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  • ItemOpen AccessAccepted version Peer-reviewed
    Platelet Tau Protein as a Potential Peripheral Biomarker in Alzheimer's Disease: An Explorative Study.
    (Bentham Science Publishers Ltd., 2018) Mukaetova-Ladinska, Elizabeta B; Abdell-All, Zeinab; Andrade, Joana; da Silva, Joaquim Alves; Boksha, Irina; Burbaeva, Gulnur; Kalaria, Raj N; T O Brien, John
    BACKGROUND: Cerebrospinal fluid (CSF) measures of tau and amyloid proteins have now been largely accepted to be a diagnostic tool to aid the clinical diagnosis of Alzheimer's disease (AD), but CSF is not routinely obtained in most clinical settings. There is a need, therefore, to uncover additional readily accessible peripheral biomarkers that will enable comprehensive detection of AD-specific proteins in blood and blood derivates. OBJECTIVES: Blood platelets contain proteins found in neuronal cell lines, including tau protein. Since tau protein is a characteristic of AD-neuropathology, platelet tau protein may be closely related to the central nervous process occurring in neurodegeneration. METHOD: Platelets from 25 AD and 26 control subjects were analysed for the microtubule-binding and C-terminal region, as well as two tau phosphorylation sites (Ser202/Thr205 and Thr181). RESULTS: Tau protein measures did not discriminate between AD and control individuals. However, subjects with MMSE 24-27 had elevated C-terminal end tau protein (p=0.049) compared to those with MMSE >27, whereas older AD subjects (>80 years) showed higher t-tau protein in comparison to younger AD (<80 years; p=0.009) and control (<80 years; p=0.011) participants. CONCLUSIONS: These initial findings not only confirm that platelet tau protein can be measured, but also indicate that platelet tau measures merit further study as they may be useful in indicating early stages of cognitive impairment. Further studies on larger number of participants are needed to confirm our findings.
  • ItemOpen AccessAccepted version Peer-reviewed
    Letter to the editor, Re: Late-onset ADHD Reconsidered with Comprehensive Repeated Assessments Between Ages 10 and 25
    (American Psychiatric Publishing, Inc., 2018-05) Chamberlain, S; Chamberlain, Samuel [0000-0001-7014-8121]
    Dear Sir, We read with great interest Sibley et al.'s article (1) examining ADHD symptoms longitudinally in a cohort without a baseline childhood diagnosis. The authors identified cases of possible late-onset ADHD via screening and then used an iterative process to rule out non-true cases. The overwhelming majority did not have true late-onset Adult ADHD, but had childhood ADHD symptoms, or did not have the disorder (rather, cognitive impairment due to heavy substance use or other psychiatric morbidities).
  • ItemOpen AccessAccepted version Peer-reviewed
    Cold forced open-water swimming: a natural intervention to improve postoperative pain and mobilisation outcomes?
    (BMJ, 2018-02-12) Mole, Tom B; Mackeith, Pieter; Mole, Tom B [0000-0001-8732-8188]
    Postoperative neuropathic pain exacerbated by movement is poorly understood and difficult to treat but a relatively common complication of surgical procedures such as endoscopic thoracic sympathectomy. Here, we describe a case of unexpected, immediate, complete and sustained remission of postoperative intercostal neuralgia after the patient engaged in an open-water swim in markedly cold conditions. Though an incidental chance association is possible, the clear temporal proximity linking the swim with pain remission makes a causal relationship possible. We discuss plausible mechanisms that may underlie the relationship and discuss the potential implications for postoperative pain management and patient-centred mobilisation. We recommend further evaluation of cold forced open-water swimming as a mobility-pain provocation challenge to see if the observed unexpectedly positive outcome can be replicated. With the poor response to traditional management, there is a need for novel, curative interventions for postoperative neuropathic pain and associated impaired mobility.
  • ItemOpen AccessPublished version Peer-reviewed
    Predictors of disengagement from Early Intervention in Psychosis services.
