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Objective: The objective of this report is to describe approaches used to ensure fidelity in the B-SWELL feasibility trial., Methods: A virtual randomized feasibility trial was conducted. Intervention fidelity was evaluated in accordance with Borrelli's five principles of fidelity: design, training, delivery, receipt, and enactment. In addition to the rigorous oversight by the research team, tools were developed or adapted for the virtual trial. Tools used in the trial included a Visual Analog Attendee Engagement Tool, weekly feedback surveys, audio recordings, a facilitator's checklist, an overall satisfaction survey, and a technology survey., Results: Using Borrelli's framework for treatment fidelity, the researchers noted high ratings from the overall satisfaction survey, designed to assess ongoing participant satisfaction with the intervention materials and continued enactment. The tools successfully guided the intervention process from design to enactment., Discussion: Adherence to Borrelli's principles of fidelity enables rigorous oversight of an intervention and its delivery. The growing use of technology to deliver programmed interventions requires that tools be adapted and created to monitor fidelity. Validation of the research-developed and -adapted tools is recommended in a larger trial., Competing Interests: The authors have no conflicts of interest to report., (Copyright © 2024 Wolters Kluwer Health, Inc. All rights reserved.)

Background: Various vitamins and minerals have been implicated in the aetiology of depression., Objective: To estimate the effects of micronutrient exposures on major depressive disorder (MDD) and recurrent depression (rMDD) using Mendelian randomisation (MR), a method using genetic data to estimate causal effects given certain assumptions., Methods: We undertook a comprehensive bidirectional MR study of multiple micronutrient exposures on MDD and rMDD. Summary statistics were obtained from the Psychiatric Genomics Consortium (PGC) genome-wide association studies (GWASs) of MDD (cases = 116,209; controls = 314,566) and rMDD (cases = 17,451; controls = 62,482)., Results: None of the micronutrients with available genetic instruments were strongly associated with MDD or rMDD using traditional MR methods. However, using methods to increase analytical power by accounting for genetically correlated variants (e.g., cIVW) highlighted five micronutrients with possible causal effects. Point estimates for rMDD were the largest magnitude, with three micronutrients suggestive of a protective effect: serum iron (OR cIVW 0.90 per SD increase; 95% CI 0.85-0.95; p = 0.0003); erythrocyte copper (OR cIVW 0.97; 95% CI 0.95-0.99; p = 0.0004); and 25(OH) vitamin D (OR cIVW 0.81; 0.66-0.99; p = 0.04). Apparent adverse effects of increased selenium on the risk of MDD (OR cIVW 1.03; 95% CI 1.02-1.05; p = 0.0003) and rMDD (OR cIVW 1.08; 95% CI 1.00-1.08; p = 0.06), and serum magnesium on rMDD (OR cIVW 1.21; 1.01-1.44; p = 0.04); were less consistent between methods and may be driven by pleiotropy., Conclusions: Our results suggest weak evidence for a protective effect of iron, copper and 25(OH)D on major depressive outcomes, with mixed evidence for selenium and magnesium. There was no evidence to support a causal effect of any other micronutrients on MDD or rMDD, although genetic instruments were lacking, with insufficient power to detect small but important effects. Future micronutrient supplementation trials should ensure ample statistical power given modest causal effect estimates and consider potential risks of supplementation, as some micronutrient effect estimates suggested potential harm in excess.

Background: Maternal vitamin-D and omega-3 fatty acid (DHA) deficiencies during pregnancy have previously been associated with offspring neurodevelopmental traits. However, observational study designs cannot distinguish causal effects from confounding., Methods: First, we conducted Mendelian randomisation (MR) using genetic instruments for vitamin-D and DHA identified in independent genome-wide association studies (GWAS). Outcomes were (1) GWAS for traits related to autism and ADHD, generated in the Norwegian mother, father, and child cohort study (MoBa) from 3 to 8 years, (2) autism and ADHD diagnoses. Second, we used mother-father-child trio-MR in MoBa (1) to test causal effects through maternal nutrient levels, (2) to test effects of child nutrient levels, and (3) as a paternal negative control., Results: Associations between higher maternal vitamin-D levels on lower ADHD related traits at age 5 did not remain after controlling for familial genetic predisposition using trio-MR. Furthermore, we did not find evidence for causal maternal effects of vitamin-D/DHA levels on other offspring traits or diagnoses. In the reverse direction, there was evidence for a causal effect of autism genetic predisposition on lower vitamin-D levels and of ADHD genetic predisposition on lower DHA levels., Conclusions: Triangulating across study designs, we did not find evidence for maternal effects. We add to a growing body of evidence that suggests that previous observational associations are likely biased by genetic confounding. Consequently, maternal supplementation is unlikely to influence these offspring neurodevelopmental traits. Notably, genetic predisposition to ADHD and autism was associated with lower DHA and vitamin-D levels respectively, suggesting previous associations might have been due to reverse causation.

Background and Hypothesis: Childhood adversity is often described as a potential cause of incident psychotic experiences, but the underlying mechanisms are not well understood. We aimed to examine the mediating role of cognitive and psychopathological factors in the relation between childhood adversity and incident psychotic experiences in early adulthood., Study Design: We analyzed data from the Avon Longitudinal Study of Parents and Children, a large population-based cohort study. Childhood adversity was measured prospectively from birth to age 11 years, mediators (anxiety, depression, external locus of control [LoC], negative symptoms) were assessed at approximately 16 years of age, and incident psychotic experiences were assessed at ages 18 and 24 years. Mediation was examined via the counterfactual g-computation formula., Study Results: In total, 7% of participants had incident suspected or definite psychotic experiences in early adulthood. Childhood adversity was related to more incident psychotic experiences (ORadjusted = 1.34, 95% CI = 1.21; 1.49), and this association was partially mediated via all mediators examined (proportion mediated: 19.9%). In separate analyses for each mediator, anxiety, depression, external LoC, and negative symptoms were all found to mediate the link between adversity and incident psychotic experiences. Accounting for potential confounders did not modify our results., Conclusions: Our study shows that cognitive biases as well as mood symptomatology may be on the causal pathway between early-life adversity and the development of psychotic experiences. Future studies should determine which mediating factors are most easily modifiable and most likely to reduce the risk of developing psychotic experiences., (© The Author(s) 2024. Published by Oxford University Press on behalf of the Maryland Psychiatric Research Center.)

Omega-3 fatty acids have been implicated in the aetiology of depressive disorders, though trials supplementing omega-3 to prevent major depressive disorder (MDD) have so far been unsuccessful. Whether this association is causal remains unclear. We used two sample Mendelian randomization (MR) to investigate causality. Genetic variants associated with circulating omega-3 and omega-6 fatty acids in UK Biobank (UKBB, n = 115,078) were selected as exposures. The Psychiatric Genomics Consortium (PGC) genome-wide association studies (GWAS) of MDD (n = 430,775; cases = 116,209; controls = 314,566) and recurrent depression (rMDD, n = 80,933; cases = 17,451; controls = 62,482), were used as outcomes. Multivariable MR (MVMR) models were used to account for biologically correlated lipids, such as high- and low-density cholesterol and triglycerides, and to explore the relative importance of longer-chain omega-3 fatty acids eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA) using data from the Cohorts for Heart and Aging Research in Genomic Epidemiology (CHARGE, n = 8866). Genetic colocalization analyses were used to explore the presence of a shared underlying causal variant between traits. Genetically predicted total omega-3 fatty acids reduced the odds of MDD (OR IVW 0.96 per standard deviation (SD, i.e. 0.22 mmol/l) (95% CIs 0.93-0.98, p = 0.003)). The largest point estimates were observed for eicosapentaenoic acid (EPA), a long-chain omega-3 fatty acid (OR EPA 0.92; 95% CI 0.88-0.96; p = 0.0002). The effect of omega-3 fatty acids was robust to MVMR models accounting for biologically correlated lipids. 'Leave-one-out' analyses highlighted the FADS gene cluster as a key driver of the effect. Colocalization analyses suggested a shared causal variant using the primary outcome sample, but genomic confounding could not be fully excluded. This study supports a role for omega-3 fatty acids, particularly EPA, in the aetiology of depression, although pleiotropic mechanisms cannot be ruled out. The findings support guidelines highlighting the importance of EPA dose and ratio for MDD and question whether targeted interventions may be superior to universal prevention trials, as modest effect sizes will limit statistical power., (© 2024. The Author(s).)

