the last month. Given this relationship is distinct from smoking heaviness, it suggests headache and smoking may share common risk factors such as personality traits. IMPLICATIONS: Using Mendelian Randomisation, this study addresses the uncertainty regarding the observed relationship between headache and smoking. There was evidence for weak causal effects of smoking initiation and lifetime smoking (but not smoking heaviness) on likelihood of experiencing headache in the last month, but not over a prolonged period of more than three months. Those at higher genetic liability for headaches were also less likely to successfully stop smoking. This partially bidirectional causal relationship distinct from smoking heaviness, suggests that observed associations are unlikely due to biological effects of tobacco smoke exposure and may be explained by shared personality traits.

Assessing the effectiveness of online emotion recognition training in healthy volunteers.

Facial emotion recognition (ER) difficulties are associated with mental health and neurodevelopmental conditions, including autism and poorer social functioning. ER interventions may therefore have clinical potential. We investigated the efficacy of ER training (ERT). We conducted three online studies with healthy volunteers completing one ERT session. Studies 1 and 2 included active and control/sham training groups and tested the efficacy of (i) four-emotion ERT (angry, happy, sad and scared) (n = 101), and (ii) six-emotion ERT (adding disgusted and surprised) (n = 109). Study 3 tested generalizability of ERT to non-trained stimuli with groups trained and tested on the same stimuli, or different stimuli (n = 120). Training effects on total correct hits were estimated using linear mixed effects models. We did not observe clear evidence of improvement in study 1 but note the effect was in the direction of improvement (b = 0.02, 95% confidence interval (CI) = -0.02 to 0.07). Study 2 indicated greater total hits following training (b = 0.07, 95% CI = 0.03-0.12). Study 3 demonstrated similar improvement across groups (b = -0.01, 95% CI = -0.05 to 0.02). Our results indicate improved ER (as measured by our task), which generalizes to different facial stimulus sets. Future studies should further explore generalizability, longer-term effects and ERT in populations with known ER difficulties.

Cognitive functioning in anxiety and depression: results from the ALSPAC cohort.

Anxiety and depression are associated with a range of impairments in cognitive functioning. Understanding the nature of these deficits may identify targets for intervention and prevent functional decline. We used observational and genetic methods to investigate the relationship of anxiety and depression with three cognitive domains: emotion recognition, response inhibition, and working memory, in the Avon Longitudinal Study of Parents and Children (ALSPAC). We examined: (i) cross-sectional associations between anxiety, depression, and cognition at age 24 (n = 2187), (ii) prospective associations between anxiety and depression at age 18 and cognition at age 24 (n = 1855), and (iii) the casual effect of anxiety and depression on cognition using Mendelian randomization (MR). Both disorders were associated with altered emotion recognition; anxiety with decreased happiness recognition (b = -0.27 [-0.54,0.01], p = 0.045), and depression with increased sadness recognition (b = 0.35 [0.07,0.64], p = 0.016). Anxiety was also associated with poorer working memory (b = -0.14 [-0.24,0.04], p = 0.005). There was no evidence for an association with response inhibition. MR provided no clear evidence of causal relationships between mental health and cognition, but these analyses were underpowered. Overall, there was little evidence for impairments in executive functioning, but moderate alterations in emotion recognition. This may inform the development of psychosocial interventions.

Impact of health warning labels and calorie labels on selection and purchasing of alcoholic and non-alcoholic drinks: A randomized controlled trial.

AIMS: To estimate the impact on selection and actual purchasing of (a) health warning labels (text-only and image-and-text) on alcoholic drinks and (b) calorie labels on alcoholic and non-alcoholic drinks. DESIGN: Parallel-groups randomised controlled trial. SETTING: Drinks were selected in a simulated online supermarket, before being purchased in an actual online supermarket. PARTICIPANTS: Adults in England and Wales who regularly consumed and purchased beer or wine online (n = 651). Six hundred and eight participants completed the study and were included in the primary analysis. INTERVENTIONS: Participants were randomized to one of six groups in a between-subjects three [health warning labels (HWLs) (i): image-and-text HWL; (ii) text-only HWL; (iii) no HWL] × 2 (calorie labels: present versus absent) factorial design (n per group 103-113). MEASUREMENTS: The primary outcome measure was the number of alcohol units selected (with intention to purchase); secondary outcomes included alcohol units purchased and calories selected and purchased. There was no time limit for selection. For purchasing, participants were directed to purchase their drinks immediately (although they were allowed up to 2 weeks to do so). FINDINGS: There was no evidence of main effects for either (a) HWLs or (b) calorie labels on the number of alcohol units selected (HWLs: F(2,599) = 0.406, P = 0.666; calorie labels: F(1,599) = 0.002, P = 0.961). There was also no evidence of an interaction between HWLs and calorie labels, and no evidence of an overall difference on any secondary outcomes. In pre-specified subgroup analyses comparing the 'calorie label only' group (n = 101) with the 'no label' group (n = 104) there was no evidence that calorie labels reduced the number of calories selected (unadjusted means: 1913 calories versus 2203, P = 0.643). Among the 75% of participants who went on to purchase drinks, those in the 'calorie label only' group (n = 74) purchased fewer calories than those in the 'no label' group (n = 79) (unadjusted means: 1532 versus 2090, P = 0.028). CONCLUSIONS: There was no evidence that health warning labels reduced the number of alcohol units selected or purchased in an online retail context. There was some evidence suggesting that calorie labels on alcoholic and non-alcoholic drinks may reduce calories purchased from both types of drinks.

