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Article ; Online: Using graphic modelling to identify modifiable mediators of the association between area-based deprivation at birth and offspring unemployment.

James Bogie / Michael Fleming / Breda Cullen / Daniel Mackay / Jill P Pell

PLoS ONE, Vol 16, Iss 3, p e

2021 Volume 0249258

Abstract: Background Deprivation can perpetuate across generations; however, the causative pathways are not well understood. Directed acyclic graphs (DAG) with mediation analysis can help elucidate and quantify complex pathways in order to identify modifiable ... ...

Abstract	Background Deprivation can perpetuate across generations; however, the causative pathways are not well understood. Directed acyclic graphs (DAG) with mediation analysis can help elucidate and quantify complex pathways in order to identify modifiable factors at which to target interventions. Methods and findings We linked ten Scotland-wide databases (six health and four education) to produce a cohort of 217,226 pupils who attended Scottish schools between 2009 and 2013. The DAG comprised 23 potential mediators of the association between area deprivation at birth and subsequent offspring 'not in education, employment or training' status, covering maternal, antenatal, perinatal and child health, school engagement, and educational factors. Analyses were performed using modified g-computation. Deprivation at birth was associated with a 7.3% increase in offspring 'not in education, employment or training'. The principal mediators of this association were smoking during pregnancy (natural indirect effect of 0·016, 95% CI 0·013, 0·019) and school absences (natural indirect effect of 0·021, 95% CI 0·018, 0·024), explaining 22% and 30% of the total effect respectively. The proportion of the association potentially eliminated by addressing these factors was 19% (controlled direct effect when set to non-smoker 0·058; 95% CI 0·053, 0·063) for smoking during pregnancy and 38% (controlled direct effect when set to no absences 0·043; 95% CI 0·037, 0·049) for school absences. Conclusions Combining a DAG with mediation analysis helped disentangle a complex public health problem and quantified the modifiable factors of maternal smoking and school absence that could be targeted for intervention. This study also demonstrates the general utility of DAGs in understanding complex public health problems.
Keywords	Medicine ; R ; Science ; Q
Subject code	370
Language	English
Publishing date	2021-01-01T00:00:00Z
Publisher	Public Library of Science (PLoS)
Document type	Article ; Online
Database	BASE - Bielefeld Academic Search Engine (life sciences selection)

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Article ; Online: Towards Validation of a New Computerised Test of Goal Neglect

Breda Cullen / David Brennan / Tom Manly / Jonathan J Evans

PLoS ONE, Vol 11, Iss 1, p e

Preliminary Evidence from Clinical and Neuroimaging Pilot Studies.

2016 Volume 0148127

Abstract: Goal neglect is a significant problem following brain injury, and is a target for rehabilitation. It is not yet known how neural activation might change to reflect rehabilitation gains. We developed a computerised multiple elements test (CMET), suitable ... ...

Abstract	Goal neglect is a significant problem following brain injury, and is a target for rehabilitation. It is not yet known how neural activation might change to reflect rehabilitation gains. We developed a computerised multiple elements test (CMET), suitable for use in neuroimaging paradigms.Pilot correlational study and event-related fMRI study.In Study 1, 18 adults with acquired brain injury were assessed using the CMET, other tests of goal neglect (Hotel Test; Modified Six Elements Test) and tests of reasoning. In Study 2, 12 healthy adults underwent fMRI, during which the CMET was administered under two conditions: self-generated switching and experimenter-prompted switching.Among the clinical sample, CMET performance was positively correlated with both the Hotel Test (r = 0.675, p = 0.003) and the Modified Six Elements Test (r = 0.568, p = 0.014), but not with other clinical or demographic measures. In the healthy sample, fMRI demonstrated significant activation in rostro-lateral prefrontal cortex in the self-generated condition compared with the prompted condition (peak 40, 44, 4; ZE = 4.25, p(FWEcorr) = 0.026).These pilot studies provide preliminary evidence towards the validation of the CMET as a measure of goal neglect. Future studies will aim to further establish its psychometric properties, and determine optimum pre- and post-rehabilitation fMRI paradigms.
Keywords	Medicine ; R ; Science ; Q
Subject code	150
Language	English
Publishing date	2016-01-01T00:00:00Z
Publisher	Public Library of Science (PLoS)
Document type	Article ; Online
Database	BASE - Bielefeld Academic Search Engine (life sciences selection)