Purpose: Most persons who have had strokes are cared for at home by family members-many of whom experience depressive symptoms and quality of life changes as a result of providing care. The objective of this study is to determine theoretically based factors associated with unhealthy days in stroke family caregivers., Research Design and Methods: Secondary data analysis was conducted using baseline data from a large randomized controlled clinical trial testing the Telephone Assessment and Skill-Building Kit program with 254 family caregivers of persons who have had strokes. Guided by a conceptual model derived from Lazarus' transactional approach to stress, data were analyzed using multiple regression with unhealthy days as the dependent variable and theoretically based factors as independent variables., Results: Caregivers were mostly female (78%), White (71%), spouses (47%), or adult children (29%). Caregivers reported nine unhealthy days on average within the past month. A total of 37.8% of the variance in unhealthy days was explained by caregiver task difficulty, level of optimism, threat appraisal, depressive symptoms, and life changes with depressive symptoms being the strongest individual predictor because of shared variance., Clinical Relevance: Unhealthy days is an important part of stroke family caregiver health. Factors associated with unhealthy days in this study provide areas to consider in future intervention development., (Copyright © 2024 Association of Rehabilitation Nurses.)

Background: Midlife Black women suffer disproportionately from cardiovascular disease and are 65% more likely to die following a cardiac event compared with White women. Recruitment and retention of midlife Black women in clinical trials has been historically low. The culturally tailored Midlife Black Women's Stress Reduction and Wellness (B-SWELL) intervention was codeveloped with the community and designed to lower cardiovascular disease risk in midlife Black women., Objectives: We sought to assess participant satisfaction in the randomized feasibility trial of the B-SWELL intervention., Methods: A feasibility trial comparing the B-SWELL to a wellness intervention was conducted in the winter and spring of 2021 in compliance with pandemic research protocols. An adapted survey tool was used to rate satisfaction with the intervention and its technology using a Likert-type scale (1 [strongly disagree] to 5 [strongly agree]). Survey subscales assessed usefulness, ease, and acceptability of the intervention(s)., Results: Randomization yielded no statistical demographic differences (N = 48). Satisfaction for the interventions was high in both the B-SWELL and Wellness intervention groups with mean scores of 4.57 and 4.56, respectively. Mean scores for technology were 4.49 for the B-SWELL and 4.47 for the Wellness group. Subscales were also rated highly. Narrative responses were positively aligned with satisfaction scores., Conclusions: Results support use of cultural adaptation and community participatory methods to develop and deliver interventions targeted to at-risk populations. Culturally adapted interventions designed in collaboration with the community have greater authenticity, increasing the potential for higher recruitment, retention, and participant satisfaction of underrepresented populations. The trial is registered in ClinicalTrials.gov (NCT04404478)., Competing Interests: Declaration of Conflicting InterestsThe author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.

Childhood undernutrition is a major global health burden that is only partially resolved by nutritional interventions. Both chronic and acute forms of child undernutrition are characterized by derangements in multiple biological systems including metabolism, immunity, and endocrine systems. A growing body of evidence supports a role of the gut microbiome in mediating these pathways influencing early life growth. Observational studies report alterations in the gut microbiome of undernourished children, while preclinical studies suggest that this can trigger intestinal enteropathy, alter host metabolism, and disrupt immune-mediated resistance against enteropathogens, each of which contribute to poor early life growth. Here, we compile evidence from preclinical and clinical studies and describe the emerging pathophysiological pathways by which the early life gut microbiome influences host metabolism, immunity, intestinal function, endocrine regulation, and other pathways contributing to child undernutrition. We discuss emerging microbiome-directed therapies and consider future research directions to identify and target microbiome-sensitive pathways in child undernutrition.

Study Objectives: To describe changes in sleep quality and associated sleep symptoms as women begin menopausal transition compared with premenopausal controls., Methods: In a repeated-measures design, we analyzed data collected every 2-6 months from a community-based sample of 223 women aged 40-50 (45.6 ± 2.3) years old over a 2-year period. Each 6-month visit included urinary follicle-stimulating hormone (FSH) as a marker of ovarian function and the Pittsburgh Sleep Quality Index (PSQI) and other questionnaires (Center for Epidemiological Studies-Depression Scale; Perceived Stress Scale). Menstrual cycle and vasomotor symptoms (Seattle Women's Health Symptom Checklist) were tracked every 2 months by phone. For women entering menopausal transition (n = 68) we used data from the two consecutive visits prior to their FSH rise and the next two visits. Data from the last four consecutive visits were used for controls remaining premenopausal (n = 155)., Results: The transition group did not differ from controls on age, vasomotor symptoms (hot flashes/night sweats), stress, or depression but did have a higher body mass index. Measures were stable over time for controls. However, the transition group experienced an increase in PSQI scores (initial PSQI = 5.7 ± 3.2 and final PSQI = 6.3 ± 3.8; P = .030) and frequency of trouble sleeping because of feeling too hot ( P = .016), which lagged the FSH rise by 6 months with no notable change in report of hot flashes/night sweats., Conclusions: Trouble sleeping because of feeling too hot, distinct from awareness of vasomotor symptoms, was the only uniform contribution to higher PSQI scores after the initial FSH increase and may signal the onset of the menopausal transition., Citation: Zak R, Zitser J, Jones HJ, Gilliss CL, Lee KA. Sleep symptoms signaling the menopausal transition. J Clin Sleep Med . 2023;19(8):1513-1521., (© 2023 American Academy of Sleep Medicine.)

Background: Adverse childhood experiences (ACEs) are classically defined as physical abuse, sexual abuse, emotional abuse, emotional neglect, bullying, parental substance use or abuse, violence between parents, parental mental health problems or suicide, parental separation, or a parent convicted of criminal offence. Exposure to ACEs can be associated with cannabis use, but no comparisons across all adversities have been made while also considering timing and frequency of cannabis use. We aimed to explore the association between ACEs and cannabis use timing and frequency in adolescence, considering the cumulative number of ACEs and individual ACEs., Methods: We used data from the Avon Longitudinal Study of Parents and Children, a longitudinal UK birth cohort study. Longitudinal latent classes of cannabis use frequency were derived from self-reported data at multiple timepoints in participants aged 13-24 years. ACEs between ages 0 years and 12 years were derived from prospective and retrospective reports at multiple timepoints by parents and the participant. Multinomial regression was used to analyse the effect of both cumulative exposure to all ACEs and the ten individual ACEs on cannabis use outcomes., Findings: 5212 participants (3132 [60·0%] were female and 2080 [40·0%] were male; 5044 [96·0%] were White and 168 [4·0%] were Black, Asian, or minority ethnic) were included in this study. After adjustment for polygenic risk and environmental risk factors, participants who had 4 or more ACEs at age 0-12 years were at increased risk of early persisting regular cannabis use (relative risk ratio [RRR] 3·15 [95% CI 1·81-5·50]), later onset regular use (1·99 [1·14-3·74]), and early persisting occasional use (2·55 [1·74-3·73]) compared with low or no cannabis use. After adjustment, early persisting regular use was associated with parental substance use or abuse (RRR 3·90 [95% CI 2·10-7·24]), parental mental health problems (2·02 [1·26-3·24]), physical abuse (2·27 [1·31-3·98]), emotional abuse (2·44 [1·49-3·99]), and parental separation (1·88 [1·08-3·27]) compared with low or no cannabis use., Interpretation: Risks for problematic adolescent cannabis use are highest for individuals reporting 4 or more ACEs, and were particularly raised for those with parental substance use or abuse. Public health measures to address ACEs might reduce adolescent cannabis use., Funding: The Wellcome Trust, UK Medical Research Council, Alcohol Research UK., Competing Interests: Declaration of interests ML is employed by Drug Science, which receives an unrestricted educational grant from a consortium of medical cannabis companies to further its mission, that is the pursuit of an unbiased and scientific assessment of drugs regardless of their regulatory class. All other authors declare no competing interests., (Copyright © 2023 The Author(s). Published by Elsevier Ltd. This is an Open Access article under the CC BY 4.0 license. Published by Elsevier Ltd.. All rights reserved.)

