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Abstract Background Bipolar disorder is a serious mental illness, which requires new strategies for prevention and management. Recent evidence suggests that a ketogenic diet may be an effective intervention. This research aimed to explore the feasibility and acceptability of a ketogenic diet intervention for bipolar disorder, fidelity to its behavioural components and the experiences of the participants and research clinicians involved. Methods A mixed-methods process evaluation was conducted. Semi-structured telephone interviews were carried out with 15 participants 1–2 months after completing a 6–8 week modified ketogenic diet intervention, and 4 research clinicians from the study team following the completion of data collection. Data were thematically analysed. Fidelity checklists completed by research dietitians were analysed using descriptive count and percentage statistics. Findings are reported post-hoc, following the analysis and publication of the main pilot study findings. Reporting was guided by the COREQ checklist. Results Five themes were identified in the qualitative data: (1) ‘Encouraging entry and supporting exit’ (e.g. recognising and managing participants’ varied motives and expectations, including around weight loss and symptom alleviation); (2) ‘Challenging but potentially transformational,’ which reflects that while it can be difficult to initiate and maintain a ketogenic diet day-to-day, many participants perceived physical and psychological benefits (e.g. significant weight loss, mood stability and enhanced ability to focus); (3) ‘Intervention facilitators,’ including a range of behavioural (e.g. goal setting), social (e.g. family and dietitians) and technological (e.g. apps for monitoring) support mechanisms; (4) ‘Intervention barriers’ (e.g. dietary preferences, concerns about the diet and its impact, the testing burden and capacity of the delivery team); and (5) ‘The wider context’ (e.g. the cost of living and sociocultural expectations) was a crucial factor explaining differential experiences. Overall, descriptive analyses indicated moderate-to-good fidelity to the behaviour change components of the study. Conclusion We provide novel insight into the experiences of people living with bipolar disorder initiating and following a ketogenic diet, as well as those of research clinicians who support the intervention. Future trials may benefit from increased clinical research capacity, better-defined entry and exit routes, additional interpersonal support, and greater understanding of how social and societal factors impact participation. Trial registration Study registration number: ISRCTN61613198 (02/03/22).

Objective: This cross-sectional study examined the weight bias attitudes and obesity beliefs of health science (HS), nursing, and pre-medicine undergraduate students. Methods: Using snowballing and convenience sampling strategies, students (N = 139) completed an online survey, including a 24-item Antifat Attitudes Scale (AFAS) and eight-item Belief About Obese Persons (BAOP) scale. Results: HS students have higher weight bias than nursing and pre-medicine students combined (M = 43.45, SD = 10.75), t(137) = -2.45, p = 0.016). A negative correlation exists between AFAS and BAOP suggesting high weight bias influences a belief that obesity is controllable. Gender positively predicted weight bias attitudes ([beta] = -11.43, t = -4.33, p < 0.001) and obesity beliefs ([beta] = 3.75, t = 3.01, p = 0.003). Conclusions: Findings confirm that HS students have weight bias attitudes. This supports undergraduate curricular changes on obesity etiology that may improve treatment plans of individuals who are obese.

Many people with bipolar disorder have disrupted circadian rhythms. This means that the timing of sleep and wake activities becomes out-of-sync with the standard 24-hour cycle. Circadian rhythms are strongly influenced by light levels and previous research suggests that people with bipolar disorder might have a heightened sensitivity to light, causing more circadian rhythm disruption, increasing the potential for triggering a mood switch into mania or depression. Lithium has been in clinical use for over 70 years and is acknowledged to be the most effective long-term treatment for bipolar disorder. Lithium has many reported actions in the body but the precise mechanism of action in bipolar disorder remains an active area of research. Central to this project is recent evidence that lithium may work by stabilising circadian rhythms of mood, cognition and rest/activity. Our primary hypothesis is that people with bipolar disorder have some pathophysiological change at the level of the retina which makes them hypersensitive to the visual and non-visual effects of light, and therefore more susceptible to circadian rhythm dysfunction. We additionally hypothesise that the mood-stabilising medication lithium is effective in bipolar disorder because it reduces this hypersensitivity, making individuals less vulnerable to light-induced circadian disruption. We will recruit 180 participants into the HELIOS-BD study. Over an 18-month period, we will assess visual and non-visual responses to light, as well as retinal microstructure, in people with bipolar disorder compared to healthy controls. Further, we will assess whether individuals with bipolar disorder who are being treated with lithium have less pronounced light responses and attenuated retinal changes compared to individuals with bipolar disorder not being treated with lithium. This study represents a comprehensive investigation of visual and non-visual light responses in a large bipolar disorder population, with great translational potential for patient stratification and treatment innovation.

IntroductionThe Burkholderia cepacia complex encompasses a group of gram-negative opportunistic pathogens that cause chronic lung infections in people with cystic fibrosis. Distinct from other respiratory pathogens, Burkholderia causes a unique clinical disease in a subset of patients known as ‘cepacia syndrome’, fulminant pneumonia accompanied by bacteraemia and sepsis with a mortality rate of up to 75%. Due to the bacteraemia associated with this disease, the mechanisms that allow Burkholderia to resist the bactericidal effects of serum complement-depending killing are vital. Antibodies usually promote serum killing; however, we have described ‘cloaking antibodies’, specific for lipopolysaccharides that paradoxically protect serum-sensitive bacteria from complement-mediated lysis. Cloaking antibodies that protect Pseudomonas aeruginosa have been found in 24%–41% of patients with chronic lung diseases. The presence of these antibodies is also associated with worse clinical outcomes. Here, we sought to determine the relevance of cloaking antibodies in patients with Burkholderia infection.MethodsTwelve Burkholderia spp. were isolated from nine pwCF and characterised for susceptibility to healthy control serum. Patient serum was analysed for the titre of the cloaking antibody. The ability of the patient serum to prevent healthy control serum (HCS) killing of its cognate isolates was determined.ResultsWe found that several of the Burkholderia strains were shared between patients. Ten of the 12 isolates were highly susceptible to HCS killing. Four of nine (44%) patients had cloaking antibodies that protected their cognate strain from serum killing. Depleting cloaking antibodies from patient serum restored HCS killing of Burkholderia isolates.DiscussionCloaking antibodies are prevalent in patients with Burkholderia pulmonary infection and protect these strains from serum killing. Removal of cloaking antibodies via plasmapheresis, as previously described for individuals with life-threatening Pseudomonas infection, may be a useful new strategy for those with serious and life-threatening Burkholderia infection.

Abstract This paper presents a physics-informed neural network (PINN) approach for monitoring the health of diesel engines. The aim is to evaluate the engine dynamics, identify unknown parameters in a “mean value” model, and anticipate maintenance requirements. The PINN model is applied to diesel engines with a variable-geometry turbocharger and exhaust gas recirculation, using measurement data of selected state variables. The results demonstrate the ability of the PINN model to predict simultaneously both unknown parameters and dynamics accurately with both clean and noisy data, and the importance of the self-adaptive weight in the loss function for faster convergence. The input data for these simulations are derived from actual engine running conditions, while the outputs are simulated data, making this a practical case study of PINN’s ability to predict real-world dynamical systems. The mean value model of the diesel engine incorporates empirical formulae to represent certain states, but these formulae may not be generalizable to other engines. To address this, the study considers the use of deep neural networks (DNNs) in addition to the PINN model. The DNNs are trained using laboratory test data and are used to model the engine-specific empirical formulae in the mean value model, allowing for a more flexible and adaptive representation of the engine’s states. In other words, the mean value model uses both the PINN model and the DNNs to represent the engine’s states, with the PINN providing a physics-based understanding of the engine’s overall dynamics and the DNNs offering a more engine-specific and adaptive representation of the empirical formulae. By combining these two approaches, the study aims to offer a comprehensive and versatile approach to monitoring the health and performance of diesel engines.