    (Royal College of Psychiatrists, 2018-08) Solmi, Francesca; Mohammadi, Abdolali; Perez, Jesus A; Hameed, Yasir; Jones, Peter B; Kirkbride, James B; Hameed, Yasir [0000-0001-9449-9460]
    BACKGROUND: The effectiveness of Early Intervention in Psychosis (EIP) services for individuals with a first episode of psychosis (FEP) could be thwarted by high rates of early disengagement.AimsTo investigate which factors predict disengagement with EIP services. METHOD: Using data from a naturalistic cohort of 786 EIP clients in East Anglia (UK), we investigated the association between sociodemographic and clinical predictors and disengagement using univariable and multivariable Cox proportional hazards models. RESULTS: Over half (54.3%) of our sample were discharged before receiving 3 years of EIP care, with 92 (11.7%) participants discharged due to disengagement. Milder negative symptoms, more severe hallucinations, not receiving an FEP diagnosis, polysubstance use and being employed were associated with greater disengagement. CONCLUSIONS: Our findings highlight heterogeneous reasons for disengagement with EIP services. For some patients, early disengagement may hinder efforts to sustain positive long-term EIP outcomes. Efforts to identify true FEP cases and target patients with substance use problems and more severe positive symptoms may increase engagement.Declaration of interestNone.
  • ItemOpen AccessAccepted version Peer-reviewed
    The use of anti-psychotic and other psychotropic medication in a specialist community service for adults with learning disabilities
    (Emerald, 2018) Clare, ICH; Wade, KA; Bolton, S; Wagner, AP; Steven, T; Holland, AJ; Holland, Anthony [0000-0003-4107-130X]
    Purpose The purpose of this paper is to examine the extent to which, in the five integrated community teams for adults with learning disabilities (CTLDs) in an English county-wide service, the use of psychotropic medication for service users was based on the presence of an appropriate mental health condition or epilepsy. Design/methodology/approach Adult participants were recruited following referral to one of the CTLDs for assessment, treatment and/or support of a possible mental health and/or behavioural need. Data were collected about participant characteristics and psychotropic medication 12 months after recruitment. Findings While a total of 42 (78 per cent) of the 54 participants were apparently prescribed regular or PRN (as required) psychotropic medication, only 24 (57 per cent) of these individuals had a recorded past or current mental health condition or epilepsy for which such medicine could be appropriate. Research limitations/implications There were several limitations: the sample size was small and its representativeness was uncertain; and data collection was compromised by barriers to explicit knowledge exchange within and across the learning disability service. Practical implications While recent guidance about the use of psychotropic medication is welcome, minimising inappropriate use requires more comprehensive person-centred interventions (including crisis management plans), underpinned by imaginative, but feasible, data collection methods and integrated formulations. Investment is needed in developments that support multi-disciplinary and inter-agency working to promote “good practice” by CTLDs in responding to referrals for possible mental health and/or behavioural needs. Originality/value Complementing recent large studies of primary care (General Practitioner) records, this is the first examination of the use of psychotropic medication by service users in English CTLDs.
  • ItemOpen AccessPublished version Peer-reviewed
    The impact of comorbid impulsive/compulsive disorders on problematic internet use
    (Akademiai Kiado, 2018-06-01) Chamberlain, S; Ioannidis, K; Grant, Jon; Chamberlain, Samuel [0000-0001-7014-8121]
    Background and Aims: Problematic Internet Use (PIU) is commonplace but is not yet recognized as a formal mental disorder. Excessive Internet use could result from other conditions such as gambling disorder. The aim of the study was to assess the impact of impulsive-compulsive comorbidities on the presentation of PIU, defined using Young’s Diagnostic Questionnaire. Methods: 123 adults aged 18-29 years were recruited using media advertisements, and attended the research center for a detailed psychiatric assessment, including interviews, completion of questionnaires and neuropsychological testing. Participants were classified into three groups: PIU with no comorbid impulsive/compulsive disorders (n=18), PIU with one or more comorbid impulsive/compulsive disorders (n=37), and healthy controls (n=67). Differences between the three groups were characterized in terms of demographic, clinical, and cognitive variables. Effect sizes for overall effects of group were also reported. Results: The three groups did not differ significantly on age, gender, levels of education, nicotine consumption, or alcohol use (small effect sizes). Quality of life was significantly impaired in PIU irrespective of whether or not individuals had comorbid impulsive/compulsive disorders (large effect size). However, impaired response inhibition and decision-making were only identified in PIU with impulsive/compulsive comorbidities (medium effect sizes).