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Article ; Online: 46 The sleep, circadian rhythms and mental health in schools (SCRAMS) feasibility study

Michael Farquhar / Heather Whalley / Sharon Simpson / Breda Cullen / Mark Matthews / Judith Brown / Daniel Smith / Malcolm von Schantz / Giulia Gaggioni / Stella Chan / Daniela Gibbons / Alice Gregory / Joanna Inchley / Laura Lyall / Alyson O’Brien / Natasha Sangha / Manuel Spitschan / Cathy Wyse

BMJ Open Respiratory Research, Vol 8, Iss Suppl

2021 Volume 1

Keywords	Medicine ; R ; Diseases of the respiratory system ; RC705-779
Language	English
Publishing date	2021-11-01T00:00:00Z
Publisher	BMJ Publishing Group
Document type	Article ; Online
Database	BASE - Bielefeld Academic Search Engine (life sciences selection)

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Article ; Online: p38 MAPK inhibition reduces diabetes-induced impairment of wound healing

Satyanarayana Medicherla / Scott Wadsworth / Breda Cullen / Derek Silcock

Diabetes, Metabolic Syndrome and Obesity, Vol 2009, Iss default, Pp 91-

2009 Volume 100

Abstract: Satyanarayana Medicherla1, Scott Wadsworth2, Breda Cullen3, Derek Silcock3, Jing Y Ma1, Ruban Mangadu1, Irene Kerr1, Sarvajit Chakravarty1, Gregory L Luedtke1, Sundeep Dugar1, Andrew A Protter1, Linda S Higgins11Scios Inc., Fremont, CA, USA; 2Center for ... ...

Abstract	Satyanarayana Medicherla1, Scott Wadsworth2, Breda Cullen3, Derek Silcock3, Jing Y Ma1, Ruban Mangadu1, Irene Kerr1, Sarvajit Chakravarty1, Gregory L Luedtke1, Sundeep Dugar1, Andrew A Protter1, Linda S Higgins11Scios Inc., Fremont, CA, USA; 2Center for Biomaterials and Advanced Technologies, Somerville, NJ, USA; 3Johnson & Johnson Wound Management, Gargrave, UKAbstract: In healthy tissue, a wound initiates an inflammatory response characterized by the presence of a hematoma, infiltration of inflammatory cells into the wound and, eventually, wound healing. In pathological conditions like diabetes mellitus, wound healing is impaired by the presence of chronic nonresolving inflammation. p38 mitogen-activated protein kinase (MAPK) inhibitors have demonstrated anti-inflammatory effects, primarily by inhibiting the expression of inflammatory cytokines and regulating cellular traffic into wounds. The db/db mouse model of type 2 diabetes was used to characterize the time course of expression of activated p38 during impaired wound healing. The p38α-selective inhibitor, SCIO-469, was applied topically and effects on p38 activation and on wound healing were evaluated. A topical dressing used clinically, PromogranTM, was used as a comparator. In this study, we established that p38 is phosphorylated on Days 1 to 7 post-wounding in db/db mice. Further, we demonstrated that SCIO-469, at a dose of 10 µg/wound, had a positive effect on wound contraction, granulation tissue formation, and re-epithelialization, and also increased wound maturity during healing. These effects were similar to or greater than those observed with PromogranTM. These results suggest a novel approach to prophylactic and therapeutic management of chronic wounds associated with diabetes or other conditions in which healing is impaired.Keywords: p38 MAPK ihibition, diabetic wound healing, db/db mouse, nonresolving healing, PromogranTM
Keywords	Specialties of internal medicine ; RC581-951
Language	English
Publishing date	2009-06-01T00:00:00Z
Publisher	Dove Medical Press
Document type	Article ; Online
Database	BASE - Bielefeld Academic Search Engine (life sciences selection)

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Article ; Online: Cross-sectional and longitudinal analyses of outdoor air pollution exposure and cognitive function in UK Biobank

Breda Cullen / Danielle Newby / Duncan Lee / Donald M. Lyall / Alejo J. Nevado-Holgado / Jonathan J. Evans / Jill P. Pell / Simon Lovestone / Jonathan Cavanagh

Scientific Reports, Vol 8, Iss 1, Pp 1-

2018 Volume 14

Abstract: Abstract Observational studies have shown consistently increased likelihood of dementia or mild cognitive impairment diagnoses in people with higher air pollution exposure history, but evidence has been less consistent for associations with cognitive ... ...