Background: Inflammation is associated with cognitive functioning and dementia in older adults, but whether inflammation is related to cognitive functioning in youth and whether these associations are causal remains unclear., Methods: In a population-based cohort (Avon Longitudinal Study of Parents and Children; ALSPAC), we investigated cross-sectional associations of inflammatory markers (C-reactive protein [CRP], Interleukin-6 [IL-6] and Glycoprotein acetyls [GlycA]) with measures of cold (working memory, response inhibition) and hot (emotion recognition) cognition at age 24 (N = 3,305 in multiple imputation models). Furthermore, we conducted one-sample and two-sample bidirectional Mendelian randomization (MR) analyses to examine potential causal effects of genetically-proxied inflammatory markers (CRP, GlycA, IL-6, IL-6 receptor, soluble IL-6 receptor) on cognitive measures (above) and on general cognitive ability., Results: In the ALSPAC cohort, there was limited evidence of an association between standardised inflammatory markers and standardised cognitive measures at age 24 after adjusting for potential confounders (N = 3,305; beta range, -0.02 [95 % confidence interval (CI) -0.06 to 0.02, p = 0.27] to 0.02 [95 % CI -0.02 to 0.05, p = 0.33]). Similarly, we found limited evidence of potential effects of 1-unit increase in genetically-proxied inflammatory markers on standardised working memory, emotion recognition or response inhibition in one-sample MR using ALSPAC data (beta range, -0.73 [95 % CI -2.47 to 1.01, p = 0.41] to 0.21 [95 % CI -1.42 to 1.84, p = 0.80]; or on standardised general cognitive ability in two-sample MR using the latest Genome-Wide Association Study (GWAS) datasets (inverse-variance weighted beta range, -0.02 [95 % CI -0.05 to 0.01, p = 0.12] to 0.03 [95 % CI -0.01 to 0.07, p = 0.19])., Conclusions: Our MR findings do not provide strong evidence of a potential causal effect of inflammatory markers (CRP, IL-6, IL-6 receptor, GlycA) on the cognitive functions examined here. Given the large confidence intervals in the one-sample MR, larger GWAS of specific cognitive measures are needed to enable well-powered MR analyses to investigate whether inflammation causally influences specific cognitive domains., Competing Interests: Declaration of Competing Interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: The CHARGE Inflammation Working Group conducted GWAS of inflammation (CRP and IL-6) used in this study. MMis co-director ofJericoeLtd, which produces software for the assessment and modification of emotion perception. The authors report no other biomedical financial interests or potential conflicts of interest. GDS reports Scientific Advisory Board Membership for Relation Therapeutics and Insitro., (Copyright © 2023 The Authors. Published by Elsevier Inc. All rights reserved.)

Background: Little is known on whether associations between childhood autistic traits and psychotic experiences persist into adulthood and whether genetic confounding and childhood trauma influence them. Here we investigate the associations between childhood autistic traits and psychotic experiences until young adulthood and assess the influence of schizophrenia polygenic risk and childhood traumatic experiences, using the Avon Longitudinal Study of Parents and Children (ALSPAC) population-based birth cohort., Study Design: We used a measure of broad autistic traits (autism factor mean score), and four dichotomised measures of autistic traits capturing social communication difficulties (age 7), repetitive behaviours (age 5), sociability (age 3), and pragmatic language (age 9). Psychotic experiences were assessed at ages 18 and 24 using the semi-structured Psychosis-Like Symptoms interview (PLIKSi). Traumatic experiences between ages 5 and 11 were assessed with questionnaires and interviews administered to children and parents at multiple ages., Study Results: Broad autistic traits, as well as social communication difficulties, were associated with psychotic experiences that were distressing and/or frequent until age 24 (autism factor mean score, n = 3707: OR 1.19, 95%CI 1.01-1.39; social communication difficulties, n = 3384: OR 1.54, 95%CI 0.97-2.45). Childhood trauma mediated a substantial proportion of the identified associations (~28% and 36% respectively, maximum n = 3577). Schizophrenia polygenic risk did not appear to confound the associations. Multiple imputation analyses (maximum n = 13 105) yielded comparable results., Conclusions: Childhood trauma may be an important, potentially modifiable pathway between autistic features and later onset of psychotic psychopathology., (© The Author(s) 2022. Published by Oxford University Press on behalf of the Maryland Psychiatric Research Center.)

Background: Black women have a disproportionately higher incidence of cardiovascular disease-related mortality than other groups, yet they are less likely to receive culturally proficient education and competent preventive care., Purpose: The purpose of this study was to determine feasibility of the Midlife Black Women's Stress and Wellness intervention (B-SWELL); a culturally adapted, 8-week group intervention leveraging stress reduction and goal setting to increase awareness and adoption of Life's Simple 7 (LS7) healthy lifestyle behaviors., Methods: A randomized feasibility trial was conducted. Participants (N = 48, mean age = 55 years) were randomized to the B-SWELL or a group wellness (WE) intervention that lacked stress reduction and goal setting instruction. We hypothesized that B-SWELL participants would achieve a lower perceived stress, greater self-efficacy, improved LS7 scores, fewer symptoms (depression and unhealthy days), and greater perceived general health compared to WE participants. Survey data were collected at three timepoints: baseline, 8 weeks, and 12 weeks., Results: Both B-SWELL and WE groups had low attrition and navigated the online platform well. Further, both groups experienced lower perceived stress, improved LS7 scores, reduced depressive symptoms, and greater perceived general health from baseline to 8 weeks. Based on data trends, participants in the B-SWELL had more improvement in perceived stress, self-efficacy, and mental and physical unhealthy days compared to WE participants., Conclusion: The B-SWELL is a feasible intervention for midlife Black women. Positive data trends were found for both B-SWELL and WE groups. Based on observations from the feasibility study, a larger outcomes-based study is planned., (© Society of Behavioral Medicine 2022. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Background: There is growing concern about the long-term cardiovascular health of patients with juvenile idiopathic arthritis (JIA). In this study we assessed the association between JIA polygenic risk and cardiovascular phenotypes (cardiovascular risk factors, early atherosclerosis/arteriosclerosis markers, and cardiac structure and function measures) early in life., Methods: JIA polygenic risk scores (PRSs) were constructed for 2,815 participants from the Avon Longitudinal Study of Parents and Children, using the single nucleotide polymorphism (SNP) weights from the most recent JIA genome wide association study. The association between JIA PRSs and cardiovascular phenotypes at age 24 years was assessed using linear and logistic regression. For outcomes with strong evidence of association, further analysis was undertaken to examine how early in life (from age seven onwards) these associations manifest., Results: The JIA PRS was associated with diastolic blood pressure (β 0.062, 95% CI 0.026 to 0.099, P = 0.001), insulin (β 0.050, 95% CI 0.011 to 0.090, P = 0.013), insulin resistance index (HOMA2_IR, β 0.054, 95% CI 0.014 to 0.095, P = 0.009), log hsCRP (β 0.053, 95% CI 0.011 to 0.095, P = 0.014), waist circumference (β 0.041, 95% CI 0.007 to 0.075, P = 0.017), fat mass index (β 0.049, 95% CI 0.016 to 0.083, P = 0.004) and body mass index (β 0.046, 95% CI 0.011 to 0.081, P = 0.010). For anthropometric measures and diastolic blood pressure, there was suggestive evidence of association with JIA PRS from age seven years. The findings were consistent across multiple sensitivity analyses., Conclusions: Genetic liability to JIA is associated with multiple cardiovascular risk factors, supporting the hypothesis of increased cardiovascular risk in JIA. Our findings suggest that cardiovascular risk is a core feature of JIA, rather than secondary to the disease activity/treatment, and that cardiovascular risk counselling should form part of patient care., (© 2022. The Author(s).)