The UK BiLEVE and Mendelian randomisation: using multivariable instrumental variables to address "damned if you, damned if you don't" adjustment problems.

OBJECTIVE: To explore the use of multivariable instrumental variables to resolve the "damned if you do, damned if you don't" adjustment problem created for Mendelian randomisation (MR) analysis using the smoking or lung function related phenotypes in the UK Biobank (UKB). RESULT: "damned if you do, damned if you don't" adjustment problems occur when both adjusting and not-adjusting for a variable will induce bias in an analysis. One instance of this occurs because the genotyping chip of UKB participants differed based on lung function/smoking status. In simulations, we show that multivariable instrumental variables analyses can attenuate potential collider bias introduced by adjusting for a proposed covariate, such as the UKB genotyping chip. We then explore the effect of adjusting for genotyping chip in a multivariable MR model exploring the effect of smoking on seven medical outcomes (lung cancer, emphysema, hypertension, stroke, heart diseases, depression, and disabilities). We additionally compare our results to a traditional univariate MR analysis using genome-wide analyses summary statistics which had and had not adjusted for genotyping chip. This analysis implies that the difference in genotyping chip has introduced only a small amount of bias.

Deriving GWAS summary estimates for paternal smoking in UK biobank: a GWAS by subtraction.

OBJECTIVE: To use genome-wide association study (GWAS) by subtraction, a method for deriving novel GWASs from existing summary statistics, to derive genome-wide summary statistics for paternal smoking. RESULT: A GWAS by subtraction was implemented using a weighted linear model that defined the child-genotype paternal-phenotype association as the child-genotype child-phenotype association minus the child-genotype maternal-phenotype association. We first use the laws of inherence to derive the weighted linear model. We then implemented the linear model to create a GWAS of paternal smoking by subtracting the summary statistics from a GWAS of maternal smoking from the summary statistics of a GWAS of the index individual's smoking. We used a Monte-Carlo simulation to validate the model and showed that this approach performed similarly in terms of bias to performing a traditional GWAS of paternal smoking. Finally, we validated the summary statistics in a Mendelian randomisation analysis by demonstrating an association of genetically predicted paternal smoking with paternal lung cancer and emphysema.

Testing the causal relationships of physical activity and sedentary behaviour with mental health and substance use disorders: a Mendelian randomisation study.

Observational studies suggest that physical activity can reduce the risk of mental health and substance use disorders. However, it is unclear whether this relationship is causal or explained by confounding bias (e.g., common underlying causes or reverse causality). We investigated the bidirectional causal relationship of physical activity (PA) and sedentary behaviour (SB) with ten mental health and substance use disorders, applying two-sample Mendelian Randomisation (MR). Genetic instruments for the exposures and outcomes were derived from the largest available, non-overlapping genome-wide association studies (GWAS). Summary-level data for objectively assessed PA (accelerometer-based average activity, moderate activity, and walking) and SB and self-reported moderate-to-vigorous PA were obtained from the UK Biobank. Data for mental health/substance use disorders were obtained from the Psychiatric Genomics Consortium and the GWAS and Sequencing Consortium of Alcohol and Nicotine Use. MR estimates were combined using inverse variance weighted meta-analysis (IVW). Sensitivity analyses were conducted to assess the robustness of the results. Accelerometer-based average PA was associated with a lower risk of depression (b = -0.043, 95% CI: -0.071 to -0.016, effect size[OR] = 0.957) and cigarette smoking (b = -0.026; 95% CI: -0.035 to -0.017, effect size[ß] = -0.022). Accelerometer-based SB decreased the risk of anorexia (b = -0.341, 95% CI: -0.530 to -0.152, effect size[OR] = 0.711) and schizophrenia (b = -0.230; 95% CI: -0.285 to -0.175, effect size[OR] = 0.795). However, we found evidence of reverse causality in the relationship between SB and schizophrenia. Further, PTSD, bipolar disorder, anorexia, and ADHD were all associated with increased PA. This study provides evidence consistent with a causal protective effect of objectively assessed but not self-reported PA on reduced depression and cigarette smoking. Objectively assessed SB had a protective relationship with anorexia. Enhancing PA may be an effective intervention strategy to reduce depressive symptoms and addictive behaviours, while promoting sedentary or light physical activities may help to reduce the risk of anorexia in at-risk individuals.