Abstract	Abstract Observational studies have shown consistently increased likelihood of dementia or mild cognitive impairment diagnoses in people with higher air pollution exposure history, but evidence has been less consistent for associations with cognitive test performance. We estimated the association between baseline neighbourhood-level exposure to airborne pollutants (particulate matter and nitrogen oxides) and (1) cognitive test performance at baseline and (2) cognitive score change between baseline and 2.8-year follow-up, in 86,759 middle- to older-aged adults from the UK Biobank general population cohort. Unadjusted regression analyses indicated small but consistent negative associations between air pollutant exposure and baseline cognitive performance. Following adjustment for a range of key confounders, associations were inconsistent in direction and of very small magnitude. The largest of these indicated that 1 interquartile range higher air pollutant exposure was associated on average with 0.35% slower reaction time (95% CI: 0.13, 0.57), a 2.92% higher error rate on a visuospatial memory test (95% CI: 1.24, 4.62), and numeric memory scores that were 0.58 points lower (95% CI: −0.96, −0.19). Follow-up analyses of cognitive change scores did not show evidence of associations. The findings indicate that in this sample, which is five-fold larger than any previous cross-sectional study, the association between air pollution exposure and cognitive performance was weak. Ongoing follow-up of the UK Biobank cohort will allow investigation of longer-term associations into old age, including longitudinal tracking of cognitive performance and incident dementia outcomes.
Keywords	Medicine ; R ; Science ; Q
Subject code	150
Language	English
Publishing date	2018-08-01T00:00:00Z
Publisher	Nature Publishing Group
Document type	Article ; Online
Database	BASE - Bielefeld Academic Search Engine (life sciences selection)

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Article ; Online: The overlap of genetic susceptibility to schizophrenia and cardiometabolic disease can be used to identify metabolically different groups of individuals

Rona J. Strawbridge / Keira J. A. Johnston / Mark E. S. Bailey / Damiano Baldassarre / Breda Cullen / Per Eriksson / Ulf deFaire / Amy Ferguson / Bruna Gigante / Philippe Giral / Nicholas Graham / Anders Hamsten / Steve E. Humphries / Sudhir Kurl / Donald M. Lyall / Laura M. Lyall / Jill P. Pell / Matteo Pirro / Kai Savonen /

Andries J. Smit / Elena Tremoli / Tomi-Pekka Tomainen / Fabrizio Veglia / Joey Ward / Bengt Sennblad / Daniel J. Smith

Scientific Reports, Vol 11, Iss 1, Pp 1-

2021 Volume 13

Abstract: 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 ... ...

Abstract	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.
Keywords	Medicine ; R ; Science ; Q
Subject code	150
Language	English
Publishing date	2021-01-01T00:00:00Z
Publisher	Nature Portfolio
Document type	Article ; Online
Database	BASE - Bielefeld Academic Search Engine (life sciences selection)

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Article ; Online: Cognitive Test Scores in UK Biobank

Donald M Lyall / Breda Cullen / Mike Allerhand / Daniel J Smith / Daniel Mackay / Jonathan Evans / Jana Anderson / Chloe Fawns-Ritchie / Andrew M McIntosh / Ian J Deary / Jill P Pell

PLoS ONE, Vol 11, Iss 4, p e

Data Reduction in 480,416 Participants and Longitudinal Stability in 20,346 Participants.

2016 Volume 0154222

Abstract: UK Biobank includes 502,649 middle- and older-aged adults from the general population who have undergone detailed phenotypic assessment. The majority of participants completed tests of cognitive functioning, and on average four years later a sub-group of ...