Abstract Background The Genetic Links to Anxiety and Depression (GLAD) Study is a large cohort of individuals with lifetime anxiety and/or depression, designed to facilitate re-contact of participants for mental health research. At the start of the pandemic, participants from three cohorts, including the GLAD Study, were invited to join the COVID-19 Psychiatry and Neurological Genetics (COPING) study to monitor mental and neurological health. However, previous research suggests that participation in longitudinal studies follows a systematic, rather than random, process, which can ultimately bias results. Therefore, this study assessed participation biases following the re-contact of GLAD Study participants. Methods In April 2020, all current GLAD Study participants (N = 36,770) were invited to the COPING study. Using logistic regression, we investigated whether sociodemographic, mental, and physical health characteristics were associated with participation in the COPING baseline survey (aim one). Subsequently, we used a zero-inflated negative binomial regression to examine whether these factors were also related to participation in the COPING follow-up surveys (aim two). Results For aim one, older age, female gender identity, non-binary or self-defined gender identities, having one or more physical health disorders, and providing a saliva kit for the GLAD Study were associated with an increased odds of completing the COPING baseline survey. In contrast, lower educational attainment, Asian or Asian British ethnic identity, Black or Black British ethnic identity, higher alcohol consumption at the GLAD sign-up survey, and current or ex-smoking were associated with a reduced odds. For aim two, older age, female gender, and saliva kit provision were associated with greater COPING follow-up survey completion. Lower educational attainment, higher alcohol consumption at the GLAD Study sign-up, ex-smoking, and self-reported attention deficit hyperactivity disorder had negative relationships. Conclusions Participation biases surrounding sociodemographic and physical health characteristics were particularly evident when re-contacting the GLAD Study volunteers. Factors associated with participation may vary depending on study design. Researchers should examine the barriers and mechanisms underlying participation bias in order to combat these issues and address recruitment biases in future studies.

Many people with bipolar disorder have disrupted circadian rhythms. This means that the timing of sleep and wake activities becomes out-of-sync with the standard 24-hour cycle. Circadian rhythms are strongly influenced by light levels and previous research suggests that people with bipolar disorder might have a heightened sensitivity to light, causing more circadian rhythm disruption, increasing the potential for triggering a mood switch into mania or depression. Lithium has been in clinical use for over 70 years and is acknowledged to be the most effective long-term treatment for bipolar disorder. Lithium has many reported actions in the body but the precise mechanism of action in bipolar disorder remains an active area of research. Central to this project is recent evidence that lithium may work by stabilising circadian rhythms of mood, cognition and rest/activity. Our primary hypothesis is that people with bipolar disorder have some pathophysiological change at the level of the retina which makes them hypersensitive to the visual and non-visual effects of light, and therefore more susceptible to circadian rhythm dysfunction. We additionally hypothesise that the mood-stabilising medication lithium is effective in bipolar disorder because it reduces this hypersensitivity, making individuals less vulnerable to light-induced circadian disruption. We will recruit 180 participants into the HELIOS-BD study. Over an 18-month period, we will assess visual and non-visual responses to light, as well as retinal microstructure, in people with bipolar disorder compared to healthy controls. Further, we will assess whether individuals with bipolar disorder who are being treated with lithium have less pronounced light responses and attenuated retinal changes compared to individuals with bipolar disorder not being treated with lithium. This study represents a comprehensive investigation of visual and non-visual light responses in a large bipolar disorder population, with great translational potential for patient stratification and treatment innovation.

Sleep is crucial for the healthy development of adolescents, yet many suffer from chronic sleep deprivation. Over the transition to and course of adolescence there are known changes to sleep patterns e.g. shifts towards evening chronotypes. To study changes and patterns of sleep over these critical developmental time-points, detailed longitudinal data is required over months/years rather than weeks/days, a typical limitation of current technology. The implementation of novel contactless sleep sensors offers significant opportunities for longer term data collection, but their application has yet to be explored in young people in terms of feasibility, acceptability, performance and operability. The Ambient Teens Sleep Study will assess the feasibility of a contactless sleep sensor with approximately 45 adolescents aged 8-18 years, for 4 weeks. The device will be compared with accelerometery and sleep diary data, collected concurrently (2 weeks). Young people will provide feedback in the form of online calls and questionnaires as well as citizen scientist and product reviewer activities. Baseline questionnaires, conducted online, will be used to determine acceptability in different cohorts such as age, sex, gender and geographic location. We aim to assess completeness of data, participant experience and performance of sleep timing measures across all three methods of sleep assessment (contactless radar, accelerometery and sleep diary). The results will be used to inform longitudinal methods of sleep data collection in future adolescent health studies, at scale, to explore links between sleep and essential health outcomes across adolescent development.

Environmental exposures during the perinatal period are known to have a long-term effect on adult physical and mental health. One such influential environmental exposure is the time of year of birth which affects the amount of daylight, nutrients, and viral load that an individual is exposed to within this key developmental period. Here, we investigate associations between season of birth (seasonality), four mental health traits (n = 137,588) and multi-modal neuroimaging measures (n = 33,212) within the UK Biobank. Summer births were associated with probable recurrent Major Depressive Disorder (β = 0.026, pcorr = 0.028) and greater mean cortical thickness in temporal and occipital lobes (β = 0.013 to 0.014, pcorr

A substantial and rapid decarbonisation of the global economy is required to limit anthropogenic climate change to well below 2°C average global heating by 2050. Yet, emissions from fossil fuel energy generation—which dominate global greenhouse gas emissions—are at an all-time high. Progress and action for an energy transition to net zero carbon is critical, and one in which geoscience sectors and geoscientists will play multiple roles. Here, we outline the landscape of the geosciences and the energy transition in the context of the climate crisis, and intergovernmental policies on climate and social justice. We show how geoscience sectors, skills, knowledge, data, and infrastructure, both directly and indirectly, will play a key role in the energy transition. This may be in the responsible sourcing of raw materials for low carbon energy technologies; in the decarbonisation of heating; and in the near-permanent geological capture and storage of carbon through novel technology development. A new and unprecedented challenge is to reach Geological Net Zero, where zero carbon emissions from geological resource production and consumption are achieved via permanent geological storage. We identify overarching and cross-cutting issues for a sustainable and fair net zero carbon energy transition, and the associated geoscience challenges and opportunities. Finally, we call for geoscience professionals to recognise and take responsibility for their role in ensuring a fair and sustainable energy transition at the pace and scale required.

Background Recent evidence from case reports suggests that a ketogenic diet may be effective for bipolar disorder. However, no clinical trials have been conducted to date. Aims To assess the recruitment and feasibility of a ketogenic diet intervention in bipolar disorder. Method Euthymic individuals with bipolar disorder were recruited to a 6–8 week trial of a modified ketogenic diet, and a range of clinical, economic and functional outcome measures were assessed. Study registration number: ISRCTN61613198. Results Of 27 recruited participants, 26 commenced and 20 completed the modified ketogenic diet for 6–8 weeks. The outcomes data-set was 95% complete for daily ketone measures, 95% complete for daily glucose measures and 95% complete for daily ecological momentary assessment of symptoms during the intervention period. Mean daily blood ketone readings were 1.3 mmol/L (s.d. = 0.77, median = 1.1) during the intervention period, and 91% of all readings indicated ketosis, suggesting a high degree of adherence to the diet. Over 91% of daily blood glucose readings were within normal range, with 9% indicating mild hypoglycaemia. Eleven minor adverse events were recorded, including fatigue, constipation, drowsiness and hunger. One serious adverse event was reported (euglycemic ketoacidosis in a participant taking SGLT2-inhibitor medication). Conclusions The recruitment and retention of euthymic individuals with bipolar disorder to a 6–8 week ketogenic diet intervention was feasible, with high completion rates for outcome measures. The majority of participants reached and maintained ketosis, and adverse events were generally mild and modifiable. A future randomised controlled trial is now warranted.