  • ItemOpen Access
    Quantitative electroencephalography as a marker of cognitive fluctuations in dementia with Lewy bodies and aid to differential diagnosis
    (Elsevier, 2018-06) Stylianou, Myrto; Murphy, Nicholas; Peraza, Luis R; Graziadio, Sara; Cromarty, Ruth; Killen, Alison; O'Brien, JT; Thomas, Alan J; LeBeau, Fiona EN; Taylor, John-Paul; O'Brien, John [0000-0002-0837-5080]
    Objective: We investigated for quantitative EEG (QEEG) differences between Alzheimer’s disease (AD), dementia with Lewy bodies (DLB) and Parkinson’s disease dementia (PDD) patients and healthy controls, and for QEEG signatures of cognitive fluctuations (CFs) in DLB. Methods: We analyzed eyes-closed, resting state EEGs from 18 AD, 17 DLB and 17 PDD patients with mild dementia, and 21 age-matched controls. Measures included spectral power, dominant frequency (DF), frequency prevalence (FP), and temporal DF variability (DFV), within defined EEG frequency bands and cortical regions. Results: DLB and PDD patients showed a leftward shift in the power spectrum and DF. AD patients showed greater DFV compared to the other groups. In DLB patients only, greater DFV and EEG slowing were correlated with CFs, measured by the clinician assessment of fluctuations (CAF) scale. The diagnostic accuracy of the QEEG measures was 94% (90.4% - 97.9%), with 92.26% (80.4% – 100%) sensitivity and 83.3% (73.6% - 93%) specificity. Conclusion: Although greater DFV was only shown in the AD group, within the DLB group a positive DFV - CF correlation was found. QEEG measures could classify DLB and AD patients with high sensitivity and specificity. Significance: The findings add to building literature suggesting that EEG is a viable diagnostic and symptom biomarker in dementia, particularly DLB.
  • ItemOpen AccessPublished version Peer-reviewed
    The incidence of healthcare use, ill health and mortality in adults with intellectual disabilities and mealtime support needs
    (2014) Perez, CM; Ball, SL; Wagner, AP; Clare, ICH; Holland, AJ; Redley, M; Clare, Isabel [0000-0002-5385-008X]; Holland, Anthony [0000-0003-4107-130X]; Redley, Marcus [0000-0001-8866-7990]
  • ItemOpen AccessPublished version Peer-reviewed
    Assessment of Symptom Network Density as a Prognostic Marker of Treatment Response in Adolescent Depression.
    (American Medical Association (AMA), 2018-01-01) Schweren, Lizanne; van Borkulo, Claudia D; Fried, Eiko; Goodyer, Ian M; Goodyer, Ian [0000-0001-9183-0373]
    This cohort study uses the 33-item Mood and Feelings Questionnaire to examine whether symptom network density is associated with treatment response in adolescent depression.
  • ItemOpen AccessPublished version Peer-reviewed
    Heritability of subcortical volumetric traits in mesial temporal lobe epilepsy.
    (Public Library of Science (PLoS), 2013) Alhusaini, Saud; Scanlon, Cathy; Ronan, Lisa; Maguire, Sinead; Meaney, James F; Fagan, Andrew J; Boyle, Gerard; Borgulya, Gabor; Iyer, Parameswaran M; Brennan, Paul; Costello, Daniel; Chaila, Elijah; Fitzsimons, Mary; Doherty, Colin P; Delanty, Norman; Cavalleri, Gianpiero L; Ronan, Lisa [0000-0001-8580-921X]
    OBJECTIVES: We aimed to 1) determine if subcortical volume deficits are common to mesial temporal lobe epilepsy (MTLE) patients and their unaffected siblings 2) assess the suitability of subcortical volumetric traits as endophenotypes for MTLE. METHODS: MRI-based volume measurements of the hippocampus, amygdala, thalamus, caudate, putamen and pallidium were generated using an automated brain reconstruction method (FreeSurfer) for 101 unrelated 'sporadic' MTLE patients [70 with hippocampal sclerosis (MTLE+HS), 31 with MRI-negative TLE], 83 unaffected full siblings of patients and 86 healthy control subjects. Changes in the volume of subcortical structures in patients and their unaffected siblings were determined by comparison with healthy controls. Narrow sense heritability was estimated ipsilateral and contralateral to the side of seizure activity. RESULTS: MTLE+HS patients displayed significant volume deficits across the hippocampus, amygdala and thalamus ipsilaterally. In addition, volume loss was detected in the putamen bilaterally. These volume deficits were not present in the unaffected siblings of MTLE+HS patients. Ipsilaterally, the heritability estimates were dramatically reduced for the volume of the hippocampus, thalamus and putamen but remained in the expected range for the amygdala. MRI-negative TLE patients and their unaffected siblings showed no significant volume changes across the same structures and heritability estimates were comparable with calculations from a healthy population. CONCLUSIONS: The findings indicate that volume deficits for many subcortical structures in 'sporadic' MTLE+HS are not heritable and likely related to acquired factors. Therefore, they do not represent suitable endophenotypes for MTLE+HS. The findings also support the view that, at a neuroanatomical level, MTLE+HS and MRI-negative TLE represent two distinct forms of MTLE.
