414 results on '"Johnstone EC"'
Search Results
2. Mutation burden and other molecular markers of prognosis in the QUASAR2 clinical trial of colorectal cancer treated with curative intent
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Domingo, E, Camps, C, Kaisaki, PJ, Parsons, MJ, Mouradov, D, Pentony, MM, Makino, S, Palmieri, M, Ward, RL, Hawkins, NJ, Gibbs, P, Askautrud, H, Oukrif, D, Wang, H, Wood, J, Tomlinson, E, Bark, Y, Kaur, K, Johnstone, EC, Palles, CL, Church, DN, Novelli, M, Danielsen, HE, Sherlock, J, Kerr, DJ, Kerr, R, Sieber, O, Taylor, JC, and Tomlinson, I
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endocrine system diseases ,neoplasms ,digestive system diseases - Abstract
Background Several relatively large studies have assessed molecular indicators of colorectal cancer (CRC) prognosis, but most analyses have been restricted to a handful of markers. Methods In stage II/III CRCs from the QUASAR2 clinical trial and from an Australian community-based series, we assessed gene panels for somatic driver mutations and overall mutation burden. We determined molecular pathways of tumorigenesis, and analysed associations with treatment response and prognosis. Findings In QUASAR2 (N=511), TP53, KRAS, BRAF and GNAS mutations were independently associated with shorter relapse-free survival, whereas total somatic mutation burden was associated with longer survival, even after excluding mismatch repair-deficient (MSI+) and POLE-mutant tumours. We successfully validated these associations in the Australian sample set (N=296). In an extended analysis of 1,752 QUASAR2 and Australian CRCs for which KRAS, BRAF and MSI status was available, we found that KRAS and BRAF mutations were specifically associated with poor prognosis in MSI- cancers. This association was not present in MSI+ cancers, and MSI+ tumours with KRAS or BRAF mutation actually had better prognosis than MSI- cancers that were wildtype for KRAS or BRAF. New rare molecular pathways were also uncovered: mutations in the genes NF1 and NRAS from the MAP kinase pathway co-occurred, mutations in TP53 and ATM appeared to be alternative ways of inactivating the DNA damage response pathway. Interpretation A multi-gene panel has identified two previously unreported prognostic associations in CRC involving both TP53 mutation and total mutation burden, and confirmed associations with KRAS and BRAF. We conclude that even a modest-sized gene panel can provide important information for use in clinical practice and out-perform MSI-based models.
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- 2018
3. Serotonin transporters in ecstasy users - Reply
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Ebmeier, KP, Semple, DM, Glabus, MF, O'Carroll, RE, and Johnstone, EC
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- 2016
4. Cortical Surface Area Differentiates Familial High Risk Individuals Who Go on to Develop Schizophrenia
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Bois, C, Ronan, Lisa, Levita, L, Whalley, HC, Giles, S, McIntosh, AM, Fletcher, Paul, Owens, DC, Johnstone, EC, and Lawrie, SM
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BACKGROUND: Schizophrenia is associated with structural brain abnormalities that may be present before disease\ud onset. It remains unclear whether these represent general vulnerability indicators or are associated with the clinical state itself.\ud \ud METHODS: To investigate this, structural brain scans were acquired at two time points (mean scan interval\ud 1.87 years) in a cohort of individuals at high familial risk of schizophrenia (n 5 142) and control subjects (n 5 36).\ud Cortical reconstructions were generated using FreeSurfer. The high-risk cohort was subdivided into individuals that\ud remained well during the study, individuals that had transient psychotic symptoms, and individuals that subsequently\ud became ill. Baseline measures and longitudinal change in global estimates of thickness and surface area and lobar\ud values were compared, focusing on overall differences between high-risk individuals and control subjects and then\ud on group differences within the high-risk cohort.\ud \ud RESULTS: Longitudinally, control subjects showed a significantly greater reduction in cortical surface area\ud compared with the high-risk group. Within the high-risk group, differences in surface area at baseline predicted\ud clinical course, with individuals that subsequently became ill having significantly larger surface area than individuals\ud that remained well during the study. For thickness, longitudinal reductions were most prominent in the frontal,\ud cingulate, and occipital lobes in all high-risk individuals compared with control subjects.\ud \ud CONCLUSIONS: Our results suggest that larger surface areas at baseline may be associated with mechanisms that\ud go above and beyond a general familial disposition. A relative preservation over time of surface area, coupled with a\ud thinning of the cortex compared with control subjects, may serve as vulnerability markers of schizophrenia.
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- 2015
5. Concluding summary
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Johnstone Ec
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Engineering ethics ,General Medicine ,Biological psychiatry ,Psychology - Published
- 1996
6. Association Between Genetic Variants on Chromosome 15q25 Locus and Objective Measures of Tobacco Exposure
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Munafò, MR, Timofeeva, MN, Morris, RW, Prieto-Merino, D, Sattar, N, Brennan, P, Johnstone, EC, Relton, C, Johnson, PC, Walther, D, Whincup, PH, Casas, JP, Uhl, GR, Vineis, P, Padmanabhan, S, Jefferis, BJ, Amuzu, A, Riboli, E, Upton, MN, Aveyard, P, Ebrahim, S, Hingorani, AD, Watt, G, Palmer, TM, Timpson, NJ, EPIC Study Group, and Davey Smith, G
- Abstract
BACKGROUND: Two single-nucleotide polymorphisms, rs1051730 and rs16969968, located within the nicotinic acetylcholine receptor gene cluster on chromosome 15q25 locus, are associated with heaviness of smoking, risk for lung cancer, and other smoking-related health outcomes. Previous studies have typically relied on self-reported smoking behavior, which may not fully capture interindividual variation in tobacco exposure. METHODS: We investigated the association of rs1051730 and rs16969968 genotype (referred to as rs1051730-rs16969968, because these are in perfect linkage disequilibrium and interchangeable) with both self-reported daily cigarette consumption and biochemically measured plasma or serum cotinine levels among cigarette smokers. Summary estimates and descriptive statistical data for 12 364 subjects were obtained from six independent studies, and 2932 smokers were included in the analyses. Linear regression was used to calculate the per-allele association of rs1051730-rs16969968 genotype with cigarette consumption and cotinine levels in current smokers for each study. Meta-analysis of per-allele associations was conducted using a random effects method. The likely resulting association between genotype and lung cancer risk was assessed using published data on the association between cotinine levels and lung cancer risk. All statistical tests were two-sided. RESULTS: Pooled per-allele associations showed that current smokers with one or two copies of the rs1051730-rs16969968 risk allele had increased self-reported cigarette consumption (mean increase in unadjusted number of cigarettes per day per allele = 1.0 cigarette, 95% confidence interval [CI] = 0.57 to 1.43 cigarettes, P = 5.22 × 10(-6)) and cotinine levels (mean increase in unadjusted cotinine levels per allele = 138.72 nmol/L, 95% CI = 97.91 to 179.53 nmol/L, P = 2.71 × 10(-11)). The increase in cotinine levels indicated an increased risk of lung cancer with each additional copy of the rs1051730-rs16969968 risk allele (per-allele odds ratio = 1.31, 95% CI = 1.21 to 1.42). CONCLUSIONS: Our data show a stronger association of rs1051730-rs16969968 genotype with objective measures of tobacco exposure compared with self-reported cigarette consumption. The association of these variants with lung cancer risk is likely to be mediated largely, if not wholly, via tobacco exposure.