IntroductionThe Burkholderia cepacia complex (BCC) encompasses a group of at least 22 genetically distinct gram-negatives bacterial species ubiquitous in nature. Recognised as a group of genetically and phenotypically flexible species, the BCC inhabits diverse ecological niches causing both plant and human diseases. Comparative genomic analysis provides an in depth understanding into the population biology, phylogenetic relationship, and genomic architecture of species.MethodsHere, we genomically characterise Burkholderia anthina isolated from patients with chronic lung infections, an understudied pathogen within the Burkholderia cepacia complex.ResultsWe demonstrate that B. anthina is polyphyletic and constitutes two distinct evolutionary lineages. Core- and pan-genome analyses demonstrated substantial metabolic diversity, with B. anthina Clade I enriched in genes associated with microbial metabolism in diverse environments, including degradation of aromatic compounds and metabolism of xenobiotics, while B. anthina Clade II demonstrated an enhanced capability for siderophore biosynthesis.DiscussionBased on our phylogenetic and comparative genomic analyses, we suggest stratifying B. anthina to recognise a distinct species harbouring increased potential for iron metabolism via siderophore synthesis, for which we propose the name Burkholderia anthinoferum (sp. nov.).

Abstract Background Progress towards stratified care for anxiety and depression will require the identification of new predictors. We collected data on retrospectively self-reported therapeutic outcomes in adults who received psychological therapy in the UK in the past ten years. We aimed to replicate factors associated with traditional treatment outcome measures from the literature. Methods Participants were from the Genetic Links to Anxiety and Depression (GLAD) Study, a UK-based volunteer cohort study. We investigated associations between retrospectively self-reported outcomes following therapy, on a five-point scale (global rating of change; GRC) and a range of sociodemographic, clinical and therapy-related factors, using ordinal logistic regression models (n = 2890). Results Four factors were associated with therapy outcomes (adjusted odds ratios, OR). One sociodemographic factor, having university-level education, was associated with favourable outcomes (OR = 1.37, 95%CI: 1.18, 1.59). Two clinical factors, greater number of reported episodes of illness (OR = 0.95, 95%CI: 0.92, 0.97) and higher levels of personality disorder symptoms (OR = 0.89, 95%CI: 0.87, 0.91), were associated with less favourable outcomes. Finally, reported regular use of additional therapeutic activities was associated with favourable outcomes (OR = 1.39, 95%CI: 1.19, 1.63). There were no statistically significant differences between fully adjusted multivariable and unadjusted univariable odds ratios. Conclusion Therapy outcome data can be collected quickly and inexpensively using retrospectively self-reported measures in large observational cohorts. Retrospectively self-reported therapy outcomes were associated with four factors previously reported in the literature. Similar data collected in larger observational cohorts may enable detection of novel associations with therapy outcomes, to generate new hypotheses, which can be followed up in prospective studies.

Abstract In this paper, we propose that lithium may exert its therapeutic effect in bipolar disorder by acting on insulin signaling pathways. Specifically, we assess the importance of the phosphatidylinositol 3-kinase/Protein Kinase B (PI3K/Akt) insulin signaling pathway and we assess how the action of lithium on both glycogen synthase kinase-3 (GSK3) and the phosphatidylinositol cycle may lead to mood stabilization mediated by PI3K/Akt insulin signaling. We also highlight evidence that several other actions of lithium (including effects on Akt, Protein kinase C (PKC), and sodium myo-inositol transporters) are putative mediators of insulin signaling. This novel mode of action of lithium is consistent with an emerging consensus that energy dysregulation represents a core deficit in bipolar disorder. It may also provide context for the significant co-morbidity between bipolar disorder, type 2 diabetes, and other forms of metabolic illness characterized by impaired glucose metabolism. It is suggested that developments in assessing neuronal insulin signaling using extracellular vesicles would allow for this hypothesis to be tested in bipolar disorder patients.

Background: Antidepressants are a first-line treatment for depression. However, only a third of individuals experience remission after the first treatment. Common genetic variation, in part, likely regulates antidepressant response, yet the success of previous genome-wide association studies has been limited by sample size. This study performs the largest genetic analysis of prospectively assessed antidepressant response in major depressive disorder to gain insight into the underlying biology and enable out-of-sample prediction. Methods: Genome-wide analysis of remission (nremit = 1852, nnonremit = 3299) and percentage improvement (n = 5218) was performed. Single nucleotide polymorphism–based heritability was estimated using genome-wide complex trait analysis. Genetic covariance with eight mental health phenotypes was estimated using polygenic scores/AVENGEME. Out-of-sample prediction of antidepressant response polygenic scores was assessed. Gene-level association analysis was performed using MAGMA and transcriptome-wide association study. Tissue, pathway, and drug binding enrichment were estimated using MAGMA. Results: Neither genome-wide association study identified genome-wide significant associations. Single nucleotide polymorphism–based heritability was significantly different from zero for remission (h2 = 0.132, SE = 0.056) but not for percentage improvement (h2 = −0.018, SE = 0.032). Better antidepressant response was negatively associated with genetic risk for schizophrenia and positively associated with genetic propensity for educational attainment. Leave-one-out validation of antidepressant response polygenic scores demonstrated significant evidence of out-of-sample prediction, though results varied in external cohorts. Gene-based analyses identified ETV4 and DHX8 as significantly associated with antidepressant response. Conclusions: This study demonstrates that antidepressant response is influenced by common genetic variation, has a genetic overlap schizophrenia and educational attainment, and provides a useful resource for future research. Larger sample sizes are required to attain the potential of genetics for understanding and predicting antidepressant response.

Background Tackling Scotland's drug-related deaths and improving outcomes from substance misuse treatments, including residential rehabilitation, is a national priority. Aims To analyse and report outcomes up to 4 years after attendance at a substance misuse residential rehabilitation programme (Lothians and Edinburgh Abstinence Programme). Method In total, 145 participants were recruited to this longitudinal quantitative cohort study of an abstinence-based residential rehabilitation programme based on the therapeutic community model; 87 of these participants were followed up at 4 years. Outcomes are reported for seven subsections of the Addiction Severity Index-X (ASI-X), together with frequency of alcohol use, heroin use, injecting drug use and rates of abstinence from substances of misuse. Results Significant improvement in most outcomes at 4 years compared with admission scores were found. Completing the programme was associated with greater rates of abstinence, reduced alcohol use and improvements in alcohol status score (Mann–Whitney U = 626, P = 0.013), work satisfaction score (U = 596, P = 0.016) and psychiatric status score (U = 562, P = 0.007) on the ASI-X, in comparison with non-completion. Abstinence rates improved from 12% at baseline to 48% at 4 years, with the rate for those completing the programme increasing from 14.5% to 60.7% (χ2(2, 87) = 9.738, P = 0.002). Remaining abstinent from substances at follow-up was associated with better outcomes in the medical (U = 540, P < 0.001), psychiatric (U = 273.5, P < 0.001) and alcohol (U = 322.5, P < 0.001) subsections of the ASI-X. Conclusions Attending this abstinence-based rehabilitation programme was associated with positive changes in psychological and social well-being and harm reduction from substance use at 4-year follow-up, with stability of change from years 1 to 4.