  • ItemOpen AccessPublished version Peer-reviewed
    Developmental cognitive neuroscience using latent change score models: A tutorial and applications.
    (Elsevier BV, 2018-10) Kievit, Rogier A; Brandmaier, Andreas M; Ziegler, Gabriel; van Harmelen, Anne-Laura; de Mooij, Susanne MM; Moutoussis, Michael; Goodyer, Ian M; Bullmore, Ed; Jones, Peter B; Fonagy, Peter; NSPN Consortium; Lindenberger, Ulman; Dolan, Raymond J; Kievit, Rogier [0000-0003-0700-4568]; van Harmelen, Anne-Laura [0000-0003-1108-2921]; Goodyer, Ian [0000-0001-9183-0373]; Bullmore, Edward [0000-0002-8955-8283]; Jones, Peter [0000-0002-0387-880X]
    Assessing and analysing individual differences in change over time is of central scientific importance to developmental neuroscience. However, the literature is based largely on cross-sectional comparisons, which reflect a variety of influences and cannot directly represent change. We advocate using latent change score (LCS) models in longitudinal samples as a statistical framework to tease apart the complex processes underlying lifespan development in brain and behaviour using longitudinal data. LCS models provide a flexible framework that naturally accommodates key developmental questions as model parameters and can even be used, with some limitations, in cases with only two measurement occasions. We illustrate the use of LCS models with two empirical examples. In a lifespan cognitive training study (COGITO, N = 204 (N = 32 imaging) on two waves) we observe correlated change in brain and behaviour in the context of a high-intensity training intervention. In an adolescent development cohort (NSPN, N = 176, two waves) we find greater variability in cortical thinning in males than in females. To facilitate the adoption of LCS by the developmental community, we provide analysis code that can be adapted by other researchers and basic primers in two freely available SEM software packages (lavaan and Ωnyx).
  • ItemOpen AccessPublished version Peer-reviewed
    Clinical and imaging correlates of amyloid deposition in dementia with Lewy bodies.
    (Wiley, 2018-07) Donaghy, Paul C; Firbank, Michael J; Thomas, Alan J; Lloyd, Jim; Petrides, George; Barnett, Nicola; Olsen, Kirsty; O'Brien, John T; Donaghy, Paul C [0000-0001-7195-4846]
    BACKGROUND: Amyloid deposition is common in dementia with Lewy bodies, but its pathophysiological significance is unclear. OBJECTIVE: The objective of this study was to investigate the relationship between amyloid deposition and clinical profile, gray matter volume, and brain perfusion in dementia with Lewy bodies. METHODS: Dementia with Lewy bodies (n = 37), Alzheimer's disease (n = 20), and controls (n = 20) underwent a thorough clinical assessment, 3T MRI, and early- and late-phase 18 F-Florbetapir PET-CT to assess cortical perfusion and amyloid deposition, respectively. Amyloid scans were visually categorized as positive or negative. Image analysis was carried out using statistical parametric mapping (SPM) 8. RESULTS: There were no significant differences between amyloid-positive and amyloid-negative dementia with Lewy bodies cases in age (P = .78), overall cognitive impairment (P = .83), level of functional impairment (P = .80), or any other clinical or cognitive scale. There were also no significant differences in hippocampal or gray matter volumes. However, amyloid-positive dementia with Lewy bodies cases had lower medial temporal lobe perfusion (P = .03) than amyloid-negative cases, although a combination of medial temporal lobe perfusion, hippocampal volume, and cognitive measures was unable to accurately predict amyloid status in dementia with Lewy bodies. CONCLUSIONS: Amyloid deposition was not associated with differences in clinical or neuropsychological profiles in dementia with Lewy bodies, but was associated with imaging evidence of medial temporal lobe dysfunction. The presence of amyloid in dementia with Lewy bodies cannot be identified on the basis of clinical and other imaging features and will require direct assessment via PET imaging or CSF. © 2018 The Authors. Movement Disorders published by Wiley Periodicals, Inc. on behalf of International Parkinson and Movement Disorder Society.