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- 2012
7. Investigating the possible causal association of smoking with depression and anxiety using Mendelian randomisation meta-analysis: the CARTA consortium
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Taylor, AE, Fluharty, ME, Bjorngaard, JH, Gabrielsen, ME, Skorpen, F, Marioni, RE, Campbell, A (Archie), Engmann, J, Mirza, Saira, Loukola, A, Laatikainen, T, Partonen, T, Kaakinen, M, Ducci, F, Cavadino, A, Husemoen, LLN, Ahluwalia, TS, Jacobsen, RK, Skaaby, T, Ebstrup, JF, Mortensen, EL, Minica, CC, Vink, JM, Willemsen, G, Marques-Vidal, P, Dale, CE, Amuzu, A, Lennon, LT, Lahti, J, Palotie, A, Raikkonen, K, Wong, A, Paternoster, L, Wong, APY, Horwood, LJ, Murphy, M, Johnstone, EC, Kennedy, MA, Pausova, Z, Paus, T, Ben-Shlomo, Y, Nohr, EA, Kuh, D, Kivimaki, M, Eriksson, JG, Morris, RW, Casas, JP, Preisig, M, Boomsma, DI, Linneberg, A, Power, C, Hypponen, E, Veijola, J, Jarvelin, MR, Korhonen, T, Tiemeier, Henning, Kumari, M, Porteous, DJ, Hayward, C, Romundstad, PR, Smith, GD, Munafo, MR, Taylor, AE, Fluharty, ME, Bjorngaard, JH, Gabrielsen, ME, Skorpen, F, Marioni, RE, Campbell, A (Archie), Engmann, J, Mirza, Saira, Loukola, A, Laatikainen, T, Partonen, T, Kaakinen, M, Ducci, F, Cavadino, A, Husemoen, LLN, Ahluwalia, TS, Jacobsen, RK, Skaaby, T, Ebstrup, JF, Mortensen, EL, Minica, CC, Vink, JM, Willemsen, G, Marques-Vidal, P, Dale, CE, Amuzu, A, Lennon, LT, Lahti, J, Palotie, A, Raikkonen, K, Wong, A, Paternoster, L, Wong, APY, Horwood, LJ, Murphy, M, Johnstone, EC, Kennedy, MA, Pausova, Z, Paus, T, Ben-Shlomo, Y, Nohr, EA, Kuh, D, Kivimaki, M, Eriksson, JG, Morris, RW, Casas, JP, Preisig, M, Boomsma, DI, Linneberg, A, Power, C, Hypponen, E, Veijola, J, Jarvelin, MR, Korhonen, T, Tiemeier, Henning, Kumari, M, Porteous, DJ, Hayward, C, Romundstad, PR, Smith, GD, and Munafo, MR
- Abstract
Objectives: To investigate whether associations of smoking with depression and anxiety are likely to be causal, using a Mendelian randomisation approach. Design: Mendelian randomisation meta-analyses using a genetic variant (rs16969968/rs1051730) as a proxy for smoking heaviness, and observational meta-analyses of the associations of smoking status and smoking heaviness with depression, anxiety and psychological distress. Participants: Current, former and never smokers of European ancestry aged >= 16 years from 25 studies in the Consortium for Causal Analysis Research in Tobacco and Alcohol (CARTA). Primary outcome measures: Binary definitions of depression, anxiety and psychological distress assessed by clinical interview, symptom scales or self-reported recall of clinician diagnosis. Results: The analytic sample included up to 58 176 never smokers, 37 428 former smokers and 32 028 current smokers (total N=127 632). In observational analyses, current smokers had 1.85 times greater odds of depression (95% CI 1.65 to 2.07), 1.71 times greater odds of anxiety (95% CI 1.54 to 1.90) and 1.69 times greater odds of psychological distress (95% CI 1.56 to 1.83) than never smokers. Former smokers also had greater odds of depression, anxiety and psychological distress than never smokers. There was evidence for positive associations of smoking heaviness with depression, anxiety and psychological distress (ORs per cigarette per day: 1.03 (95% CI 1.02 to 1.04), 1.03 (95% CI 1.02 to 1.04) and 1.02 (95% CI 1.02 to 1.03) respectively). In Mendelian randomisation analyses, there was no strong evidence that the minor allele of rs16969968/rs1051730 was associated with depression (OR=1.00, 95% CI 0.95 to 1.05), anxiety (OR= 1.02, 95% CI 0.97 to 1.07) or psychological distress (OR= 1.02, 95% CI 0.98 to 1.06) in current smokers. Results were similar for former smokers. Conclusions: Findings from Mendelian randomisation analyses do not support a causal role of smoking heaviness in the dev
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- 2014
8. The Relationship of Anterior Thalamic Radiation Integrity to Psychosis Risk Associated Neuregulin-1 Variants
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Sprooten, E, primary, Lymer, GKS, additional, Maniega, S Muñoz, additional, McKirdy, J, additional, Clayden, JD, additional, Bastin, ME, additional, Porteous, D, additional, Johnstone, EC, additional, Lawrie, SM, additional, Hall, J, additional, and McIntosh, AM, additional
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- 2009
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9. Fronto-temporal Connectivity in Bipolar Disorder and Schizophrenia Related to Auditory Verbal Hallucinations
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Sprooten, E, primary, Romaniuk, L, additional, Giles, S, additional, Job, DE, additional, Mukherjee, P, additional, Whalley, HC, additional, Lawrie, SM, additional, Johnstone, EC, additional, van de Ven, VG, additional, and McIntosh, AM, additional
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- 2009
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10. The dopamine D2 receptor C32806T polymorphism (DRD2 Taq1A RFLP) exhibits no association with smoking behaviour in a healthy UK population
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Johnstone, EC, primary, Yudkin, P, additional, Griffiths, SE, additional, Fuller, A, additional, Murphy, M, additional, and Walton, R, additional
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- 2004
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11. The Nature and the Management of Schizophrenia
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Johnstone Ec