Background Antidepressants are one of the most widely prescribed drugs in the global north. However, little is known about the health consequences of long-term treatment. Aims This study aimed to investigate the association between antidepressant use and adverse events. Method The study cohort consisted of UK Biobank participants whose data was linked to primary care records (N = 222 121). We assessed the association between antidepressant use by drug class (selective serotonin reuptake inhibitors (SSRIs) and ‘other’) and four morbidity (diabetes, hypertension, coronary heart disease (CHD), cerebrovascular disease (CV)) and two mortality (cardiovascular disease (CVD) and all-cause) outcomes, using Cox's proportional hazards model at 5- and 10-year follow-up. Results SSRI treatment was associated with decreased risk of diabetes at 5 years (hazard ratio 0.64, 95% CI 0.49–0.83) and 10 years (hazard ratio 0.68, 95% CI 0.53–0.87), and hypertension at 10 years (hazard ratio 0.77, 95% CI 0.66–0.89). At 10-year follow-up, SSRI treatment was associated with increased risks of CV (hazard ratio 1.34, 95% CI 1.02–1.77), CVD mortality (hazard ratio 1.87, 95% CI 1.38–2.53) and all-cause mortality (hazard ratio 1.73, 95% CI 1.48–2.03), and ‘other’ class treatment was associated with increased risk of CHD (hazard ratio 1.99, 95% CI 1.31–3.01), CVD (hazard ratio 1.86, 95% CI 1.10–3.15) and all-cause mortality (hazard ratio 2.20, 95% CI 1.71–2.84). Conclusions Our findings indicate an association between long-term antidepressant usage and elevated risks of CHD, CVD mortality and all-cause mortality. Further research is needed to assess whether the observed associations are causal, and elucidate the underlying mechanisms.

Abstract Anhedonia is a core symptom of multiple psychiatric disorders and has been associated with alterations in brain structure. Genome-wide association studies suggest that anhedonia is heritable, with a polygenic architecture, but few studies have explored the association between genetic loading for anhedonia—indexed by polygenic risk scores for anhedonia (PRS-anhedonia)—and structural brain imaging phenotypes. Here, we investigated how anhedonia and PRS-anhedonia were associated with brain structure within the UK Biobank cohort. Brain measures (including total grey/white matter volumes, subcortical volumes, cortical thickness (CT) and white matter integrity) were analysed using linear mixed models in relation to anhedonia and PRS-anhedonia in 19,592 participants (9225 males; mean age = 62.6 years, SD = 7.44). We found that state anhedonia was significantly associated with reduced total grey matter volume (GMV); increased total white matter volume (WMV); smaller volumes in thalamus and nucleus accumbens; reduced CT within the paracentral cortex, the opercular part of inferior frontal gyrus, precentral cortex, insula and rostral anterior cingulate cortex; and poorer integrity of many white matter tracts. PRS-anhedonia was associated with reduced total GMV; increased total WMV; reduced white matter integrity; and reduced CT within the parahippocampal cortex, superior temporal gyrus and insula. Overall, both state anhedonia and PRS-anhedonia were associated with individual differences in multiple brain structures, including within reward-related circuits. These associations may represent vulnerability markers for psychopathology relevant to a range of psychiatric disorders.

Abstract Background Severe mental illness (SMI), comprising schizophrenia, bipolar disorder and major depression, is associated with higher myocardial infarction (MI) mortality but lower coronary revascularisation rates. Previous studies have largely focused on schizophrenia, with limited information on bipolar disorder and major depression, long-term mortality or the effects of either sociodemographic factors or year of MI. We investigated the associations between SMI and MI prognosis and how these differed by age at MI, sex and year of MI. Methods We conducted a national retrospective cohort study, including adults with a hospitalised MI in Scotland between 1991 and 2014. We ascertained previous history of schizophrenia, bipolar disorder and major depression from psychiatric and general hospital admission records. We used logistic regression to obtain odds ratios adjusted for sociodemographic factors for 30-day, 1-year and 5-year mortality, comparing people with each SMI to a comparison group without a prior hospital record for any mental health condition. We used Cox regression to analyse coronary revascularisation within 30 days, risk of further MI and further vascular events (MI or stroke). We investigated associations for interaction with age at MI, sex and year of MI. Results Among 235,310 people with MI, 923 (0.4%) had schizophrenia, 642 (0.3%) had bipolar disorder and 6239 (2.7%) had major depression. SMI was associated with higher 30-day, 1-year and 5-year mortality and risk of further MI and stroke. Thirty-day mortality was higher for schizophrenia (OR 1.95, 95% CI 1.64–2.30), bipolar disorder (OR 1.53, 95% CI 1.26–1.86) and major depression (OR 1.31, 95% CI 1.23–1.40). Odds ratios for 1-year and 5-year mortality were larger for all three conditions. Revascularisation rates were lower in schizophrenia (HR 0.57, 95% CI 0.48–0.67), bipolar disorder (HR 0.69, 95% CI 0.56–0.85) and major depression (HR 0.78, 95% CI 0.73–0.83). Mortality and revascularisation disparities persisted from 1991 to 2014, with absolute mortality disparities more apparent for MIs that occurred around 70 years of age, the overall mean age of MI. Women with major depression had a greater reduction in revascularisation than men with major depression. Conclusions There are sustained SMI disparities in MI intervention and prognosis. There is an urgent need to understand and tackle the reasons for these disparities.

Abstract Understanding why individuals with severe mental illness (Schizophrenia, Bipolar Disorder and Major Depressive Disorder) have increased risk of cardiometabolic disease (including obesity, type 2 diabetes and cardiovascular disease), and identifying those at highest risk of cardiometabolic disease are important priority areas for researchers. For individuals with European ancestry we explored whether genetic variation could identify sub-groups with different metabolic profiles. Loci associated with schizophrenia, bipolar disorder and major depressive disorder from previous genome-wide association studies and loci that were also implicated in cardiometabolic processes and diseases were selected. In the IMPROVE study (a high cardiovascular risk sample) and UK Biobank (general population sample) multidimensional scaling was applied to genetic variants implicated in both psychiatric and cardiometabolic disorders. Visual inspection of the resulting plots used to identify distinct clusters. Differences between these clusters were assessed using chi-squared and Kruskall-Wallis tests. In IMPROVE, genetic loci associated with both schizophrenia and cardiometabolic disease (but not bipolar disorder or major depressive disorder) identified three groups of individuals with distinct metabolic profiles. This grouping was replicated within UK Biobank, with somewhat less distinction between metabolic profiles. This work focused on individuals of European ancestry and is unlikely to apply to more genetically diverse populations. Overall, this study provides proof of concept that common biology underlying mental and physical illness may help to stratify subsets of individuals with different cardiometabolic profiles.