Inflammation is implicated in depression and psychosis, including association of childhood inflammatory markers on the subsequent risk of developing symptoms. However, it is unknown whether early-life inflammatory markers are associated with the number of depressive and psychotic symptoms from childhood to adulthood. Using the prospective Avon Longitudinal Study of Children and Parents birth cohort (N = up-to 6401), we have examined longitudinal associations of early-life inflammation [exposures: interleukin-6 (IL-6), C-reactive protein (CRP) levels at age 9y; IL-6 and CRP DNA-methylation (DNAm) scores at birth and age 7y; and IL-6 and CRP polygenic risk scores (PRSs)] with the number of depressive episodes and psychotic experiences (PEs) between ages 10-28 years. Psychiatric outcomes were assessed using the Short Mood and Feelings Questionnaire and Psychotic Like Symptoms Questionnaires, respectively. Exposure-outcome associations were tested using negative binomial models, which were adjusted for metabolic and sociodemographic factors. Serum IL-6 levels at age 9y were associated with the total number of depressive episodes between 10 and 28y in the base model (n = 4835; β = 0.066; 95%CI:0.020-0.113; pFDR = 0.041) which was weaker when adjusting for metabolic and sociodemographic factors. Weak associations were observed between inflammatory markers (serum IL-6 and CRP DNAm scores) and total number of PEs. Other inflammatory markers were not associated with depression or PEs. Early-life inflammatory markers are associated with the burden of depressive episodes and of PEs subsequently from childhood to adulthood. These findings support a potential role of early-life inflammation in the aetiology of depression and psychosis and highlight inflammation as a potential target for treatment and prevention., Competing Interests: All authors have nothing to disclose., (© 2022 The Author(s).)

Background and Objective: Content validation is an integral part of intervention development and should be established before initiation of trials. In collaboration with a community research advisory board, the objective of this study was to analyze expert ratings and qualitative feedback for the Midlife Black Women's Stress-Reduction Wellness (B-SWELL) intervention materials., Methods: The B-SWELL intervention is a culturally tailored 8-week intervention designed to lower cardiovascular disease risk in midlife Black women by leveraging stress reduction and promoting the adoption of the American Heart Association's Life's Simple 7 healthy lifestyle behaviors. Using a mixed methods approach, 12 experts consisting of midlife Black women (n = 6), researchers (n = 3), and integrative health specialists (n = 3) rated the B-SWELL materials for content accuracy, topic relevance, stress relevance, cultural appropriateness, feasibility, usefulness, ease of use, and appeal using a 5-point Likert scale (1, strongly disagree, to 5, strongly agree). Qualitative narrative data were integrated with the ratings., Results: Combined expert ratings for the B-SWELL materials were high (range, 4.43-4.66). Group ratings differed, with midlife Black women having the highest mean ratings for both the individual B-SWELL modules and the overall binder (4.71 and 4.97, respectively), followed by researchers (4.56 and 4.73, respectively) and integrative health specialists (4.11 and 4.40, respectively). Qualitative data provided insight into deficiencies, supporting refinements of the B-SWELL materials., Conclusions: The B-SWELL materials exhibited strong evidence of content and face validity. Researchers and clinicians are encouraged to establish content validity before implementation of culturally appropriate interventions aimed at high-risk populations., Competing Interests: The authors have no conflicts of interest to disclose., (Copyright © 2021 Wolters Kluwer Health, Inc. All rights reserved.)

Background: Validity of the Pittsburgh Sleep Quality Index (PSQI) has not been established for midlife women before menopause, and evidence suggests that two-factor or three-factor models may be more informative than the PSQI global score derived from its seven components. We hypothesized that the PSQI and its factor structure would be valid in premenopausal women. Materials and Methods: We performed a validation study of the PSQI against wrist actigraphy in a community-based convenience sample of 71 healthy premenopausal women (aged 40-50 years). For convergent validity, PSQI and its component scores were compared with homologous actigraphy measures. For discriminant validity, characteristics known to affect sleep quality were compared, including body mass index, exercise, menopausal status, menopausal symptoms, and depressive symptoms measured with the Center for Epidemiological Studies-Depression (CES-D) Scale. Results: The PSQI global score and Components 1 (quality) and 5 (disturbance) were correlated ( p  < 0.05) with actigraphy-measured wake after sleep onset. The PSQI global score and Components 1 (quality) and 7 (daytime dysfunction) were correlated with CES-D scores. PSQI Components 2 (onset latency) and 4 (efficiency) were not congruent with homologous actigraphy measures, while component 3 (duration) was congruent with actigraphy duration. The single-factor PSQI global score had a higher McDonald's omega (0.705) and Cronbach's alpha (0.702) than the two-factor or three-factor models. Conclusions: The PSQI global score is a valid measure of sleep quality in healthy midlife women, performing better than two-factor or three-factor models. However, overlapping CES-D and PSQI scores warrant further clinical assessment and research to better differentiate poor sleep quality from depression.

Evidence linking parental inflammatory bowel disease (IBD) with autism in children is inconclusive. We conducted four complementary studies to investigate associations between parental IBD and autism in children, and elucidated their underlying etiology. Conducting a nationwide population-based cohort study using Swedish registers, we found evidence of associations between parental diagnoses of IBD and autism in children. Polygenic risk score analyses of the Avon Longitudinal Study of Parents and Children suggested associations between maternal genetic liability to IBD and autistic traits in children. Two-sample Mendelian randomization analyses provided evidence of a potential causal effect of genetic liability to IBD, especially ulcerative colitis, on autism. Linkage disequilibrium score regression did not indicate a genetic correlation between IBD and autism. Triangulating evidence from these four complementary approaches, we found evidence of a potential causal link between parental, particularly maternal, IBD and autism in children. Perinatal immune dysregulation, micronutrient malabsorption and anemia may be implicated., (© 2022. The Author(s).)