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medicine.medical_specialty ,business.industry ,Schizophrenia (object-oriented programming) ,MEDLINE ,General Medicine ,030227 psychiatry ,03 medical and health sciences ,0302 clinical medicine ,Management of schizophrenia ,Schizophrenia ,medicine ,Humans ,030212 general & internal medicine ,Psychiatry ,business - Published
- 1991
12. New variant Creutzfeldt-Jakob disease: psychiatric features
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Zeidler, M, primary, Johnstone, EC, additional, Bamber, RW K, additional, Dickens, CM, additional, Fisher, CJ, additional, Francis, AF, additional, Goldbeck, R, additional, Higgo, R, additional, Johnson-Sabine, EC, additional, Lodge, GJ, additional, McGarry, P, additional, Mitchell, S, additional, Tarlo, L, additional, Turner, M, additional, Ryley, P, additional, and Will, RG, additional
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- 1997
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13. Hippocampal function in schizophrenia and bipolar disorder.
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Hall J, Whalley HC, Marwick K, McKirdy J, Sussmann J, Romaniuk L, Johnstone EC, Wan HI, McIntosh AM, and Lawrie SM
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BACKGROUND: The hippocampus plays a central role in memory formation. There is considerable evidence of abnormalities in hippocampal structure and function in schizophrenia, which may differentiate it from bipolar disorder. However, no previous studies have compared hippocampal activation in schizophrenia and bipolar disorder directly. METHOD: Fifteen patients with schizophrenia, 14 patients with bipolar disorder and 14 healthy comparison subjects took part in the study. Subjects performed a face-name pair memory task during functional magnetic resonance imaging (fMRI). Differences in blood oxygen level-dependent (BOLD) activity were determined during encoding and retrieval of the face-name pairs. RESULTS: The patient groups showed significant differences in hippocampal and prefrontal cortex (PFC) activation during face-name pair learning. During encoding, patients with schizophrenia showed decreased anterior hippocampal activation relative to subjects with bipolar disorder, whereas patients with bipolar disorder showed decreased dorsal PFC activation relative to patients with schizophrenia. During retrieval, patients with schizophrenia showed greater activation of the dorsal PFC than patients with bipolar disorder. Patients with schizophrenia also differed from healthy control subjects in the activation of several brain regions, showing impaired superior temporal cortex activation during encoding and greater dorsal PFC activation during retrieval. These effects were evident despite matched task performance. CONCLUSIONS: Patients with schizophrenia showed deficits in hippocampal activation during a memory task relative to patients with bipolar disorder. The disorders were further distinguished by differences in PFC activation. The results demonstrate that these disorders can distinguished at a group level using non-invasive neuroimaging. [ABSTRACT FROM AUTHOR]
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- 2010
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14. Smoking status moderates the association of the dopamine D4 receptor (DRD4) gene VNTR polymorphism with selective processing of smoking-related cues.
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Munafò MR and Johnstone EC
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- 2008
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15. Precursors and prodromata of schizophrenia: findings from the Edinburgh High Risk Study and their literature context.
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Cunningham Owens DG and Johnstone EC
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Background. In schizophrenia research, 'high risk' traditionally referred to studies of the offspring of schizophrenic parents at genetically enhanced risk of illness development. Sixteen major high-risk studies have been undertaken although only six followed through to formal illness so data on prediction remain weak. Recently, 'high risk' has widened to encompass individuals considered 'at risk' by having 'high risk mental states', regardless of family history, in whom initiation of early treatment is postulated to improve outcome.Method. The major familial high-risk studies are reviewed from the perspective of the Edinburgh High Risk Study of Schizophrenia (EHRS), with emphasis on prediction.Results. Familial high-risk studies have established multiple biological markers, the most reproducible of which relate to neuromotor development and cognition, especially aspects of memory/learning. Although most are probably not specific, they support a neurodevelopmental hypothesis. Family and environmental variables point largely to secondary or indirect associations. Pre-illness, non-specific affective symptomatology may be of greater predictive power than most psychotic phenomena.Conclusions. Traditional high-risk designs embody many problems but are able to distinguish non-specific markers from illness predictors, and are ideally suited to exploring the evolution of schizophrenia both clinically and biologically (especially with imaging techniques). The EHRS supports the view that greater specificity may accrue to cognitive domains as precursors of predictive utility. [ABSTRACT FROM AUTHOR]
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- 2006
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16. Event-related fMRI of word classification and successful word recognition in subjects at genetically enhanced risk of schizophrenia.