Abstract Background Research comparing sex differences in the effects of antipsychotic medications on acute ischemic heart disease (IHD) is limited and the findings ambiguous. This study aimed to investigate these associations within a primary care setting. Methods Hong Kong public general outpatient electronic records of patients aged 45+ during 2007–2010 were extracted, with the last consultation date as the baseline for a 4-year follow-up period to observe acute IHD hospitalizations (2011–2014). Antipsychotic use was defined as any prescription over the previous 12 months from a list of 16 antipsychotics, while acute IHD was defined by ICD-9: 410.00–411.89. Both sex-specific and sex-combined (both sexes) mixed-effects Cox models (random intercept across 74 clinics) were implemented to examine the association and test the interaction between antipsychotics and sex. Results Among 1,043,236 included patients, 17,780 (1.7%) were prescribed antipsychotics, and 8342 (0.8%) developed IHD. In sex-specific analyses, antipsychotic prescription was associated with a 32% increased hazard rate of acute IHD among women (95% CI 1.05–1.67) but not among men. A likelihood ratio test comparing sex-combined models with and without the interaction between antipsychotic use and sex suggested significant interaction (χ 2 = 4.72, P = 0.030). The association between antipsychotic use and IHD among women attenuated and became non-significant when haloperidol was omitted from the operationalization of antipsychotic use (HR = 1.23, 95% CI 0.95–1.60). Conclusion Our results suggest that antipsychotic prescription is moderately associated with an increased risk of acute IHD among women in primary care and this relationship may be explained by specific antipsychotics. Further research should observe and capture the potential intermediary mechanisms and the dose-response relationship of this association to provide more rigorous evidence to establish causality and inform clinical practices.

There is a growing interest in performing time-resolved cryo-EM studies. Here, the authors present a time-resolved sample preparation method for cryo-EM called trEM, which uses a microfluidic device to initiate the biochemical reaction by rapid mixing of the components and then spraying the sample onto a cryo-EM grid to snap-freeze it in a blot-free, automated manner within several milliseconds.

TeenCovidLife is part of Generation Scotland’s CovidLife projects, a set of longitudinal observational studies designed to assess the psychosocial and health impacts of the COVID-19 pandemic. TeenCovidLife focused on how adolescents in Scotland were coping during the pandemic. As of September 2021, Generation Scotland had conducted three TeenCovidLife surveys. Participants from previous surveys were invited to participate in the next, meaning the age ranges shifted over time. TeenCovidLife Survey 1 consists of data from 5,543 young people age 12 to 17, collected from 22 May to 5 July 2020, during the first school closures period in Scotland. TeenCovidLife Survey 2 consists of data from 2,245 young people aged 12 to 18, collected from 18 August to 14 October 2020, when the initial lockdown measures were beginning to ease, and schools reopened in Scotland. TeenCovidLife Survey 3 consists of data from 597 young people age 12 to 19, collected from 12 May to 27 June 2021, a year after the first survey, after the schools returned following the second lockdown in 2021. A total of 316 participants took part in all three surveys. TeenCovidLife collected data on general health and well-being, as well as topics specific to COVID-19, such as adherence to COVID-19 health guidance, feelings about school closures, and the impact of exam cancellations. Limited work has examined the impact of the COVID-19 pandemic on young people. TeenCovidLife provides relevant and timely data to assess the impact of the pandemic on young people in Scotland. The dataset is available under authorised access from Generation Scotland; see the Generation Scotland website for more information.

Aim: To conduct a systematic literature review of the existing evidence on incidence, characteristics and outcomes after out-of-hospital cardiac arrest (OHCA) in patients with psychiatric illness. Methods: We searched Embase, Medline, PsycINFO and Web of Science using a comprehensive electronic search strategy to identify observational studies reporting on OHCA incidence, characteristics or outcomes by psychiatric illness status. One reviewer screened all titles and abstracts, and a second reviewer screened a random 10%. Two reviewers independently performed data extraction and quality assessment. Results: Our search retrieved 11,380 studies, 10 of which met our inclusion criteria (8 retrospective cohort studies and two nested case-control studies). Three studies focused on depression, whilst seven included various psychiatric conditions. Among patients with an OHCA, those with psychiatric illness (compared to those without) were more likely to have: an arrest in a private location; an unwitnessed arrest; more comorbidities; less bystander cardiopulmonary resuscitation; and an initial non-shockable rhythm. Two studies reported on OHCA incidence proportion and two reported on survival, showing higher risk, but lower survival, in patients with psychiatric illness. Conclusion: Psychiatric illness in relation to OHCA incidence and outcomes has rarely been studied and only a handful of studies have reported on OHCA characteristics, highlighting the need for further research in this area. The scant existing literature suggests that psychiatric illness may be associated with higher risks of OHCA, unfavourable characteristics and poorer survival. Future studies should further investigate these links and the role of potential contributory factors such as socioeconomic status and comorbidities.

Climate change, the greatest public health threat of the 21st century, will uniquely affect rural areas that are geographically isolated and experience greater health inequities. This systematic review describes and evaluates interventions to lessen the effects of climate change on human health in the rural United States, including interventions on air pollution, vector ecology, water quality, severe weather, extreme heat, allergens, and water and food supply. Searches were constructed based on the eight domains of the Centers for Disease Control and Prevention (CDC) Framework “Impact of Climate Change on Human Health.” Searches were conducted in EBSCO Environment Complete, EBSCO GreenFILE, Embase.com, MEDLINE via PubMed, and Web of Science. Duplicate citations were removed, abstracts were screened for initial inclusion, and full texts were screened for final inclusion. Pertinent data were extracted and synthesized across the eight domains. Article quality was assessed using the Mixed Methods Appraisal Tool. Of 8471 studies screened, 297 were identified for full text review, and a total 49 studies were included in this review. Across the domains, 34 unique interventions addressed health outcomes due to air pollution ( n = 8), changes in vector ecology ( n = 6), water quality ( n = 5), severe weather ( n = 3), extreme heat ( n = 2) increasing allergens ( n = 1), water and food supply ( n = 1), and across multiple CDC domains ( n = 8). Participatory action research methodology was commonly used and strived to mobilize/empower communities to tackle climate change. Our review identified three randomized controlled trials, with two of these three published in the last five years. While original research on the impact of climate change on health has increased in the past decade, randomized control trials may not be ethical, cost effective, or feasible. There is a need for time-efficient and high-quality scholarship that investigates intervention efficacy and effectiveness for reducing health impacts of climate change upon rural populations.

Abstract Background A cancer diagnosis can have a substantial impact on mental health and wellbeing. Depression and anxiety may hinder cancer treatment and recovery, as well as quality of life and survival. We argue that more research is needed to prevent and treat co-morbid depression and anxiety among people with cancer and that it requires greater clinical priority. For background and to support our argument, we synthesise existing systematic reviews relating to cancer and common mental disorders, focusing on depression and anxiety. We searched several electronic databases for relevant reviews on cancer, depression and anxiety from 2012 to 2019. Several areas are covered: factors that may contribute to the development of common mental disorders among people with cancer; the prevalence of depression and anxiety; and potential care and treatment options. We also make several recommendations for future research. Numerous individual, psychological, social and contextual factors potentially contribute to the development of depression and anxiety among people with cancer, as well as characteristics related to the cancer and treatment received. Compared to the general population, the prevalence of depression and anxiety is often found to be higher among people with cancer, but estimates vary due to several factors, such as the treatment setting, type of cancer and time since diagnosis. Overall, there are a lack of high-quality studies into the mental health of people with cancer following treatment and among long-term survivors, particularly for the less prevalent cancer types and younger people. Studies that focus on prevention are minimal and research covering low- and middle-income populations is limited. Conclusion Research is urgently needed into the possible impacts of long-term and late effects of cancer treatment on mental health and how these may be prevented, as increasing numbers of people live with and beyond cancer.