Objective: Colorectal cancer is a common cause of death and morbidity. A significant amount of data are routinely collected during patient treatment, but they are not generally available for research. The National Institute for Health Research Health Informatics Collaborative in the UK is developing infrastructure to enable routinely collected data to be used for collaborative, cross-centre research. This paper presents an overview of the process for collating colorectal cancer data and explores the potential of using this data source., Methods: Clinical data were collected from three pilot Trusts, standardised and collated. Not all data were collected in a readily extractable format for research. Natural language processing (NLP) was used to extract relevant information from pseudonymised imaging and histopathology reports. Combining data from many sources allowed reconstruction of longitudinal histories for each patient that could be presented graphically., Results: Three pilot Trusts submitted data, covering 12 903 patients with a diagnosis of colorectal cancer since 2012, with NLP implemented for 4150 patients. Timelines showing individual patient longitudinal history can be grouped into common treatment patterns, visually presenting clusters and outliers for analysis. Difficulties and gaps in data sources have been identified and addressed., Discussion: Algorithms for analysing routinely collected data from a wide range of sites and sources have been developed and refined to provide a rich data set that will be used to better understand the natural history, treatment variation and optimal management of colorectal cancer., Conclusion: The data set has great potential to facilitate research into colorectal cancer., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2022. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Background: Metabolic and inflammatory disorders commonly co-occur with depression and psychosis, with emerging evidence implicating immuno-metabolic dysfunction in their aetiology. Previous studies have reported metabolic dysfunction and inflammation in adults with depression and psychosis. However, longitudinal studies testing the direction of association, and the effects of different dimensions of early-life immuno-metabolic dysfunction on adult psychopathology are limited., Methods: Using data from 3258 birth cohort participants we examined longitudinal associations of three metabolic hormones (leptin, adiponectin, insulin) at age 9 with risks for depression- and psychosis-spectrum outcomes at age 24. In addition, using nine immuno-metabolic biomarkers (leptin, adiponectin, insulin, interleukin-6, C-Reactive protein, low density lipoprotein, high density lipoprotein, triglycerides, and BMI), we constructed an exploratory bifactor model showing a general immuno-metabolic factor and three specific factors (adiposity, inflammation, and insulin resistance), which were also used as exposures., Results: Childhood leptin was associated with adult depressive episode (adjusted odds ratio (aOR)= 1.31; 95% CI, 1.02-1.71) and negative symptoms (aOR=1.15; 95% CI, 1.07-1.24), but not positive psychotic symptoms. The general immuno-metabolic factor was associated with atypical depressive symptoms (aOR=1.07; 95% CI, 1.01-1.14) and psychotic experiences (aOR=1.21; 95% CI, 1.02-1.44). The adiposity factor was associated with negative symptoms (aOR=1.07; 95% CI 1.02-1.12). Point estimates tended to be larger in women, though 95% credible intervals overlapped with those for men. In women, the inflammatory factor was associated with depressive episodes (aOR=1.27; 95% CI, 1.03-1.57)., Conclusions: While general immuno-metabolic dysfunction in childhood may contribute to risks for both psychotic and depressive symptoms in adulthood, childhood adiposity and inflammation appear to be particularly linked to affective (depressive and negative), but not positive psychotic symptoms., (Copyright © 2022 Elsevier Ltd. All rights reserved.)

Midlife Black women suffer disproportionately from heart disease and stroke in comparison to White women of similar age and demographic. Risk for cardiovascular disease (CVD) and stroke is largely considered to be modifiable yet CVD prevention and awareness campaigns have been less effective among Black women. Decreased awareness of personal CVD risk is associated with delays in the presentation of women to the emergency room or health care providers for symptoms of myocardial infarction. The Midlife Black Women's Stress and Wellness (B-SWELL) program was designed to increase awareness about CVD risk factors, stress, and healthy lifestyle behaviors among midlife Black women. In partnership with an existing Community Research Advisory Board (C-RAB), materials were developed and culturally adapted for the B-SWELL program. Following successful development of the B-SWELL materials, a trial of the B-SWELL program was conducted with a sample of midlife Black women recruited from the community. The program was co-facilitated by members of the C-RAB. We outline the strategies used to successfully co-create and trial the B-SWELL program materials and reflect on the strengths and challenges associated with the development of a culturally tailored heart disease prevention program using community participatory methods.

Background: It is not clear to what extent associations between schizophrenia, cannabis use and cigarette use are due to a shared genetic etiology. We, therefore, examined whether schizophrenia genetic risk associates with longitudinal patterns of cigarette and cannabis use in adolescence and mediating pathways for any association to inform potential reduction strategies., Methods: Associations between schizophrenia polygenic scores and longitudinal latent classes of cigarette and cannabis use from ages 14 to 19 years were investigated in up to 3925 individuals in the Avon Longitudinal Study of Parents and Children. Mediation models were estimated to assess the potential mediating effects of a range of cognitive, emotional, and behavioral phenotypes., Results: The schizophrenia polygenic score, based on single nucleotide polymorphisms meeting a training-set p threshold of 0.05, was associated with late-onset cannabis use (OR = 1.23; 95% CI = 1.08,1.41), but not with cigarette or early-onset cannabis use classes. This association was not mediated through lower IQ, victimization, emotional difficulties, antisocial behavior, impulsivity, or poorer social relationships during childhood. Sensitivity analyses adjusting for genetic liability to cannabis or cigarette use, using polygenic scores excluding the CHRNA5-A3-B4 gene cluster, or basing scores on a 0.5 training-set p threshold, provided results consistent with our main analyses., Conclusions: Our study provides evidence that genetic risk for schizophrenia is associated with patterns of cannabis use during adolescence. Investigation of pathways other than the cognitive, emotional, and behavioral phenotypes examined here is required to identify modifiable targets to reduce the public health burden of cannabis use in the population.

The successful prevention of mental illness relies upon the identification of causal, modifiable risk factors. However, observational evidence exploring such risk factors often produces contradictory results and randomised control trials are often expensive, time-consuming or unethical to conduct. Mendelian randomisation (MR) is a complementary approach that uses naturally occurring genetic variation to identify possible causal effects between a risk factor and an outcome in a time-efficient and low-cost manner. MR utilises genetic variants as instrumental variables for the risk factor of interest. MR studies are becoming more frequent in the field of psychiatry, warranting a reflection upon both the possibilities and the pitfalls. In this Perspective, we consider several limitations of the MR method that are of particular relevance to psychiatry. We also present new MR methods that have exciting applications to questions of mental illness. While we believe that MR can make an important contribution to the field of psychiatry, we also wish to emphasise the importance of clear causal questions, thorough sensitivity analyses, and triangulation with other forms of evidence., (© 2021. The Author(s).)

Background: Although studies suggest that concentrations of omega-3 and omega-6 fatty acids are lower in individuals with schizophrenia, evidence for beneficial effects of fatty acid supplementation is scarce. Therefore, in this study, we aimed to determine whether omega-3 and omega-6 fatty acid concentrations are causally related to schizophrenia., Methods: We did a two-sample Mendelian randomisation study, using deidentified summary-level data that were publicly available. Exposure-outcome relationships were evaluated using the inverse variance weighted two-sample Mendelian randomisation method using results from genome-wide association studies (GWASs) of fatty acid concentrations and schizophrenia. GWAS results were available for European (fatty acids) and European and Asian (schizophrenia) ancestry samples. Overall age and gender information were not calculable from the summary-level GWAS results. Weighted median, weighted mode, and Mendelian randomisation Egger regression methods were used as sensitivity analyses. To address underlying mechanisms, further analyses were done using single instruments within the FADS gene cluster and ELOVL2 gene locus. FADS gene cluster and ELOVL2 gene causal effects on schizophrenia were calculated by dividing the single nucleotide polymorphism (SNP)-schizophrenia effect estimate by the SNP-fatty acid effect estimate with standard errors derived using the first term from a delta method expansion for the ratio estimate. Multivariable Mendelian randomisation was used to estimate direct effects of omega-3 fatty acids on schizophrenia, independent of omega-6 fatty acids, lipoproteins (ie, HDL and LDL), and triglycerides., Findings: Mendelian randomisation analyses indicated that long-chain omega-3 and long-chain omega-6 fatty acid concentrations were associated with a lower risk of schizophrenia (eg, inverse variance weighted odds ratio [OR] 0·83 [95% CI 0·75-0·92] for docosahexaenoic acid). By contrast, there was weak evidence that short-chain omega-3 and short-chain omega-6 fatty acids were associated with an increased risk of schizophrenia (eg, inverse variance weighted OR 1·07 [95% CI 0·98-1·18] for α-linolenic acid). Effects were consistent across the sensitivity analyses and the FADS single-SNP analyses, suggesting that long-chain omega-3 and long-chain omega-6 fatty acid concentrations were associated with lower risk of schizophrenia (eg, OR 0·74 [95% CI 0·58-0·96] for docosahexaenoic acid) whereas short-chain omega-3 and short-chain omega-6 fatty acid concentrations were associated with an increased risk of schizophrenia (eg, OR 1·08 [95% CI 1·02-1·15] for α-linolenic acid). By contrast, estimates from the ELOVL2 single-SNP analyses were more imprecise and compatible with both risk-increasing and protective effects for each of the fatty acid measures. Multivariable Mendelian randomisation indicated that the protective effect of docosahexaenoic acid on schizophrenia persisted after conditioning on other lipids, although evidence was slightly weaker (multivariable inverse variance weighted OR 0·84 [95% CI 0·71-1·01])., Interpretation: Our results are compatible with the protective effects of long-chain omega-3 and long-chain omega-6 fatty acids on schizophrenia, suggesting that people with schizophrenia might have difficulty converting short-chain polyunsaturated fatty acids to long-chain polyunsaturated fatty acids. Further studies are required to determine whether long-chain polyunsaturated fatty acid supplementation or diet enrichment might help prevent onset of schizophrenia., Funding: National Institute for Health Research Biomedical Research Centre at University Hospitals Bristol and Weston NHS Foundation Trust and the University of Bristol., Competing Interests: Declaration of interests DM has a patent application (UK Patent Application number 1919155.0 for biomarkers to predict psychosis) pending. DM is also a Fellow on the Irish Clinical Academic Training Programme, which is supported by the Wellcome Trust and the Health Research Board (grant number 203930/B/16/Z), the Health Service Executive National Doctors Training and Planning, and the Health and Social Care, Research and Development Division, Northern Ireland. MCB is supported by a UK Medical Research Council Skills Development Fellowship (grant number MR/P014054/1). RC is supported by the Wellcome Trust (grant number WT 212557/Z/18/Z). All other authors declare no competing interests., (Copyright © 2021 Elsevier Ltd. All rights reserved.)