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Whyte M, Whalley HC, Simonotto E, Flett S, Shillcock R, Marshall I, Goddard NH, Johnstone EC, and Lawrie SM
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Background. Verbal declarative memory is a core deficit in schizophrenia patients, seen to a lesser extent in unaffected biological relatives. Neuroimaging studies suggest volumetric differences and aberrant function in prefrontal and temporal regions in schizophrenia patients compared to controls. These deficits are also reflected in the small number of similar investigations in unaffected biological relatives. However, it is unclear the extent to which dysfunction is genetically mediated or a feature of the established illness.Method. Event-related blood-oxygen-level-dependent (BOLD) functional magnetic resonance imaging (fMRI) was used to measure brain activation in 68 biological relatives of schizophrenia patients (of whom 27 experienced transient or isolated psychotic symptoms) and 21 controls during verbal classification and recognition.Results. During word classification, the high-risk group showed a greater response relative to controls in the right inferior frontal gyrus. During correct recognition (relative to correct rejection), the high-risk group showed significantly greater response relative to controls in the right cerebellum. When the high-risk group was split into those with (HR+) and without (HR-) psychotic symptoms, the increased response in the right inferior frontal gyrus was only seen when the HR+ were compared to controls. The greater cerebellar response was seen when both HR groups were compared to controls.Conclusions. Activation increases in the right inferior frontal gyrus and cerebellum in high-risk subjects compared to controls during a relatively low-load memory task are likely to represent compensation for genetically mediated abnormalities. This is consistent with a leftward shift of the inverted 'U' load-response model of cognitive function in schizophrenia. [ABSTRACT FROM AUTHOR]
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- 2006
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17. fMRI correlates of state and trait effects in subjects at genetically enhanced risk of schizophrenia.
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Whalley HC, Simonotto E, Flett S, Marshall I, Ebmeier KP, Owens DGC, Goddard NH, Johnstone EC, and Lawrie SM
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- 2004
18. Correlations between clinical and historical variables, and cerebral structural variables in people with mild intellectual disability and schizophrenia.
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Sanderson TL, Doody GA, Best J, Owens DGC, and Johnstone EC
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The increased prevalence of schizophrenia in the population with mildly intellectual disability (ID) remains unexplained. The present study explores several possibilities by examining historical/clinical findings in relation to structural neuroimaging findings in three groups: (1) comorbid mild ID and schizophrenia; (2) schizophrenia alone; and (3) mild ID alone. Information about clinical and historical variables was obtained from 101 subjects (39 with comorbidity, 34 with schizophrenia and 28 with mild ID), out of whom 68 (23, 25 and 20, respectively) had had a cerebral magnetic resonance imaging (MRI) scan. Although a number of significant correlations exist between clinical variables and structural MRI abnormalities in all three groups, no clearly predictive inter- or between-group differences emerged. More striking was the finding that showed small amygdalo-hippocampal size to be associated with a history of central nervous system injury, especially meningitis. These findings provide support for the view that cognitive impairment and comorbid psychosis can result from a common cause, such as meningitis or obstetric complications, possibly interacting with other factors, such as family history. [ABSTRACT FROM AUTHOR]
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- 2001
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19. Group psychological treatment for chest pain with normal coronary arteries.
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Potts, SG, Lewin, R, Fox, KAA, and Johnstone, EC
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- 1999
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20. Neuroendocrine markers of CNS drug effects.
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Johnstone, EC and Ferrier, IN
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- 1980
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21. Serum prolactin as an index of dopamine receptor blockade in acute schizophrenia [proceedings]
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Cotes, PM, primary, Crow, TJ, additional, and Johnstone, EC, additional
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- 1977
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22. The clinical effects of the isomers of flupenthixol-the consequences of dopamine receptor blockade in acute schizophrenia [proceedings]
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Crow, TJ, primary, Frith, C, additional, and Johnstone, EC, additional
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- 1977
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23. The urinary excretion of phenelzine.
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Caddy, B, primary, Stead, AH, additional, and Johnstone, EC, additional
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- 1978
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24. Low birthweight and preterm birth in young people with special educational needs: a magnetic resonance imaging analysis.
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Spencer MD, Moorhead TW, Gibson RJ, McIntosh AM, Sussmann JE, Owens DG, Lawrie SM, Johnstone EC, Spencer, Michael D, Moorhead, T William J, Gibson, Rod J, McIntosh, Andrew M, Sussmann, Jessika E D, Owens, David G C, Lawrie, Stephen M, and Johnstone, Eve C
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Background: Although neuroanatomical and cognitive sequelae of low birthweight and preterm birth have been investigated, little is understood as to the likely prevalence of a history of low birthweight or preterm birth, or neuroanatomical correlates of such a history, within the special educational needs population. Our aim was to address these issues in a sample of young people receiving additional learning support.Methods: One hundred and thirty-seven participants aged 13-22 years, receiving additional learning support, were recruited via their schools or colleges and underwent structural magnetic resonance imaging (MRI). Obstetric records, available in 98 cases, included birthweight and gestational data in 90 and 95 cases, respectively. Both qualitative and quantitative voxel-based analyses of MRI data were conducted.Results: A history of low birthweight and preterm birth was present in 13.3% and 13.7% of cases, respectively. Low birthweight and preterm birth were associated with specific qualitative anomalies, including enlargement of subarachnoid cisterns and thinning of the corpus callosum. Low birthweight was associated with reduced grey matter density (GMD) in the superior temporal gyrus (STG) bilaterally, left inferior temporal gyrus and left insula. Prematurity of birth was associated with reduced GMD in the STG bilaterally, right inferior frontal gyrus and left cerebellar hemisphere. Comparison of subjects with no history of low birthweight or preterm birth with a previously defined control sample of cognitively unimpaired adolescents (n = 72) demonstrated significantly greater scores for several anomalies, including thinning of the corpus callosum, loss of white matter and abnormalities of shape of the lateral ventricles.Conclusion: Although a two-fold increased prevalence of a history of low birthweight and preterm birth exists within the special educational needs population, other aetiological factors must be considered for the overwhelming majority of cases. Neuroanatomical findings within this sample include qualitative anomalies of brain structure and grey matter deficits within temporal lobe structures and the cerebellum that persist into adolescence. These findings suggest a neurodevelopmental mechanism for the cognitive difficulties associated with these obstetric risk factors. [ABSTRACT FROM AUTHOR]- Published
- 2008
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25. The clinical landscape for AAV gene therapies.
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Kuzmin DA, Shutova MV, Johnston NR, Smith OP, Fedorin VV, Kukushkin YS, van der Loo JCM, and Johnstone EC
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- Animals, Genetic Vectors genetics, Humans, Dependovirus genetics, Genetic Therapy methods
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- 2021
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26. Categorical and Dimensional Approaches to Examining the Joint Effect of Autism and Schizotypal Personality Disorder on Sustained Attention.