Hydrous and alkali rich magmas rise through the lithosphere and may host gold-rich ore deposits – a poorly understood process. Here, the authors present new chalcophile element data across a metallogenic section of the lithosphere and suggest a continuous or staged ascent of magmatic-hydrothermal settings from mantle to upper crust.

Background: Suicide is a major issue for global public health. Suicidality describes a broad spectrum of thoughts and behaviours, some of which are common in the general population. Although suicide results from a complex interaction of multiple social and psychological factors, predisposition to suicidality is at least partly genetic. Methods: Ordinal genome-wide association study of suicidality in the UK Biobank cohort comparing: ‘no suicidality’ controls (N = 83,557); ‘thoughts that life was not worth living’ (N = 21,063); ‘ever contemplated self-harm’ (N = 13,038); ‘act of deliberate self-harm in the past’ (N = 2498); and ‘previous suicide attempt’ (N = 2666). Outcomes: We identified three novel genome-wide significant loci for suicidality (on chromosomes nine, 11 and 13) and moderate-to-strong genetic correlations between suicidality and a range of psychiatric disorders, most notably depression (rg 0·81). Interpretation: These findings provide new information about genetic variants relating to increased risk of suicidal thoughts and behaviours. Future work should assess the extent to which polygenic risk scores for suicidality, in combination with non-genetic risk factors, may be useful for stratified approaches to suicide prevention at a population level. Fund: UKRI Innovation-HDR-UK Fellowship (MR/S003061/1). MRC Mental Health Data Pathfinder Award (MC_PC_17217). MRC Doctoral Training Programme Studentship at the University of Glasgow (MR/K501335/1). MRC Doctoral Training Programme Studentship at the Universities of Glasgow and Edinburgh. UKRI Innovation Fellowship (MR/R024774/1).

Summary: Seasonal disease outbreaks are perennial features of human infectious disease but the factors generating these patterns are unclear. Here we investigate seasonal and daytime variability in multiple immune parameters in 329,261 participants in UK Biobank and test for associations with a wide range of environmental and lifestyle factors, including changes in day length, outdoor temperature and vitamin D at the time the blood sample was collected. Seasonal patterns were evident in lymphocyte and neutrophil counts, and C-reactive protein CRP, but not monocytes, and these were independent of lifestyle, demographic, and environmental factors. All the immune parameters assessed demonstrated significant daytime variation that was independent of confounding factors. At a population level, human immune parameters vary across season and across time of day, independent of multiple confounding factors. Both season and time of day are fundamental dimensions of immune function that should be considered in all studies of immuno-prophylaxis and disease transmission.

Chronic pain is highly prevalent worldwide and imparts a significant socioeconomic and public health burden. Factors influencing susceptibility to, and mechanisms of, chronic pain development, are not fully understood, but sex is thought to play a significant role, and chronic pain is more prevalent in women than in men. To investigate sex differences in chronic pain, we carried out a sex-stratified genome-wide association study of Multisite Chronic Pain (MCP), a derived chronic pain phenotype, in UK Biobank on 178,556 men and 209,093 women, as well as investigating sex-specific genetic correlations with a range of psychiatric, autoimmune and anthropometric phenotypes and the relationship between sex-specific polygenic risk scores for MCP and chronic widespread pain. We also assessed whether MCP-associated genes showed expression pattern enrichment across tissues. A total of 123 SNPs at five independent loci were significantly associated with MCP in men. In women, a total of 286 genome-wide significant SNPs at ten independent loci were discovered. Meta-analysis of sex-stratified GWAS outputs revealed a further 87 independent associated SNPs. Gene-level analyses revealed sex-specific MCP associations, with 31 genes significantly associated in females, 37 genes associated in males, and a single gene, DCC, associated in both sexes. We found evidence for sex-specific pleiotropy and risk for MCP was found to be associated with chronic widespread pain in a sex-differential manner. Male and female MCP were highly genetically correlated, but at an rg of significantly less than 1 (0.92). All 37 male MCP-associated genes and all but one of 31 female MCP-associated genes were found to be expressed in the dorsal root ganglion, and there was a degree of enrichment for expression in sex-specific tissues. Overall, the findings indicate that sex differences in chronic pain exist at the SNP, gene and transcript abundance level, and highlight possible sex-specific pleiotropy for MCP. Results support the proposition of a strong central nervous-system component to chronic pain in both sexes, additionally highlighting a potential role for the DRG and nociception.

Levels of activity are often affected in psychiatric disorders and can be core symptoms of illness. Advances in technology now allow the accurate assessment of activity levels but it remains unclear whether alterations in activity arise from shared risk factors for developing psychiatric disorders, such as genetics, or are better explained as consequences of the disorders and their associated factors. We aimed to examine objectively-measured physical activity in individuals with psychiatric disorders, and assess the role of genetic liability for psychiatric disorders on physical activity. Accelerometer data were available on 95,529 UK Biobank participants, including measures of overall mean activity and minutes per day of moderate activity, walking, sedentary activity, and sleep. Linear regressions measured associations between psychiatric diagnosis and activity levels, and polygenic risk scores (PRS) for psychiatric disorders and activity levels. Genetic correlations were calculated between psychiatric disorders and different types of activity. Having a diagnosis of schizophrenia, bipolar disorder, depression, or autism spectrum disorders (ASD) was associated with reduced overall activity compared to unaffected controls. In individuals without a psychiatric disorder, reduced overall activity levels were associated with PRS for schizophrenia, depression, and ASD. ADHD PRS was associated with increased overall activity. Genetic correlations were consistent with PRS findings. Variation in physical activity is an important feature across psychiatric disorders. Whilst levels of activity are associated with genetic liability to psychiatric disorders to a very limited extent, the substantial differences in activity levels in those with psychiatric disorders most likely arise as a consequences of disorder-related factors.

AbstractBackgroundSystemic inflammation has been linked with mood disorder and cognitive impairment. The extent of this relationship remains uncertain, with the effects of serum inflammatory biomarkers compared to genetic predisposition toward inflammation yet to be clearly established.MethodsWe investigated the magnitude of associations between C-reactive protein (CRP) measures, lifetime history of bipolar disorder or major depression, and cognitive function (reaction time and visuospatial memory) in 84,268 UK Biobank participants. CRP was measured in serum and a polygenic risk score for CRP was calculated, based on a published genome-wide association study. Multiple regression models adjusted for sociodemographic and clinical confounders.ResultsIncreased serum CRP was significantly associated with mood disorder history (Kruskal–Wallis H = 196.06, p

Abstract Background Physical illness and mental disorders play a significant role in fatal and non-fatal suicidal behaviour. However, there is no clear evidence for the effect of physical and mental illness co-occurrence (multimorbidity) in suicidal ideation and attempts. The aim of the current study was to investigate, whether physical/mental health multimorbidity predicted suicidal thoughts and behaviours as outcomes. Methods Data from the West of Scotland Twenty-07 cohort were analysed. Twenty-07 is a multiple cohort study following people for 20 years, through five waves of data collection. Participants who responded to past-year suicidal thoughts and suicide attempt items were grouped into four distinct health-groups based on having: (1) neither physical nor mental health condition (controls); (2) one or more physical health condition; (3) one or more mental health condition and; (4) multimorbidity. The role of multimorbidity in predicting suicidal ideation and suicide attempts was tested with a generalised estimating equation (GEE) model and odds ratios (ORs) and 95% CIs are presented. Whether the effect of multimorbidity was stronger than either health condition alone was also assessed. Results Multimorbidity had a significant effect on suicidal thoughts and suicide attempts, compared to the control group, but was not found to increase the risk of either suicide-related outcomes, more than mental illness alone. Conclusions We identified an effect of physical/mental multimorbidity on risk of suicidal thoughts and suicide attempts. Considering that suicide and related behaviour are rare events, future studies should employ a prospective design on the role of multimorbidity in suicidality, employing larger datasets.