Background: Psychotic experiences are reported by 5-10% of young people, although only a minority persist and develop into psychotic disorders. It is unclear what characteristics differentiate those with transient psychotic experiences from those with persistent psychotic experiences that are more likely to be of clinical relevance., Aims: To investigate how longitudinal profiles of psychotic experiences, created from assessments at three different time points, are influenced by early life and co-occurring factors., Method: Using data from 8045 individuals from a birth cohort study, longitudinal profiles of psychotic experiences based on semi-structured interviews conducted at 12, 18 and 24 years were defined. Environmental, cognitive, psychopathological and genetic determinants of these profiles were investigated, along with concurrent changes in psychopathology and cognition., Results: Following multiple imputations, the distribution of longitudinal profiles of psychotic experiences was none (65.7%), transient (24.1%), low-frequency persistent (8.4%) and high-frequency persistent (1.7%). Individuals with high-frequency persistent psychotic experiences were more likely to report traumatic experiences, other psychopathology, a more externalised locus of control, reduced emotional stability and conscientious personality traits in childhood, compared with those with transient psychotic experiences. These characteristics also differed between those who had any psychotic experiences and those who did not., Conclusions: These findings indicate that the same risk factors are associated with incidence as with persistence of psychotic experiences. Thus, it might be that the severity of exposure, rather than the presence of specific disease-modifying factors, is most likely to determine whether psychotic experiences are transient or persist, and potentially develop into a clinical disorder over time.

African Americans and people of color have been disproportionately affected by the coronavirus (COVID-19) pandemic. As the second wave of the virus raged across the nation, there was a renewed effort to increase adherence to social distancing and mask-wearing guidelines. A community-based study led by members of the local National Black Nurses Association (NBNA) was conducted in a Midwest metropolitan city to identify barriers to mask-wearing experienced by business owners and employees in predominantly African American neighborhoods. Neighborhood business owners and their employees are essential to the life of a community as they provide needed goods and services from convenient neighborhood locations. Thus, attitudes and behaviors exhibited by business owners, supervisors, and other employees are important to combat COVID-19 in underserved communities. Semi-structured interviews were conducted with 39 business owners or supervising employees. Simple content analysis was used to identify codes and themes from the narrative data. Responses to the question 'What can make mask-wearing easier for your business and businesses in the neighborhood?' yielded three themes. Themes included 'a sense of community', the 'need for external support', and 'internal leadership'. These themes can be used to develop interventions to improve mask-wearing behaviors, support business owners and their customers, and lower the spread of COVID-19 in high-risk communities., (© 2021. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

Aims: Most patients with heart failure (HF) have symptoms. Poor self-care has been associated with the development or worsening symptoms. Thus, to improve HF symptoms, it may be critical to understand self-care and interventions targeting improvements in HF symptoms needed from patients' perspectives. To explore patients' perceptions of self-care strategies of individual symptoms, HF symptom improvement, and interventions needed to improve HF symptoms in patients with HF., Methods and Results: Qualitative data were collected from 20 patients with HF using a semi-structured open-ended interview guide. Data were analysed using content analysis. Five themes appeared: (i) use of a variety of strategies with some knowledge deficit and inefficiency, (ii) uncertainty in symptom improvement, (iii) consideration of several possible self-care strategies, (iv) use of situation-specific strategies in seeking treatment, and (v) willingness to receive comprehensive and realistic interventions. Patients used a variety of self-care strategies, including taking medication, reducing activities, and changing diet and position, but many reported having a lack of knowledge and multiple HF symptoms. Several patients were uncertain whether symptoms could be improved, but all patients reported that they would participate in comprehensive and realistic intervention sessions to gain knowledge about their symptoms and management strategies, and to receive emotional support from healthcare providers and peer patients., Conclusion: Patients with HF used several self-care strategies with the hope of symptom improvements but were uncertain about the effectiveness. More effective, comprehensive, and realistic interventions need to be delivered to patients with HF to enhance their ability to manage their symptoms., (Published on behalf of the European Society of Cardiology. All rights reserved. © The Author(s) 2021. For permissions, please email: journals.permissions@oup.com.)

Background: There is a wealth of literature on the observed association between childhood trauma and psychotic illness. However, the relationship between childhood trauma and psychosis is complex and could be explained, in part, by gene-environment correlation., Methods: The association between schizophrenia polygenic scores (PGS) and experiencing childhood trauma was investigated using data from the Avon Longitudinal Study of Parents and Children (ALSPAC) and the Norwegian Mother, Father and Child Cohort Study (MoBa). Schizophrenia PGS were derived in each cohort for children, mothers, and fathers where genetic data were available. Measures of trauma exposure were derived based on data collected throughout childhood and adolescence (0-17 years; ALSPAC) and at age 8 years (MoBa)., Results: Within ALSPAC, we found a positive association between schizophrenia PGS and exposure to trauma across childhood and adolescence; effect sizes were consistent for both child or maternal PGS. We found evidence of an association between the schizophrenia PGS and the majority of trauma subtypes investigated, with the exception of bullying. These results were comparable with those of MoBa. Within ALSPAC, genetic liability to a range of additional psychiatric traits was also associated with a greater trauma exposure., Conclusions: Results from two international birth cohorts indicate that genetic liability for a range of psychiatric traits is associated with experiencing childhood trauma. Genome-wide association study of psychiatric phenotypes may also reflect risk factors for these phenotypes. Our findings also suggest that youth at higher genetic risk might require greater resources/support to ensure they grow-up in a healthy environment.