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Abu-Akel A, Philip RCM, Lawrie SM, Johnstone EC, and Stanfield AC
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Introduction: Accumulating evidence for the co-occurrence autism spectrum disorder (ASD) and schizotypal personality disorder (SPD) at both the diagnostic and symptom levels raises important questions about the nature of their association and the effect of their co-occurrence on the individual's phenotype and functional outcome. Research comparing adults with ASD and SPD, as well as the impact of their co-occurrence on outcomes is extremely limited. We investigated executive functioning in terms of response inhibition and sustained attention, candidate endophenotypes of both conditions, in adults with ASD, SPD, comorbid ASD and SPD, and neurotypical adults using both categorical and dimensional approaches., Methods: A total of 88 adults (Mean Age = 37.54; SD = 10.17): ASD ( n = 26; M/F = 20/6); SPD ( n = 20; M/F = 14/6); comorbid ASD and SPD ( n =9; M/F=6/3) and neurotypicals ( n =33; M/F=23/10) completed the Sustained Attention to Response Task (SART) in both its fixed and random forms. Positive and autistic symptom severity was assessed with the positive subscale of the Positive and Negative Syndrome Scale (PANSSpos) and the PANSS Autism Severity Score (PAUSS), respectively., Results: Controlling for full scale IQ, working memory and medication dosage, group analyses revealed that the comorbid group committed fewer omission errors than the ASD group on the fixed SART, and fewer omission errors than the ASD and SPD groups on the random SART. The individual difference analyses of the entire sample revealed that the PANSSpos and PAUSS interactively reduced omission errors in both the fixed and random SARTs, as well as increased d' scores, indicative of improved overall performance. We observed no significant results for commission errors or reaction time., Conclusions: Concurrent elevated levels of autistic and positive psychotic symptoms seem to be associated with improved sustained attention abilities (reduced omission errors) but not inhibition (commission errors). Our findings highlight the importance of investigating the concurrent effect of ASD and SPD at both the symptom and diagnostic levels, and raise important questions for future research regarding the clinical and behavioral phenotypes of adults with dual diagnosis and, more generally, about the nature of the relationship between ASD and SPD., (Copyright © 2020 Abu-Akel, Philip, Lawrie, Johnstone and Stanfield.)
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- 2020
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27. Predictors of psychotic symptoms among young people with special educational needs.
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Stanfield AC, McKechanie AG, Lawrie SM, Johnstone EC, and Owens DGC
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- Adolescent, Case-Control Studies, Comorbidity, Female, Humans, Male, Prospective Studies, Risk Factors, Scotland epidemiology, Young Adult, Intellectual Disability epidemiology, Psychotic Disorders epidemiology
- Abstract
Background: Psychotic symptoms and psychotic disorders occur at increased rates in adults with intellectual disability, including borderline intellectual functioning, compared with the general population. Little is known about the development of such symptoms in this population.AimsTo examine whether clinical factors predictive of psychotic disorder in a familial study of schizophrenia also apply to those with intellectual disability., Method: Adolescents with special educational needs (SEN) were assessed with the Structured Interview for Schizotypy (SIS) and Childhood Behavioural Checklist (CBCL). These scores were used to prospectively divide participants based on their anticipated risk for psychotic disorder. A subsample were reassessed three times over 6 years, using the Positive and Negative Syndrome Scale (PANSS)., Results: The SEN group were more symptomatic than controls throughout (Cohen's d range for PANSS subscale scores: 0.54-1.4, all P < 0.007). Over 6 years of follow-up, those above the SIS and CBCL cut-off values at baseline were more likely than those below to display morbid positive psychotic symptoms (odds ratio, 3.5; 95% CI 1.3-9.0) and develop psychotic disorder (odds ratio, 11.4; 95% CI 2.6-50.1). Baseline SIS and CBCL cut-off values predicted psychotic disorder with sensitivity of 0.67, specificity of 0.85, positive predictive value of 0.26 and negative predictive value of 0.97., Conclusions: Adolescents with SEN have increased psychotic and non-psychotic symptoms. The personality and behavioural features associated with later psychotic disorder in this group are similar to those in people with familial loading. Relatively simple screening measures may help identify those in this vulnerable group who do and do not require monitoring for psychotic symptoms.Declaration of interestNone.
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- 2019
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28. Reversal of proliferation deficits caused by chromosome 16p13.11 microduplication through targeting NFκB signaling: an integrated study of patient-derived neuronal precursor cells, cerebral organoids and in vivo brain imaging.
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Johnstone M, Vasistha NA, Barbu MC, Dando O, Burr K, Christopher E, Glen S, Robert C, Fetit R, Macleod KG, Livesey MR, Clair DS, Blackwood DHR, Millar K, Carragher NO, Hardingham GE, Wyllie DJA, Johnstone EC, Whalley HC, McIntosh AM, Lawrie SM, and Chandran S
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- Abnormalities, Multiple genetics, Adult, Aged, Brain diagnostic imaging, Brain physiopathology, Cell Proliferation, Chromosome Duplication genetics, Female, Humans, Induced Pluripotent Stem Cells metabolism, Intellectual Disability genetics, Male, Middle Aged, NF-kappa B genetics, Neuroimaging methods, Neurons, Organoids physiology, Signal Transduction, Stem Cells physiology, Chromosomes, Human, Pair 16 genetics, Mental Disorders genetics, NF-kappa B metabolism
- Abstract
The molecular basis of how chromosome 16p13.11 microduplication leads to major psychiatric disorders is unknown. Here we have undertaken brain imaging of patients carrying microduplications in chromosome 16p13.11 and unaffected family controls, in parallel with iPS cell-derived cerebral organoid studies of the same patients. Patient MRI revealed reduced cortical volume, and corresponding iPSC studies showed neural precursor cell (NPC) proliferation abnormalities and reduced organoid size, with the NPCs therein displaying altered planes of cell division. Transcriptomic analyses of NPCs uncovered a deficit in the NFκB p65 pathway, confirmed by proteomics. Moreover, both pharmacological and genetic correction of this deficit rescued the proliferation abnormality. Thus, chromosome 16p13.11 microduplication disturbs the normal programme of NPC proliferation to reduce cortical thickness due to a correctable deficit in the NFκB signalling pathway. This is the first study demonstrating a biologically relevant, potentially ameliorable, signalling pathway underlying chromosome 16p13.11 microduplication syndrome in patient-derived neuronal precursor cells.