Trends in Psychological Distress Among Adults in England, 2020-2022.

Importance: In the last 3 years, people in England have lived through a pandemic and cost-of-living and health care crises, all of which may have contributed to worsening mental health in the population. Objective: To estimate trends in psychological distress among adults over this period and to examine differences by key potential moderators. Design, Setting, and Participants: A monthly cross-sectional, nationally representative household survey of adults aged 18 years or older was conducted in England between April 2020 and December 2022. Main Outcomes and Measures: Past-month distress was assessed with the Kessler Psychological Distress Scale. Time trends in any distress (moderate to severe, scores ≥5) and severe distress (scores ≥13) were modeled, and interactions with age, gender, occupational social grade, children in the household, smoking status, and drinking risk status were tested. Results: Data were collected from 51 861 adults (weighted mean [SD] age, 48.6 [18.5] years; 26 609 women [51.3%]). There was little overall change in the proportion of respondents reporting any distress (from 34.5% to 32.0%; prevalence ratio [PR], 0.93; 95% CI, 0.87-0.99), but the proportion reporting severe distress increased by 46%, from 5.7% to 8.3% (PR, 1.46; 95% CI, 1.21-1.76). Although trends differed by sociodemographic characteristics, smoking, and drinking, the increase in severe distress was observed across all subgroups (with PR estimates ranging from 1.17 to 2.16), with the exception of those aged 65 years and older (PR, 0.79; 95% CI, 0.43-1.38); the increase was particularly pronounced since late 2021 among those younger than 25 years (increasing from 13.6% in December 2021 to 20.2% in December 2022). Conclusions and Relevance: In this survey study of adults in England, the proportion reporting any psychological distress was similar in December 2022 to that in April 2020 (an extremely difficult and uncertain moment of the COVID-19 pandemic), but the proportion reporting severe distress was 46% higher. These findings provide evidence of a growing mental health crisis in England and underscore an urgent need to address its cause and to adequately fund mental health services.

Associations between health behaviours, fertility and reproductive outcomes: triangulation of evidence in the Norwegian Mother, Father and Child Cohort Study (MoBa).

BACKGROUND: Guidance to improve fertility includes reducing alcohol and caffeine consumption, achieving healthy weight-range and stopping smoking. Advice is informed by observational evidence, which is often biased by confounding. METHODS: This study primarily used data from a pregnancy cohort, the Norwegian Mother, Father and Child Cohort Study. First, we conducted multivariable regression of health behaviours (alcohol and caffeine consumption, body-mass index (BMI), and smoking) on fertility outcomes (e.g. time to conception) and reproductive outcomes (e.g. age at first birth) (n = 84,075 females, 68,002 males), adjusting for birth year, education and attention-deficit and hyperactive-impulsive (ADHD) traits. Second, we used individual-level Mendelian randomisation (MR) to explore possible causal effects of health behaviours on fertility/reproductive outcomes (n = 63,376 females, 45,460 males). Finally, we performed summary-level MR for available outcomes in UK Biobank (n = 91,462-1,232,091) and controlled for education and ADHD liability using multivariable MR. RESULTS: In multivariable regression analyses, higher BMI associated with fertility (longer time to conception, increased odds of infertility treatment and miscarriage), and smoking was associated with longer time to conception. In individual-level MR analyses, there was strong evidence for effects of smoking initiation and higher BMI on younger age at first birth, of higher BMI on increased time to conception, and weak evidence for effects of smoking initiation on increased time to conception. Age at first birth associations were replicated in summary-level MR analysis; however, effects attenuated using multivariable MR. CONCLUSIONS: Smoking behaviour and BMI showed the most consistent associations for increased time to conception and a younger age at first birth. Given that age at first birth and time to conception are positively correlated, this suggests that the mechanisms for reproductive outcomes are distinct to the mechanisms acting on fertility outcomes. Multivariable MR suggested that effects on age at first birth might be explained by underlying liability to ADHD and education.