BackgroundUK Biobank is a well-characterised cohort of over 500 000 participants including genetics, environmental data and imaging. An online mental health questionnaire was designed for UK Biobank participants to expand its potential.AimsDescribe the development, implementation and results of this questionnaire.MethodAn expert working group designed the questionnaire, using established measures where possible, and consulting a patient group. Operational criteria were agreed for defining likely disorder and risk states, including lifetime depression, mania/hypomania, generalised anxiety disorder, unusual experiences and self-harm, and current post-traumatic stress and hazardous/harmful alcohol use.ResultsA total of 157 366 completed online questionnaires were available by August 2017. Participants were aged 45–82 (53% were ≥65 years) and 57% women. Comparison of self-reported diagnosed mental disorder with a contemporary study shows a similar prevalence, despite respondents being of higher average socioeconomic status. Lifetime depression was a common finding, with 24% (37 434) of participants meeting criteria and current hazardous/harmful alcohol use criteria were met by 21% (32 602), whereas other criteria were met by less than 8% of the participants. There was extensive comorbidity among the syndromes. Mental disorders were associated with a high neuroticism score, adverse life events and long-term illness; addiction and bipolar affective disorder in particular were associated with measures of deprivation.ConclusionsThe UK Biobank questionnaire represents a very large mental health survey in itself, and the results presented here show high face validity, although caution is needed because of selection bias. Built into UK Biobank, these data intersect with other health data to offer unparalleled potential for crosscutting biomedical research involving mental health.

Many economists, including former Federal Reserve chairman Ben Bernanke, believe that the gold standard generates poor economic outcomes including output volatility, price instability, financial panics, the spread of recessions via the exchange rate, and speculation-induced collapse. These problems, however, do not by themselves demonstrate the superiority of central banks over the gold standard. Comparative institutional analysis requires demonstrating that the relevant alternative, in this case a central bank, can improve upon these outcomes in practice. We use this standard to compare central banking and the gold standard in the United States. Recent theoretical and empirical evidence suggests that the Fed has not been able to measurably improve upon the gold standard even when it comes to these deficiencies.

Background: Circadian rhythms are fundamental to health and are particularly important for mental wellbeing. Disrupted rhythms of rest and activity are recognised as risk factors for major depressive disorder and bipolar disorder. Methods: We conducted a genome-wide association study (GWAS) of low relative amplitude (RA), an objective measure of rest-activity cycles derived from the accelerometer data of 71,500 UK Biobank participants. Polygenic risk scores (PRS) for low RA were used to investigate potential associations with psychiatric phenotypes. Outcomes: Two independent genetic loci were associated with low RA, within genomic regions for Neurofascin (NFASC) and Solute Carrier Family 25 Member 17 (SLC25A17). A secondary GWAS of RA as a continuous measure identified a locus within Meis Homeobox 1 (MEIS1). There were no significant genetic correlations between low RA and any of the psychiatric phenotypes assessed. However, PRS for low RA was significantly associated with mood instability across multiple PRS thresholds (at PRS threshold 0·05: OR = 1·02, 95% CI = 1·01–1·02, p = 9·6 × 10−5), and with major depressive disorder (at PRS threshold 0·1: OR = 1·03, 95% CI = 1·01–1·05, p = 0·025) and neuroticism (at PRS threshold 0·5: Beta = 0·02, 95% CI = 0·007–0·04, p = 0·021). Interpretation: Overall, our findings contribute new knowledge on the complex genetic architecture of circadian rhythmicity and suggest a putative biological link between disrupted circadian function and mood disorder phenotypes, particularly mood instability, but also major depressive disorder and neuroticism. Funding: Medical Research Council (MR/K501335/1). Keywords: Circadian rhythmicity, Mood instability, Relative amplitude, Gwas, Polygenic risk score

BackgroundUK Biobank is a well-characterised cohort of over 500 000 participants that offers unique opportunities to investigate multiple diseases and risk factors.AimsAn online mental health questionnaire completed by UK Biobank participants was expected to expand the potential for research into mental disorders.MethodAn expert working group designed the questionnaire, using established measures where possible, and consulting with a patient group regarding acceptability. Case definitions were defined using operational criteria for lifetime depression, mania, anxiety disorder, psychotic-like experiences and self-harm, as well as current post-traumatic stress and alcohol use disorders.Results157 366 completed online questionnaires were available by August 2017. Comparison of self-reported diagnosed mental disorder with a contemporary study shows a similar prevalence, despite respondents being of higher average socioeconomic status than the general population across a range of indicators. Thirty-five per cent (55 750) of participants had at least one defined syndrome, of which lifetime depression was the most common at 24% (37 434). There was extensive comorbidity among the syndromes. Mental disorders were associated with high neuroticism score, adverse life events and long-term illness; addiction and bipolar affective disorder in particular were associated with measures of deprivation.ConclusionsThe questionnaire represents a very large mental health survey in itself, and the results presented here show high face validity, although caution is needed owing to selection bias. Built into UK Biobank, these data intersect with other health data to offer unparalleled potential for crosscutting biomedical research involving mental health.Declaration of interestG.B. received grants from the National Institute for Health Research during the study; and support from Illumina Ltd. and the European Commission outside the submitted work. B.C. received grants from the Scottish Executive Chief Scientist Office and from The Dr Mortimer and Theresa Sackler Foundation during the study. C.S. received grants from the Medical Research Council and Wellcome Trust during the study, and is the Chief Scientist for UK Biobank. M.H. received grants from the Innovative Medicines Initiative via the RADAR-CNS programme and personal fees as an expert witness outside the submitted work.

The UK Biobank provides data for three depression-related phenotypes. Here, Howard et al. perform a genome-association study for broad depression, probable major depressive disorder (MDD) and hospital record-coded MDD in up to 322,580 UK Biobank participants which highlights excitatory synaptic pathways.

Abstract Previous reports of altered grey and white matter structure in Major Depressive Disorder (MDD) have been inconsistent. Recent meta-analyses have, however, reported reduced hippocampal grey matter volume in MDD and reduced white matter integrity in several brain regions. The use of different diagnostic criteria, scanners and imaging sequences may, however, obscure further anatomical differences. In this study, we tested for differences in subcortical grey matter volume (n = 1157) and white matter integrity (n = 1089) between depressed individuals and controls in the subset of 8590 UK Biobank Imaging study participants who had undergone depression assessments. Whilst we found no significant differences in subcortical volumes, significant reductions were found in depressed individuals versus controls in global white matter integrity, as measured by fractional anisotropy (FA) (β = −0.182, p = 0.005). We also found reductions in FA in association/commissural fibres (β = −0.184, pcorrected = 0.010) and thalamic radiations (β = −0.159, pcorrected = 0.020). Tract-specific FA reductions were also found in the left superior longitudinal fasciculus (β = −0.194, pcorrected = 0.025), superior thalamic radiation (β = −0.224, pcorrected = 0.009) and forceps major (β = −0.193, pcorrected = 0.025) in depression (all betas standardised). Our findings provide further evidence for disrupted white matter integrity in MDD.