  • ItemOpen AccessPublished version Peer-reviewed
    Association between childhood infection, serum inflammatory markers and intelligence: findings from a population-based prospective birth cohort study.
    (Cambridge University Press (CUP), 2018-01) Mackinnon, N; Zammit, S; Lewis, G; Jones, PB; Khandaker, GM; Jones, Peter [0000-0002-0387-880X]; Khandaker, Golam [0000-0002-4935-9220]
    A link between infection, inflammation, neurodevelopment and adult illnesses has been proposed. The objective of this study was to examine the association between infection burden during childhood - a critical period of development for the immune and nervous systems - and subsequent systemic inflammatory markers and general intelligence. In the Avon Longitudinal Study of Parents and Children, a prospective birth cohort in England, we examined the association of exposure to infections during childhood, assessed at seven follow-ups between age 1·5 and 7·5 years, with subsequent: (1) serum interleukin 6 and C-reactive protein (CRP) levels at age 9; (2) intelligence quotient (IQ) at age 8. We also examined the relationship between inflammatory markers and IQ. Very high infection burden (90+ percentile) was associated with higher CRP levels, but this relationship was explained by body mass index (adjusted odds ratio (OR) 1·19; 95% confidence interval (CI) 0·95-1·50), maternal occupation (adjusted OR 1·23; 95% CI 0·98-1·55) and atopic disorders (adjusted OR 1·24; 95% CI 0·98-1·55). Higher CRP levels were associated with lower IQ; adjusted β = -0·79 (95% CI -1·31 to -0·27); P = 0·003. There was no strong evidence for an association between infection and IQ. The findings indicate that childhood infections do not have an independent, lasting effect on circulating inflammatory marker levels subsequently in childhood; however, elevated inflammatory markers may be harmful for intellectual development/function.
  • ItemOpen AccessAccepted version Peer-reviewed
    Effect of kindness-based meditation on health and well-being: a systematic review and meta-analysis.
    (American Psychological Association (APA), 2014-12) Galante, Julieta; Galante, Ignacio; Bekkers, Marie-Jet; Gallacher, John; Galante, Julieta [0000-0002-4108-5341]
    OBJECTIVE: Kindness-based meditation (KBM) is a rubric covering meditation techniques developed to elicit kindness in a conscious way. Some techniques, for example, loving-kindness meditation and compassion meditation, have been included in programs aimed at improving health and well-being. Our aim was to systematically review and meta-analyze the evidence available from randomized controlled trials (RCTs) comparing the effects of KBM on health and well-being against passive and active control groups in patients and the general population. METHOD: Searches were completed in March 2013. Two reviewers applied predetermined eligibility criteria (RCTs, peer-reviewed publications, theses or conference proceedings, adult participants, KBM interventions) and extracted the data. Meta-analyses used random-effects models. RESULTS: Twenty-two studies were included. KBM was moderately effective in decreasing self-reported depression (standard mean difference [Hedges's g] = -0.61, 95% confidence interval [CI] [-1.08, -0.14]) and increasing mindfulness (Hedges's g = 0.63, 95% CI [0.22, 1.05]), compassion (Hedges's g = 0.61, 95% CI [0.24, 0.99]) and self-compassion (Hedges's g = 0.45, 95% CI [0.15, 0.75]) against passive controls. Positive emotions were increased (Hedges's g = 0.42, 95% CI [0.10, 0.75]) against progressive relaxation. Exposure to KBM may initially be challenging for some people. RESULTS were inconclusive for some outcomes, in particular against active controls. The methodological quality of the reports was low to moderate. RESULTS suffered from imprecision due to wide CIs deriving from small studies. CONCLUSIONS: KBM showed evidence of benefits for the health of individuals and communities through its effects on well-being and social interaction. Further research including well-conducted large RCTs is warranted.
  • ItemOpen AccessPublished version Peer-reviewed
    What distinguishes adolescents with suicidal thoughts from those who have attempted suicide? A population-based birth cohort study.