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- 2019
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29. The development of antipsychotic drugs.
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Cunningham Owens D and Johnstone EC
- Abstract
Antipsychotic drugs revolutionised psychiatric practice and provided a range of tools for exploring brain function in health and disease. Their development and introduction were largely empirical but based on long and honourable scientific credentials and remarkable powers of clinical observation. The class shares a common core action of attenuating central dopamine transmission, which underlies the major limitation to their use - high liability to disrupt extrapyramidal function - and also the most durable hypothesis of the basis of psychotic disorders, especially schizophrenia. However, the Dopamine Hypothesis, which has driven drug development for almost half a century, has become a straight-jacket, stifling innovation, resulting in a class of compounds that are largely derivative. Recent efforts only cemented this tendency as no clinical evidence supports the notion that newer compounds, modelled on clozapine, share that drug's unique neurological tolerability and can be considered 'atypical'. Patients and doctors alike must await a more profound understanding of central dopamine homeostasis and novel methods of maintaining it before they can again experience the intoxicating promise antipsychotics once held., Competing Interests: Declaration of conflicting interests: The author(s) declared no potential conflicts of interest with respect to the research, authorship and/or publication of this article., (© The Author(s) 2018.)
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- 2018
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30. Is there a symptomatic distinction between the affective psychoses and schizophrenia? A machine learning approach.
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Jauhar S, Krishnadas R, Nour MM, Cunningham-Owens D, Johnstone EC, and Lawrie SM
- Subjects
- Adolescent, Adult, Affective Disorders, Psychotic psychology, Aged, Cohort Studies, Diagnosis, Computer-Assisted, Female, Humans, Male, Middle Aged, ROC Curve, Schizophrenic Psychology, Young Adult, Affective Disorders, Psychotic diagnosis, Machine Learning, Schizophrenia diagnosis
- Abstract
Dubiety exists over whether clinical symptoms of schizophrenia can be distinguished from affective psychosis, the assumption being that absence of a "point of rarity" indicates lack of nosological distinction, based on prior group-level analyses. Advanced machine learning techniques, using unsupervised (hierarchical clustering) and supervised (regularized logistic regression algorithm and nested-cross-validation) were applied to a dataset of 202 patients with functional psychosis (schizophrenia n = 120, affective psychosis, n = 82). Patients were initially assessed with the Present State Examination (PSE), and followed up 2.5 years later, when DSM III diagnoses were applied (independent of initial PSE). Based on PSE syndromes, unsupervised learning discriminated depressive (approximately unbiased probability, AUP = 0.92) and mania/psychosis (AUP = 0.94) clusters. The mania/psychosis cluster further split into two groups - a mania (AUP = 0.84) and a psychosis cluster (AUP = 0.88). Supervised machine learning classified schizophrenia or affective psychosis with 83.66% (95% CI = 77.83% to 88.48%) accuracy. Area under the ROC curve (AUROC) was 89.14%. True positive rate for schizophrenia was 88.24% (95%CI = 81.05-93.42%) and affective psychosis 77.11% (95%CI = 66.58-85.62). Classification accuracy and AUROC remained high when PSE syndromes corresponding to affective symptoms (those that corresponded to the depressive and mania clusters) were removed. PSE syndromes, based on clinical symptoms, therefore discriminated between schizophrenia and affective psychosis, suggesting validity to these diagnostic constructs., (Copyright © 2018. Published by Elsevier B.V.)
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- 2018
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31. Mutation burden and other molecular markers of prognosis in colorectal cancer treated with curative intent: results from the QUASAR 2 clinical trial and an Australian community-based series.
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Domingo E, Camps C, Kaisaki PJ, Parsons MJ, Mouradov D, Pentony MM, Makino S, Palmieri M, Ward RL, Hawkins NJ, Gibbs P, Askautrud H, Oukrif D, Wang H, Wood J, Tomlinson E, Bark Y, Kaur K, Johnstone EC, Palles C, Church DN, Novelli M, Danielsen HE, Sherlock J, Kerr D, Kerr R, Sieber O, Taylor JC, and Tomlinson I
- Subjects
- Australia, Colorectal Neoplasms pathology, Colorectal Neoplasms therapy, Gene Drive Technology, Humans, Neoplasm Staging, Prognosis, Sequence Analysis, DNA, Biomarkers, Tumor, Colorectal Neoplasms genetics, Mutation
- Abstract
Background: Molecular indicators of colorectal cancer prognosis have been assessed in several studies, but most analyses have been restricted to a handful of markers. We aimed to identify prognostic biomarkers for colorectal cancer by sequencing panels of multiple driver genes., Methods: In stage II or III colorectal cancers from the QUASAR 2 open-label randomised phase 3 clinical trial and an Australian community-based series, we used targeted next-generation sequencing of 82 and 113 genes, respectively, including the main colorectal cancer drivers. We investigated molecular pathways of tumorigenesis, and analysed individual driver gene mutations, combinations of mutations, or global measures such as microsatellite instability (MSI) and mutation burden (total number of non-synonymous mutations and coding indels) for associations with relapse-free survival in univariable and multivariable models, principally Cox proportional hazards models., Findings: In QUASAR 2 (511 tumours), TP53, KRAS, BRAF, and GNAS mutations were independently associated with shorter relapse-free survival (p<0·035 in all cases), and total somatic mutation burden with longer survival (hazard ratio [HR] 0·81 [95% CI 0·68-0·96]; p=0·014). MSI was not independently associated with survival (HR 1·12 [95% CI 0·57-2·19]; p=0·75). We successfully validated these associations in the Australian sample set (296 tumours). In a combined analysis of both the QUASAR 2 and the Australian sample sets, mutation burden was also associated with longer survival (HR 0·84 [95% CI 0·74-0·94]; p=0·004) after exclusion of MSI-positive and POLE mutant tumours. In an extended analysis of 1732 QUASAR 2 and Australian colorectal cancers for which KRAS, BRAF, and MSI status were available, KRAS and BRAF mutations were specifically associated with poor prognosis in MSI-negative cancers. MSI-positive cancers with KRAS or BRAF mutations had better prognosis than MSI-negative cancers that were wild-type for KRAS or BRAF. Mutations in the genes NF1 and NRAS from the MAPK pathway co-occurred, and mutations in the DNA damage-response genes TP53 and ATM were mutually exclusive. We compared a prognostic model based on the gold standard of clinicopathological variables and MSI with our new model incorporating clinicopathological variables, mutation burden, and driver mutations in KRAS, BRAF, and TP53. In both QUASAR 2 and the Australian cohort, our new model was significantly better (p=0·00004 and p=0·0057, respectively, based on a likelihood ratio test)., Interpretation: Multigene panels identified two previously unreported prognostic associations in colorectal cancer involving TP53 mutation and total mutation burden, and confirmed associations with KRAS and BRAF. Even a modest-sized gene panel can provide important information for use in clinical practice and outperform MSI-based prognostic models., Funding: UK Technology Strategy Board, National Institute for Health Research Oxford Biomedical Research Centre, Cancer Australia Project, Cancer Council Victoria, Ludwig Institute for Cancer Research, Victorian Government., (Copyright © 2018 The Author(s). Published by Elsevier Ltd. This is an Open Access article under the CC BY 4.0 license. Published by Elsevier Ltd.. All rights reserved.)