Background: Deferral of conventional surgery for rectal cancer after neo-adjuvant chemo-radiotherapy is gaining increasing interest, particularly for patients who are too frail to undergo major surgery but also those who wish to avoid the adverse effects of major surgery. We elected to undertake a pragmatic approach to include all comers in a cohort with the aim of reflecting the clinical outcomes for patients on a deferral from conventional rectal surgery pathway, treated with neo-adjuvant chemo-radiation (CRT) with or without selective local excision (LE) offered to those who failed to demonstrate a complete clinical response (cCR)., Methods: Rectal cancer patients treated with neo-adjuvant CRT were stratified to a group of complete responders to CRT on a "watch and wait" (WW) pathway and a group who were treated with an additional local excision for persistent tumour., Results: Regrowth was noted in 26% (11/42) in the WW group after 2 years surveillance, disease free survival was 94.5% (80-99%) at 1 year and 74.9% (44-76.4%) at 3 years. Recurrence was noted in 45% (10/22) in the CRT + LE group, disease free survival at 1 and 3 years was 74% (53.4-88.1) and 66.2% (45.6-82.4) respectively., Conclusion: A WW strategy for cCR is a viable pathway in the non-operative management of rectal cancer. We found the use of CRT + LE is a useful option for those who hope to avoid surgery but caution should be exercised due to substantially higher risk of recurrence., (Copyright © 2021 Elsevier Ltd. All rights reserved.)

Polyunsaturated fatty acids (PUFAs) may be pertinent to the development of mental disorders, for example via modulation of inflammation and synaptogenesis. We wished to examine cross-sectional and longitudinal associations between PUFAs and mental disorders in a large cohort of young people. Participants in the Avon Longitudinal Study of Parents and Children were interviewed and provided blood samples at two sampling periods when approximately 17 and 24 years old. Plasma PUFA measures (total omega-6 [n-6], total omega-3 [n-3], n-6:n-3 ratio and docosahexaenoic acid [DHA] percentage of total fatty acids) were assessed using nuclear magnetic resonance spectroscopy. Cross-sectional and longitudinal associations between standardised PUFA measures and three mental disorders (psychotic disorder, moderate/severe depressive disorder and generalised anxiety disorder [GAD]) were measured by logistic regression, adjusting for age, sex, body mass index and cigarette smoking. There was little evidence of cross-sectional associations between PUFA measures and mental disorders at age 17. At age 24, the n-6:n-3 ratio was positively associated with psychotic disorder, depressive disorder and GAD, while DHA was inversely associated with psychotic disorder. In longitudinal analyses, there was evidence of an inverse association between DHA at age 17 and incident psychotic disorder at age 24 (adjusted odds ratio 0.44, 95% confidence interval 0.22-0.87) with little such evidence for depressive disorder or GAD. There was little evidence for associations between change in PUFA measures from 17 to 24 years and incident mental disorders at 24 years. These findings provide support for associations between PUFAs and mental disorders in early adulthood, and in particular, for DHA in adolescence in relation to prevention of psychosis.

Background: Empirical evidence supporting the distinction between suicide attempt (SA) and non-suicidal self-harm (NSSH) is lacking. Although NSSH is a risk factor for SA, we do not currently know whether these behaviours lie on a continuum of severity, or whether they are discrete outcomes with different aetiologies. We conducted this exploratory genetic epidemiology study to investigate this issue further., Methods: We explored the extent of genetic overlap between NSSH and SA in a large, richly-phenotyped cohort (the Avon Longitudinal Study of Parents and Children; N = 4959), utilising individual-level genetic and phenotypic data to conduct analyses of genome-wide complex traits and polygenic risk scores (PRS)., Results: The single nucleotide polymorphism heritability of NSSH was estimated to be 13% (SE 0.07) and that of SA to be 0% (SE 0.07). Of the traits investigated, NSSH was most strongly correlated with higher IQ (rG = 0.31, SE = 0.22), there was little evidence of high genetic correlation between NSSH and SA (rG = - 0.1, SE = 0.54), likely due to the low heritability estimate for SA. The PRS for depression differentiated between those with NSSH and SA in multinomial regression. The optimal PRS prediction model for SA (Nagelkerke R 2 0.022, p < 0.001) included ADHD, depression, income, anorexia and neuroticism and explained more variance than the optimal prediction model for NSSH (Nagelkerke R 2 0.010, p < 0.001) which included ADHD, alcohol consumption, autism spectrum conditions, depression, IQ, neuroticism and suicide attempt., Conclusions: Our findings suggest that SA does not have a large genetic component, and that although NSSH and SA are not discrete outcomes there appears to be little genetic overlap between the two. The relatively small sample size and resulting low heritability estimate for SA was a limitation of the study. Combined with low heritability estimates, this implies that family or population structures in SA GWASs may contribute to signals detected.

Background: Insulin resistance predisposes to cardiometabolic disorders, which are commonly comorbid with schizophrenia and are key contributors to the significant excess mortality in schizophrenia. Mechanisms for the comorbidity remain unclear, but observational studies have implicated inflammation in both schizophrenia and cardiometabolic disorders separately. We aimed to examine whether there is genetic evidence that insulin resistance and 7 related cardiometabolic traits may be causally associated with schizophrenia, and whether evidence supports inflammation as a common mechanism for cardiometabolic disorders and schizophrenia., Methods and Findings: We used summary data from genome-wide association studies of mostly European adults from large consortia (Meta-Analyses of Glucose and Insulin-related traits Consortium (MAGIC) featuring up to 108,557 participants; Diabetes Genetics Replication And Meta-analysis (DIAGRAM) featuring up to 435,387 participants; Global Lipids Genetics Consortium (GLGC) featuring up to 173,082 participants; Genetic Investigation of Anthropometric Traits (GIANT) featuring up to 339,224 participants; Psychiatric Genomics Consortium (PGC) featuring up to 105,318 participants; and Cohorts for Heart and Aging Research in Genomic Epidemiology (CHARGE) consortium featuring up to 204,402 participants). We conducted two-sample uni- and multivariable mendelian randomization (MR) analysis to test whether (i) 10 cardiometabolic traits (fasting insulin, high-density lipoprotein and triglycerides representing an insulin resistance phenotype, and 7 related cardiometabolic traits: low-density lipoprotein, fasting plasma glucose, glycated haemoglobin, leptin, body mass index, glucose tolerance, and type 2 diabetes) could be causally associated with schizophrenia; and (ii) inflammation could be a shared mechanism for these phenotypes. We conducted a detailed set of sensitivity analyses to test the assumptions for a valid MR analysis. We did not find statistically significant evidence in support of a causal relationship between cardiometabolic traits and schizophrenia, or vice versa. However, we report that a genetically predicted inflammation-related insulin resistance phenotype (raised fasting insulin (raised fasting insulin (Wald ratio OR = 2.95, 95% C.I, 1.38-6.34, Holm-Bonferroni corrected p-value (p) = 0.035) and lower high-density lipoprotein (Wald ratio OR = 0.55, 95% C.I., 0.36-0.84; p = 0.035)) was associated with schizophrenia. Evidence for these associations attenuated to the null in multivariable MR analyses after adjusting for C-reactive protein, an archetypal inflammatory marker: (fasting insulin Wald ratio OR = 1.02, 95% C.I, 0.37-2.78, p = 0.975), high-density lipoprotein (Wald ratio OR = 1.00, 95% C.I., 0.85-1.16; p = 0.849), suggesting that the associations could be fully explained by inflammation. One potential limitation of the study is that the full range of gene products from the genetic variants we used as proxies for the exposures is unknown, and so we are unable to comment on potential biological mechanisms of association other than inflammation, which may also be relevant., Conclusions: Our findings support a role for inflammation as a common cause for insulin resistance and schizophrenia, which may at least partly explain why the traits commonly co-occur in clinical practice. Inflammation and immune pathways may represent novel therapeutic targets for the prevention or treatment of schizophrenia and comorbid insulin resistance. Future work is needed to understand how inflammation may contribute to the risk of schizophrenia and insulin resistance., Competing Interests: We have read the journal's policy and the authors of this manuscript have the following competing interests. SB is a paid statistical consultant on PLOS Medicine's statistical board. CL is an Academic Editor on PLOS Medicine's editorial board. PBJ has received honoraria for providing scientific advice to Jansen, Ricordati and Lundbeck.