    (Wiley, 2019-01) Mars, Becky; Heron, Jon; Klonsky, E David; Moran, Paul; O'Connor, Rory C; Tilling, Kate; Wilkinson, Paul; Gunnell, David; Wilkinson, Paul [0000-0003-3302-9662]
    BACKGROUND: Only one-third of young people who experience suicidal ideation attempt suicide. It is important to identify factors which differentiate those who attempt suicide from those who experience suicidal ideation but do not act on these thoughts. METHODS: Participants were 4,772 members of the Avon Longitudinal Study of Parents and Children (ALSPAC), a UK population-based birth cohort. Suicide ideation and attempts were assessed at age 16 years via self-report questionnaire. Multinomial regression was used to examine associations between factors that differentiated adolescents in three groups: no suicidal ideation or attempts, suicidal ideation only and suicide attempts. Analyses were conducted on an imputed data set based on those with complete outcome data (suicidal thoughts and attempts) at age 16 years (N = 4,772). RESULTS: The lifetime prevalence of suicidal ideation and attempts in the sample was 9.6% and 6.8% respectively. Compared to adolescents who had experienced suicidal ideation, those who attempted suicide were more likely to report exposure to self-harm in others (adjusted OR for family member self-harm: 1.95, for friend self-harm: 2.61 and for both family and friend self-harm: 5.26). They were also more likely to have a psychiatric disorder (adjusted OR for depression: 3.63; adjusted OR for anxiety disorder: 2.20; adjusted OR for behavioural disorder: 2.90). Other risk factors included female gender, lower IQ, higher impulsivity, higher intensity seeking, lower conscientiousness, a greater number of life events, body dissatisfaction, hopelessness, smoking and illicit drug use (excluding cannabis). CONCLUSIONS: The extent of exposure to self-harm in others and the presence of psychiatric disorder most clearly differentiate adolescents who attempt suicide from those who only experience suicidal ideation. Further longitudinal research is needed to explore whether these risk factors predict progression from suicidal ideation to attempts over time.
  • ItemOpen AccessPublished version Peer-reviewed
    Aspirin in the Treatment of Cancer: Reductions in Metastatic Spread and in Mortality: A Systematic Review and Meta-Analyses of Published Studies.
    (Public Library of Science (PLoS), 2016) Elwood, Peter C; Morgan, Gareth; Pickering, Janet E; Galante, Julieta; Weightman, Alison L; Morris, Delyth; Kelson, Mark; Dolwani, Sunil; Galante, Julieta [0000-0002-4108-5341]
    BACKGROUND: Low-dose aspirin has been shown to reduce the incidence of cancer, but its role in the treatment of cancer is uncertain. OBJECTIVES: We conducted a systematic search of the scientific literature on aspirin taken by patients following a diagnosis of cancer, together with appropriate meta-analyses. METHODS: Searches were completed in Medline and Embase in December 2015 using a pre-defined search strategy. References and abstracts of all the selected papers were scanned and expert colleagues were contacted for additional studies. Two reviewers applied pre-determined eligibility criteria (cross-sectional, cohort and controlled studies, and aspirin taken after a diagnosis of cancer), assessed study quality and extracted data on cancer cause-specific deaths, overall mortality and incidence of metastases. Random effects meta-analyses and planned sub-group analyses were completed separately for observational and experimental studies. Heterogeneity and publication bias were assessed in sensitivity analyses and appropriate omissions made. Papers were examined for any reference to bleeding and authors of the papers were contacted and questioned. RESULTS: Five reports of randomised trials were identified, together with forty two observational studies: sixteen on colorectal cancer, ten on breast and ten on prostate cancer mortality. Pooling of eleven observational reports of the effect of aspirin on cause-specific mortality from colon cancer, after the omission of one report identified on the basis of sensitivity analyses, gave a hazard ratio (HR) of 0.76 (95% CI 0.66, 0.88) with reduced heterogeneity (P = 0.04). The cause specific mortality in five reports of patients with breast cancer showed significant heterogeneity (P<0.0005) but the omission of one outlying study reduced heterogeneity (P = 0.19) and led to an HR = 0.87 (95% CI 0.69, 1.09). Heterogeneity between nine studies of prostate cancer was significant, but again, the omission of one study led to acceptable homogeneity (P = 0.26) and an overall HR = 0.89 (95% CI 0.79-0.99). Six single studies of other cancers suggested reductions in cause specific mortality by aspirin, and in five the effect is statistically significant. There were no significant differences between the pooled HRs for the three main cancers and after the omission of three reports already identified in sensitivity analyses heterogeneity was removed and revealed an overall HR of 0.83 (95% CI 0.76-0.90). A mutation of PIK3CA was present in about 20% of patients, and appeared to explain most of the reduction in colon cancer mortality by aspirin. Data were not adequate to examine the importance of this or any other marker in the effect of aspirin in the other cancers. On bleeding attributable to aspirin two reports stated that there had been no side effect or bleeding attributable to aspirin. Authors on the other reports were written to and 21 replied stating that no data on bleeding were available. CONCLUSIONS AND IMPLICATIONS: The study highlights the need for randomised trials of aspirin treatment in a variety of cancers. While these are awaited there is an urgent need for evidence from observational studies of aspirin and the less common cancers, and for more evidence of the relevance of possible bio-markers of the aspirin effect on a wide variety of cancers. In the meantime it is urged that patients in whom a cancer is diagnosed should be given details of this research, together with its limitations, to enable each to make an informed decision as to whether or not to take low-dose aspirin. SYSTEMATIC REVIEW PROTOCOL NUMBER: CRD42015014145.