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- 2018
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32. Polygenic risk for schizophrenia, transition and cortical gyrification: a high-risk study.
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Neilson E, Bois C, Clarke TK, Hall L, Johnstone EC, Owens DGC, Whalley HC, McIntosh AM, and Lawrie SM
- Subjects
- Adolescent, Adult, Female, Genetic Predisposition to Disease, Humans, Longitudinal Studies, Magnetic Resonance Imaging, Male, Polymorphism, Single Nucleotide, Prospective Studies, Risk Assessment, Young Adult, Multifactorial Inheritance, Schizophrenia genetics, Schizophrenia pathology, Temporal Lobe pathology
- Abstract
Background: Schizophrenia is a highly heritable disorder, linked to several structural abnormalities of the brain. More specifically, previous findings have suggested that increased gyrification in frontal and temporal regions are implicated in the pathogenesis of schizophrenia., Methods: The current study included participants at high familial risk of schizophrenia who remained well (n = 31), who developed sub-diagnostic symptoms (n = 28) and who developed schizophrenia (n = 9) as well as healthy controls (HC) (n = 16). We first tested whether individuals at high familial risk of schizophrenia carried an increased burden of trait-associated alleles using polygenic risk score analysis. We then assessed the extent to which polygenic risk was associated with gyral folding in the frontal and temporal lobes., Results: We found that individuals at high familial risk of schizophrenia who developed schizophrenia carried a significantly greater burden of risk-conferring variants for the disorder compared to those at high risk (HR) who developed sub-diagnostic symptoms or remained well and HC. Furthermore, within the HR cohort, there was a significant and positive association between schizophrenia polygenic risk score and bilateral frontal gyrification., Conclusions: These results suggest that polygenic risk for schizophrenia impacts upon early neurodevelopment to confer greater gyral folding in adulthood and an increased risk of developing the disorder.
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- 2018
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33. The value of additional bevacizumab in patients with high-risk stroma-high colon cancer. A study within the QUASAR2 trial, an open-label randomized phase 3 trial.
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Huijbers A, van Pelt GW, Kerr RS, Johnstone EC, Tollenaar RAEM, Kerr DJ, and Mesker WE
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- Aged, Bevacizumab administration & dosage, Capecitabine administration & dosage, Cohort Studies, Colonic Neoplasms pathology, Female, Follow-Up Studies, Humans, Male, Neoplasm Invasiveness, Prognosis, Risk Factors, Stromal Cells pathology, Survival Rate, Antineoplastic Combined Chemotherapy Protocols therapeutic use, Colonic Neoplasms drug therapy, Stromal Cells drug effects
- Abstract
Introduction: Patients with a high stroma percentage within the primary tumor have a poor prognosis. In this study, we investigate whether anti-angiogenic therapy might improve survival of patients with a stroma-high profile with potentially increased angiogenesis., Materials and Methods: Tissue samples of the primary tumor of 965 colon cancer patients participating in the QUASAR2 trial were analyzed for tumor-stroma ratio (TSR). Stroma-high (>50%) and stroma-low (≤50%) groups were evaluated with respect to survival., Results: Disease free survival (DFS) was significantly lower in the stroma-high group (HR 1.53, 95%CI 1.19-1.95, P = 0.001). No difference in DFS was seen with respect to treatment with capecitabine alone (CAP) or capecitabine with bevacizumab (CAPBEV) (Stroma-high HR 1.00, 95%CI 0.69-1.46, P = 0.996; stroma-low HR 1.02, 95%CI 0.75-1.41, P = 0.883). A significant difference in survival was seen comparing groups with or without vascular invasion (DFS P < 0.001). A correlation between vascular invasion and stroma-high was seen (χ
2 -test P = 0.043)., Discussion and Conclusions: The TSR confirmed to be a strong prognosticator for disease-free survival in a selected high-risk patient population. No benefit was found in response to treatment with bevacizumab when stratified for TSR. TSR showed to have an additional prognostic value in patients with vascular invasion present in the primary tumor., (© 2018 Wiley Periodicals, Inc.)- Published
- 2018
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34. Dissociation of Brain Activation in Autism and Schizotypal Personality Disorder During Social Judgments.