Children and adolescents commonly suffer from sleep and circadian rhythm disturbances, which may contribute to poorer mental health and wellbeing during this critical developmental phase. Many studies however rely on self-reported sleep measures. This study assessed whether accelerometry data collection was feasible within the school setting as a method for investigating the extent of sleep and circadian disruption, and associations with subjective wellbeing, in Scotland. Fourteen days of wrist-worn accelerometry data were collected from 69 pupils, aged 10-14 years. Objective measures of sleep timing, sleep duration and circadian rest-activity patterns were derived. Questionnaires assessed subjective sleep timing, depressive symptoms, and experiences of wearing the accelerometer. Pupils slept on average less than 8 hours per night, failing to meet standard age-specific recommendations. Sleep timing was later and duration longer on weekends compared to weekdays (B = 0.87, 95% confidence interval (CI) 0.70, 1.04; B = 0.49, 95% CI 0.29, 0.69), indicating social jetlag. Lower daytime activity was correlated with higher depressive symptoms (r = -0.84, p = 0.008). Compared to primary school pupils, secondary pupils had shorter sleep window duration and lower circadian relative amplitude. Over half of participants reported some discomfort/inconvenience wearing the accelerometer. These data highlight that inadequate sleep is prevalent in this sample of schoolchildren. Future, larger scale investigations will examine in more detail the associations between sleep, circadian function and physical activity with mental health and wellbeing.

This study investigates if cyberbullying is associated with wellbeing independently of traditional bullying and if social support and eating family meals together promotes resilience by buffering adolescents against the consequences of both types of bullying. Data for 5286 eleven, thirteen and fifteen year olds participating in the cross-sectional 2018 Scottish Health Behaviour in School-aged Children study were analysed. Adolescent self-report measures were used to assess traditional bullying, cyberbullying, classmate and teacher support and frequency of family meals together. Psychological wellbeing was assessed with the 5-item World Health Organization Wellbeing index. Analyses were conducted separately by gender with multilevel models, adjusting for sociodemographic factors. Resilience to bullying and cyberbullying was operationalised using statistical interactions. For both genders, cyberbullying and traditional bullying measures were associated with reduced wellbeing and all social support indicators were associated with increased wellbeing. In models containing both bullying measures, frequent traditional bullying victimisation was associated with a 7.2 (95% CI: 3.4–10.1) reduction in wellbeing score for boys and a 7.2 (95% CI: 4.5–10.0) reduction for girls, while cyberbullying was associated with 10.5 (95% CI: 5.8–15.1) reduction in wellbeing score for boys and 11.1 (95% CI: 6.7–15.5) reduction for girls. For both genders adjusting for classmate support explained away the relationships between traditional bullying and wellbeing, but cyberbullying was associated negatively with wellbeing independent of social support. Only one of 12 interaction tests provided any evidence of resilience. Cyberbullying was associated with a 7.8 (95% CI: 0.2–15.4) reduction in wellbeing score for girls who ate with their family every day, and 17.3 (95% CI: 10.5–24.1) reduction for girls who ate with their families less than weekly. In conclusion, cyberbullying is a strong, albeit rare, threat to adolescent wellbeing. Social support is important for wellbeing, but its ability to buffer adolescents against the consequences of bullying may be limited. Keywords: Cyberbullying, Bullying, Wellbeing, Resilience, Social support

S. mitis is an abundant member of the commensal microbiota of the oral cavity and pharynx, which has the potential to promote systemic infections. By analyzing a collection of S. mitis strains isolated from the oral cavity at commensal states or from systemic infections (blood strains), we established that S. mitis ubiquitously express the surface immunodominant protein, PcsB (also called GbpB), required for binding to sucrose-derived exopolysaccharides (EPS). Immuno dot blot assays with anti-PcsB antibodies and RT-qPCR transcription analyses revealed strain-specific profiles of PcsB production associated with diversity in pcsB transcriptional activities. Additionally, blood strains showed significantly higher levels of PcsB expression compared to commensal isolates. Because Streptococcus mutans co-colonizes S. mitis dental biofilms, and secretes glucosyltransferases (GtfB/C/D) for the synthesis of highly insoluble EPS from sucrose, profiles of S. mitis binding to EPS, biofilm formation and evasion of the complement system were assessed in sucrose-containing BHI medium supplemented or not with filter-sterilized S. mutans culture supernatants. These analyses showed significant S. mitis binding to EPS and biofilm formation in the presence of S. mutans supernatants supplemented with sucrose, compared to BHI or BHI-sucrose medium. In addition, these phenotypes were abolished if strains were grown in culture supernatants of a gtfBCD-defective S. mutans mutant. Importantly, GtfB/C/D-associated phenotypes were enhanced in high PcsB-expressing strains, compared to low PcsB producers. Increased PcsB expression was further correlated with increased resistance to deposition of C3b/iC3b of the complement system after exposure to human serum, when strains were previously grown in the presence of S. mutans supernatants. Finally, analyses of PcsB polymorphisms and bioinformatic prediction of epitopes with significant binding to MHC class II alleles revealed that blood isolates harbor PcsB polymorphisms in its functionally conserved CHAP-domain, suggesting antigenic variation. These findings reveal important roles of PcsB in S. mitis-host interactions under commensal and pathogenic states, highlighting the need for studies to elucidate mechanisms regulating PcsB expression in this species.

BackgroundPoor physical health in severe mental illness (SMI) remains a major issue for clinical practice.AimsTo use electronic health records of routinely collected clinical data to determine levels of screening for cardiometabolic disease and adverse health outcomes in a large sample (n = 7718) of patients with SMI, predominantly schizophrenia and bipolar disorder.MethodWe linked data from the Glasgow Psychosis Clinical Information System (PsyCIS) to morbidity records, routine blood results and prescribing data.ResultsThere was no record of routine blood monitoring during the preceding 2 years for 16.9% of the cohort. However, monitoring was poorer for male patients, younger patients aged 16–44, those with schizophrenia, and for tests of cholesterol, triglyceride and glycosylated haemoglobin. We estimated that 8.0% of participants had diabetes and that lipids levels, and use of lipid-lowering medication, was generally high.ConclusionsElectronic record linkage identified poor health screening and adverse health outcomes in this vulnerable patient group. This approach can inform the design of future interventions and health policy.

Objective Smoking in people with serious mental illness is a major public health problem and contributes to significant levels of morbidity and mortality. The aim of the review was to systematically examine the efficacy of methods used to aid smoking cessation in people with serious mental illness.Method A systematic review and meta-analysis of randomised controlled trials to compare the effectiveness and safety of pharmacological and behavioural programmes for smoking cessation in people with serious mental illness. Electronic databases were searched for trials to July 2018. We used the Cochrane Collaboration’s tool for assessing the risk of bias.Results Twenty-eight randomised controlled trials were identified. Varenicline increased the likelihood of smoking cessation at both 3 months (risk ratio (RR) 3.56, 95% CI 1.82 to 6.96, p=0.0002) and at 6 months (RR 3.69, 95% CI 1.08 to 12.60, p=0.04). Bupropion was effective at 3 months (RR 3.96, 95% CI 1.86 to 8.40, p=0.0003), especially at a dose of 300 mg/day, but there was no evidence of effect at 6 months (RR 2.22, 95% CI 0.52 to 9.47, p=0.28). In one small study, nicotine therapy proved effective at increasing smoking cessation up to a period of 3 months. Bupropion used in conjunction with nicotine replacement therapy showed more effect than single use. Behavioural and bespoke interventions showed little overall benefit. Side effects were found to be low.Conclusion The new information of this review was the effectiveness of varenicline for smoking cessation at both 3 and 6 months and the lack of evidence to support the use of both bupropion and nicotine products for sustained abstinence longer than 3 months. Overall, the review found relatively few studies in this population.