  • ItemOpen AccessPublished version Peer-reviewed
    Mapping Cortical Laminar Structure in the 3D BigBrain.
    (Oxford University Press (OUP), 2018-07-01) Wagstyl, Konrad; Lepage, Claude; Bludau, Sebastian; Zilles, Karl; Fletcher, Paul C; Amunts, Katrin; Evans, Alan C; Fletcher, Paul [0000-0001-8257-1517]
    Histological sections offer high spatial resolution to examine laminar architecture of the human cerebral cortex; however, they are restricted by being 2D, hence only regions with sufficiently optimal cutting planes can be analyzed. Conversely, noninvasive neuroimaging approaches are whole brain but have relatively low resolution. Consequently, correct 3D cross-cortical patterns of laminar architecture have never been mapped in histological sections. We developed an automated technique to identify and analyze laminar structure within the high-resolution 3D histological BigBrain. We extracted white matter and pial surfaces, from which we derived histologically verified surfaces at the layer I/II boundary and within layer IV. Layer IV depth was strongly predicted by cortical curvature but varied between areas. This fully automated 3D laminar analysis is an important requirement for bridging high-resolution 2D cytoarchitecture and in vivo 3D neuroimaging. It lays the foundation for in-depth, whole-brain analyses of cortical layering.
  • ItemOpen AccessPublished version Peer-reviewed
    Dysglycaemia, Inflammation and Psychosis: Findings From the UK ALSPAC Birth Cohort.
    (Oxford University Press (OUP), 2019-03-07) Perry, Benjamin Ian; Upthegrove, Rachel; Thompson, Andrew; Marwaha, Steven; Zammit, Stanley; Singh, Swaran Preet; Khandaker, Golam; Perry, Ben [0000-0002-1533-026X]; Khandaker, Golam [0000-0002-4935-9220]
    BACKGROUND: Psychosis is associated with both dysglycaemia and low-grade inflammation, but population-based studies investigating the interplay between these factors are scarce. AIMS: (1) To explore the direction of association between markers of dysglycaemia, inflammation and psychotic experiences (PEs); and (2) To explore whether dysglycaemia moderates and/or mediates the association between inflammation and PEs. METHOD: Data from the Avon Longitudinal Study of Parents and Children (ALSPAC) birth cohort were modeled using logistic and linear regression to examine cross-sectional and longitudinal associations between markers of dysglycaemia (ages 9 and 18), interleukin-6 (IL-6) (age 9), and PEs (ages 12 and 18). We tested for an interaction between dysglycaemia and IL-6 on risk of PEs at age 18, and tested whether dysglycaemia mediated the relationship between IL-6 and PEs. RESULTS: Based on 2627 participants, at age 18, insulin resistance (IR) was associated with PEs (adjusted OR = 2.32; 95% CI, 1.37-3.97). IR was associated with IL-6 both cross-sectionally and longitudinally. Interaction analyses under a multiplicative model showed that IR moderated the association between IL-6 at age 9 and PEs at age 18 (adjusted OR for interaction term = 2.18; 95% C.I., 1.06-4.49). Mediation analysis did not support a model of IR mediating the relationship between IL-6 and PEs. IMPLICATIONS: IR is associated with PEs in young people even before the onset of clinical psychosis. Metabolic alterations may interact with childhood inflammation to increase risk of PEs. The findings have implications for clinical practice and future research.