Abstract	UK Biobank includes 502,649 middle- and older-aged adults from the general population who have undergone detailed phenotypic assessment. The majority of participants completed tests of cognitive functioning, and on average four years later a sub-group of N = 20,346 participants repeated most of the assessment. These measures will be used in a range of future studies of health outcomes in this cohort. The format and content of the cognitive tasks were partly novel. The aim of the present study was to validate and characterize the cognitive data: to describe the inter-correlational structure of the cognitive variables at baseline assessment, and the degree of stability in scores across longitudinal assessment. Baseline cognitive data were used to examine the inter-correlational/factor-structure, using principal components analysis (PCA). We also assessed the degree of stability in cognitive scores in the subsample of participants with repeat data. The different tests of cognitive ability showed significant raw inter-correlations in the expected directions. PCA suggested a one-factor solution (eigenvalue = 1.60), which accounted for around 40% of the variance. Scores showed varying levels of stability across time-points (intraclass correlation range = 0.16 to 0.65). UK Biobank cognitive data has the potential to be a significant resource for researchers looking to investigate predictors and modifiers of cognitive abilities and associated health outcomes in the general population.
Keywords	Medicine ; R ; Science ; Q
Subject code	150
Language	English
Publishing date	2016-01-01T00:00:00Z
Publisher	Public Library of Science (PLoS)
Document type	Article ; Online
Database	BASE - Bielefeld Academic Search Engine (life sciences selection)

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Article ; Online: Correction

Donald M Lyall / Breda Cullen / Mike Allerhand / Daniel J Smith / Daniel Mackay / Jonathan Evans / Jana Anderson / Chloe Fawns-Ritchie / Andrew M McIntosh / Ian J Deary / Jill P Pell

PLoS ONE, Vol 11, Iss 5, p e

Cognitive Test Scores in UK Biobank: Data Reduction in 480,416 Participants and Longitudinal Stability in 20,346 Participants.

2016 Volume 0156366

Abstract: This corrects the article DOI:10.1371/journal.pone.0154222.]. ...

Abstract	[This corrects the article DOI:10.1371/journal.pone.0154222.].
Keywords	Medicine ; R ; Science ; Q
Language	English
Publishing date	2016-01-01T00:00:00Z
Publisher	Public Library of Science (PLoS)
Document type	Article ; Online
Database	BASE - Bielefeld Academic Search Engine (life sciences selection)

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Article ; Online: Identification of novel genome-wide associations for suicidality in UK Biobank, genetic correlation with psychiatric disorders and polygenic association with completed suicideResearch in context

Rona J. Strawbridge / Joey Ward / Amy Ferguson / Nicholas Graham / Richard J. Shaw / Breda Cullen / Robert Pearsall / Laura M. Lyall / Keira J.A. Johnston / Claire L. Niedzwiedz / Jill P. Pell / Daniel Mackay / Julie Langan Martin / Donald M. Lyall / Mark E.S. Bailey / Daniel J. Smith

EBioMedicine, Vol 41, Iss , Pp 517-

2019 Volume 525

Abstract: 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 ... ...

Abstract	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).
Keywords	Medicine ; R ; Medicine (General) ; R5-920
Subject code	300
Language	English
Publishing date	2019-03-01T00:00:00Z
Publisher	Elsevier
Document type	Article ; Online
Database	BASE - Bielefeld Academic Search Engine (life sciences selection)

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Article ; Online: Genome-Wide Association Study of Circadian Rhythmicity in 71,500 UK Biobank Participants and Polygenic Association with Mood InstabilityResearch in context

Amy Ferguson / Laura M. Lyall / Joey Ward / Rona J. Strawbridge / Breda Cullen / Nicholas Graham / Claire L. Niedzwiedz / Keira J.A. Johnston / Daniel MacKay / Stephany M. Biello / Jill P. Pell / Jonathan Cavanagh / Andrew M. McIntosh / Aiden Doherty / Mark E.S. Bailey / Donald M. Lyall / Cathy A. Wyse / Daniel J. Smith

EBioMedicine, Vol 35, Iss , Pp 279-

2018 Volume 287

Abstract: 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 ...

Abstract	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
Keywords	Medicine ; R ; Medicine (General) ; R5-920
Subject code	150
Language	English
Publishing date	2018-09-01T00:00:00Z
Publisher	Elsevier
Document type	Article ; Online
Database	BASE - Bielefeld Academic Search Engine (life sciences selection)

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