Background: There is increasing evidence that smoking is a risk factor for severe mental illness, including bipolar disorder. Conversely, patients with bipolar disorder might smoke more (often) as a result of the psychiatric disorder., Aims: We conducted a bidirectional Mendelian randomisation (MR) study to investigate the direction and evidence for a causal nature of the relationship between smoking and bipolar disorder., Method: We used publicly available summary statistics from genome-wide association studies on bipolar disorder, smoking initiation, smoking heaviness, smoking cessation and lifetime smoking (i.e. a compound measure of heaviness, duration and cessation). We applied analytical methods with different, orthogonal assumptions to triangulate results, including inverse-variance weighted (IVW), MR-Egger, MR-Egger SIMEX, weighted-median, weighted-mode and Steiger-filtered analyses., Results: Across different methods of MR, consistent evidence was found for a positive effect of smoking on the odds of bipolar disorder (smoking initiation ORIVW = 1.46, 95% CI 1.28-1.66, P = 1.44 × 10-8, lifetime smoking ORIVW = 1.72, 95% CI 1.29-2.28, P = 1.8 × 10-4). The MR analyses of the effect of liability to bipolar disorder on smoking provided no clear evidence of a strong causal effect (smoking heaviness betaIVW = 0.028, 95% CI 0.003-0.053, P = 2.9 × 10-2)., Conclusions: These findings suggest that smoking initiation and lifetime smoking are likely to be a causal risk factor for developing bipolar disorder. We found some evidence that liability to bipolar disorder increased smoking heaviness. Given that smoking is a modifiable risk factor, these findings further support investment into smoking prevention and treatment in order to reduce mental health problems in future generations.

Background: Prescribing patient care providers regularly experience insufficient sleep, putting them at increased risk of committing occupational injuries, accidents, and errors and developing chronic health conditions., Objective: Identify antecedents to short sleep (≤6-hours sleep in 24-hour period) in the understudied population of hospital-based Advanced Practice Providers (APPs)., Methods: Using an ethnographic research design, data included APP and key stakeholder interviews, hospital observations, and relevant documents. Interview data were analyzed using modified constant comparative method., Results: Nine APPs were interviewed, revealing four themes: Social/Family Obligations and Value of Connectivity, Community Value of Sleep, Organizational Value of Sleep, and Individual Biology and How the Body Values Sleep. APP decisions to prioritize sleep are based on an interplay of societal, professional, organizational, and personal values. Triangulated data verified results, except regarding how APP sleep deficit can lead to mood disturbances and the lack sleep consideration in patient care error reporting., Conclusions: Findings demonstrate the importance of consistency in messaging, action, and policy when promoting occupational sleep health among healthcare workers. Implications include instituting worker sleep education, leadership modeling healthy sleep habits, and inclusion of sleep in root cause analyses. Additional consideration includes evaluating the influence of nursing culture on nurse practitioners' sleep habits.

A Black woman has an 85.7% chance of developing hypertension in her lifetime, yet she is less likely to be optimally treated. The purpose of this research report is to describe the factors associated with self-reported hypertension in a sample of Black women. A descriptive study was conducted using a researcher-developed survey. Responses were obtained from 201 adult Black women from 19 to 92 years of age. Descriptive and comparative analyses were performed. The frequency of self-reported hypertension in the sample was low (n = 54, 27%). The self-report hypertension group was significantly older (p < 0.05) and obese (61%). There were significant associations between self-report hypertension and greater income (c2 = 9.24, p = 0.002, f = 0.232), self-report hypertension and higher education (c2 = 5.66, p = 0.017, phi = 0.182), and self-report hypertension and not having Medicaid (c2 = 5.05, p = 0.025, f = 0.174). APRNs should stress the importance of routine health screenings and healthy lifestyle behaviors in accordance with patient needs., Competing Interests: The authors have no conflicts of interest to disclose., (Copyright© by the National Black Nurses Association, Inc.)

Bacteriophages (phages) have great potential not only as therapeutics but as diagnostics. Indeed, they have been developed and used to diagnose and detect bacterial infections, primarily in human clinical settings. The ability to rapidly detect and control bacterial pathogens in agriculture is of primary importance to maintain food security, improve animal health, and prevent the passage of zoonotic pathogens into the human population. Culture-based detection methods are often labor-intensive, and require further confirmatory tests, increasing costs and processing times needed for diagnostics. Molecular detection methods such as polymerase chain reaction are commonly used to determine the safety of food, however, a major drawback is their inability to differentiate between viable and nonviable bacterial pathogens in food. Phage diagnostics have been proven to be rapid, capable of identifying viable pathogens and do not require cultivation to detect bacteria. Phage detection takes advantage of the specificity of interaction between phage and their hosts. Furthermore, phage detection is cost effective, which is vitally important in agricultural supply chains where there is a drive to keep costs down to ensure that the cost of food does not increase. The full potential of phage detection/diagnostics is not wholly realized or commercialized. This review explores the current use and potential future scope of phage diagnostics and their application to various bacterial pathogens across agriculture and food supply chains., Competing Interests: The authors declare that the Actiphage technology described in this review has been patented (Rees and Swift; PCT/GB2014/052970; European patent No. EP 3052650; U.S. Patent 10,344,339) and BMCS is a Director at PBD Biotech Ltd., the company commercializing the Actiphage technology., (Copyright 2020, Mary Ann Liebert, Inc., publishers.)

Extreme chronotype and circadian disrupting work hours may increase nurse disease risks. This national, cross-sectional study of nurses ( N = 527) had three hypotheses. When chronotype and shift times are incongruent, nurses will experience increased likelihood of (1) obesity, (2) cardiovascular disease/risk factors, and (3) obesity or cardiovascular disease/risk factors when theoretically linked variables exist. Chronotype mismatched nurses' ( n = 206) average sleep (6.1 hours, SD = 1.2) fell below 7-9 hours/24-hours sleep recommendations. Proportion of male nurses was significantly higher chronotype mismatched (12.3%) than matched (6.3%). Analyses found no direct relationship between chronotype match/mismatch with outcome variables. Exploratory interaction analysis demonstrated nurses with mismatched chronotype and above average sleep quality had an estimated 3.51 times the adjusted odds (95% CI 1.52,8.17; p = .003) of being obese. Although mechanism is unclear, this suggests sleep quality may be intricately associated with obesity. Further research is needed to inform nurses on health risks from disrupted sleep, chronotypes, and shift work.

Background: Smoking prevalence is higher amongst individuals with schizophrenia and depression compared with the general population. Mendelian randomisation (MR) can examine whether this association is causal using genetic variants identified in genome-wide association studies (GWAS)., Methods: We conducted two-sample MR to explore the bi-directional effects of smoking on schizophrenia and depression. For smoking behaviour, we used (1) smoking initiation GWAS from the GSCAN consortium and (2) we conducted our own GWAS of lifetime smoking behaviour (which captures smoking duration, heaviness and cessation) in a sample of 462690 individuals from the UK Biobank. We validated this instrument using positive control outcomes (e.g. lung cancer). For schizophrenia and depression we used GWAS from the PGC consortium., Results: There was strong evidence to suggest smoking is a risk factor for both schizophrenia (odds ratio (OR) 2.27, 95% confidence interval (CI) 1.67-3.08, p < 0.001) and depression (OR 1.99, 95% CI 1.71-2.32, p < 0.001). Results were consistent across both lifetime smoking and smoking initiation. We found some evidence that genetic liability to depression increases smoking (β = 0.091, 95% CI 0.027-0.155, p = 0.005) but evidence was mixed for schizophrenia (β = 0.022, 95% CI 0.005-0.038, p = 0.009) with very weak evidence for an effect on smoking initiation., Conclusions: These findings suggest that the association between smoking, schizophrenia and depression is due, at least in part, to a causal effect of smoking, providing further evidence for the detrimental consequences of smoking on mental health.