  • ItemOpen AccessPublished version Peer-reviewed
    Systemic Inflammation and Intelligence in Early Adulthood and Subsequent Risk of Schizophrenia and Other Non-Affective Psychoses: A Longitudinal Cohort and Co-Relative Study
    (Cambridge University Press, 2019-01) Khandaker, GM; Kappelmann, Nils; Stochl, Jan; Jones, Peter B; Khandaker, Golam [0000-0002-4935-9220]; Stochl, Jan [0000-0002-9693-9930]; Jones, Peter [0000-0002-0387-880X]
    Background Schizophrenia is associated with impaired neurodevelopment as indexed by lower premorbid IQ. We examined associations between erythrocyte sedimentation rate (ESR), a marker of low-grade systemic inflammation, IQ, and subsequent schizophrenia and other non-affective psychoses (ONAP) to elucidate the role of neurodevelopment and inflammation in pathogenesis of psychosis. Methods Population-based data on ESR and IQ from 638213 Swedish men assessed during military conscription between 1969 and 1983 were linked to National Hospital Discharge Register for hospitalisation with schizophrenia and ONAP. The associations of ESR with IQ (cross-sectional) and psychoses (longitudinal) were investigated using linear and Cox-regression. Co-relative analysis was used to examine effects of shared familial confounding. We examined mediation and moderation of effect between ESR and IQ on psychosis risk. Results Baseline IQ was associated with subsequent risk of schizophrenia (adjusted HR per 1-point increase in IQ=0.961; 95% CI: 0.960-0.963) and ONAP (adjusted HR=0.973; 95% CI: 0.971-0.975). Higher ESR was associated with lower IQ in a dose-response fashion. High ESR was associated with increased risk for schizophrenia (adjusted HR=1.14; 95% CI: 1.01-1.28) and decreased risk for ONAP (adjusted HR=0.85; 95% CI: 0.74-0.96), although these effects were specific to one ESR band (7-10mm/hr). Familial confounding explained ESR-IQ but not ESR-psychoses associations. IQ partly mediated the ESR-psychosis relationships. Conclusions Lower IQ is associated with low-grade systemic inflammation and with increased risk of schizophrenia and ONAP in adulthood. Low-grade inflammation may influence schizophrenia risk by affecting neurodevelopment. Future studies should explore the differential effects of inflammation on different types of psychosis.
  • ItemOpen AccessPublished version Peer-reviewed
    Differences in change blindness to real-life scenes in adults with autism spectrum conditions
    (Public Library of Science (PLoS)) ashwin, C; wheelwright, S; Baron-Cohen, S; Baron-Cohen, Simon [0000-0001-9217-2544]
    People often fail to detect large changes to visual scenes following a brief interruption, an effect known as ‘change blindness’. People with autism spectrum conditions (ASC) have superior attention to detail and better discrimination of targets, and often notice small details that are missed by others. Together these predict people with autism should show enhanced perception of changes in simple change detection paradigms, including reduced change blindness. However, change blindness studies to date have reported mixed results in ASC, which have sometimes included no differences to controls or even enhanced change blindness. Attenuated change blindness has only been reported to date in ASCin children and adolescents, with no study reporting reduced change blindness in adults with ASC. The present study used a change blindness flicker task to investigate the detection of changes in images of everyday life in adults with ASC (n=22) and controls (n=22) using a simple change detection task design and full range of original scenes as stimuli. The adults with ASC had reduced change blindness compared to adult controls for changes to items of marginal interest in scenes, with no group difference for changes to items of central interest. There were no group differences in overall response latencies to correctly detect changes nor in the overall number of missed detections in the experiment. However, the ASC group showed greater missed changes for marginal interest changes of location, showing some evidence of greater change blindness as well. These findings show both reduced change blindness to marginal interest changes in ASC, based on response latencies, as well as greater change blindness to changes of location of marginal interest items, based on detection rates. The findings of reduced change blindness are consistent with clinical reports that people with ASC often notice small changes to less salient items within their environment, and are in-line with theories of enhanced local processing and greater attention to detail in ASC. The findings of lower detection rates for one of the marginal interest conditions may be related to problems in shifting attention or an overly focused attention spotlight.