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Stanfield AC, Philip RCM, Whalley H, Romaniuk L, Hall J, Johnstone EC, and Lawrie SM
- Subjects
- Adult, Autism Spectrum Disorder diagnostic imaging, Cerebellum diagnostic imaging, Cerebral Cortex diagnostic imaging, Female, Humans, Judgment physiology, Magnetic Resonance Imaging, Male, Middle Aged, Schizotypal Personality Disorder diagnostic imaging, Young Adult, Autism Spectrum Disorder physiopathology, Brain Mapping methods, Cerebellum physiopathology, Cerebral Cortex physiopathology, Facial Recognition physiology, Schizotypal Personality Disorder physiopathology, Social Perception
- Abstract
Background: There are overlaps between autism and schizophrenia but these are particularly pronounced, especially in social domains, for higher functioning individuals with autism spectrum disorders (ASD) or schizotypal personality disorder (SPD). It is not known whether these overlapping social deficits result from shared or distinct brain mechanisms. We therefore compared social cognition in ASD and SPD using functional magnetic resonance imaging (fMRI)., Methods: Twenty-one individuals with SPD, 28 with ASD and 33 controls were compared with respect to clinical symptoms using the Positive and Negative Syndrome Scale; social cognition, using a social judgment task and Ekman 60 faces task; and brain activation using an fMRI task of social judgment., Results: The ASD and SPD groups showed few differences in symptoms or social cognition. However, fMRI showed that, compared to ASD, the SPD group showed significantly greater activation during social compared to gender judgments in the amygdala and 3 clusters: right posterior cerebellum, extending into fusiform and inferior temporal gyri; left posterior cerebellum; and left intraparietal sulcus extending through medial portions of the temporal gyri into the fusiform gyrus (all P < .05 family-wise error corrected). Control activations lay between the ASD and SPD groups., Conclusions: Although social cognitive deficits in ASD and SPD appear superficially similar they are the result of different brain mechanisms. These findings have implications for therapeutic interventions targeted at social dysfunction in these conditions., (© The Author 2017. Published by Oxford University Press on behalf of the Maryland Psychiatric Research Center.)
- Published
- 2017
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35. Links between Autism Spectrum Disorder Diagnostic Status and Family Quality of Life.
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McKechanie AG, Moffat VJ, Johnstone EC, and Fletcher-Watson S
- Abstract
Quality of life is often relatively lowered in families of children with additional needs, and this may be particularly the case where additional needs are accompanied by an autism spectrum disorder (ASD). Here we explore the effects of diagnostic status specifically, comparing families with children with an ASD diagnosis with others who a) have additional needs but no signs of ASD; and b) have additional needs and signs of ASD but no diagnosis. Mothers (n = 76) of children with additional needs completed standardised questionnaires about quality of life, stress, service provision, child behaviour and presence and severity of ASD traits. In addition, a group of mothers of typically developing young people (n = 17) completed standardised questionnaires on individual and family quality of life and on the behaviour of their son or daughter. Mothers of typically developing young people had significantly higher individual and family quality of life scores than each of the three other groups. Increased severity of ASD was associated with increased maternal stress, which in turn was associated with decreased family and maternal quality of life. The group reporting the lowest quality of life and the highest stress were the mothers of individuals with signs of ASD but no diagnosis. This pattern did not seem to be explained by lack of access to services, or rates of intellectual disability or challenging behaviour in this sub-group. The finding that poor quality of life and high stress was most apparent in the sub-group of mothers with children who had signs of ASD but did not have a diagnosis of ASD suggests that an interesting topic for further investigation is whether receipt of a diagnosis itself can positively influence quality of life and levels of maternal stress.
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- 2017
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36. Improved individualized prediction of schizophrenia in subjects at familial high risk, based on neuroanatomical data, schizotypal and neurocognitive features.
- Author
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Zarogianni E, Storkey AJ, Johnstone EC, Owens DG, and Lawrie SM
- Subjects
- Adolescent, Adult, Cognition, Family, Feasibility Studies, Female, Follow-Up Studies, Genetic Predisposition to Disease, Humans, Longitudinal Studies, Magnetic Resonance Imaging, Male, Multivariate Analysis, Neuropsychological Tests, Schizophrenia classification, Schizophrenia genetics, Support Vector Machine, Young Adult, Brain diagnostic imaging, Diagnosis, Computer-Assisted, Memory, Schizophrenia diagnosis, Schizophrenic Psychology, Schizotypal Personality Disorder psychology
- Abstract
To date, there are no reliable markers for predicting onset of schizophrenia in individuals at high risk (HR). Substantial promise is, however, shown by a variety of pattern classification approaches to neuroimaging data. Here, we examined the predictive accuracy of support vector machine (SVM) in later diagnosing schizophrenia, at a single-subject level, using a cohort of HR individuals drawn from multiply affected families and a combination of neuroanatomical, schizotypal and neurocognitive variables. Baseline structural magnetic resonance imaging (MRI), schizotypal and neurocognitive data from 17 HR subjects, who subsequently developed schizophrenia and a matched group of 17 HR subjects who did not make the transition, yet had psychotic symptoms, were included in the analysis. We employed recursive feature elimination (RFE), in a nested cross-validation scheme to identify the most significant predictors of disease transition and enhance diagnostic performance. Classification accuracy was 94% when a self-completed measure of schizotypy, a declarative memory test and structural MRI data were combined into a single learning algorithm; higher than when either quantitative measure was used alone. The discriminative neuroanatomical pattern involved gray matter volume differences in frontal, orbito-frontal and occipital lobe regions bilaterally as well as parts of the superior, medial temporal lobe and cerebellar regions. Our findings suggest that an early SVM-based prediction of schizophrenia is possible and can be improved by combining schizotypal and neurocognitive features with neuroanatomical variables. However, our predictive model needs to be tested by classifying a new, independent HR cohort in order to estimate its validity., (Copyright © 2016 Elsevier B.V. All rights reserved.)
- Published
- 2017
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37. SIRS 5th Biennial Schizophrenia International Research Meeting-Florence, April 2016: Possibilities and Pitfalls-Reflections on 42 Years in Academic Psychiatry and Lessons for a Suggested Repeat Performance.
- Author
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Johnstone EC
- Subjects
- Humans, Congresses as Topic, Physicians, Psychiatry methods, Schizophrenia therapy
- Published
- 2017
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38. Childhood adversity and hippocampal and amygdala volumes in a population at familial high risk of schizophrenia.
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Barker V, Bois C, Neilson E, Johnstone EC, Owens DGC, Whalley HC, McIntosh AM, and Lawrie SM
- Subjects
- Family, Female, Functional Laterality, Humans, Image Processing, Computer-Assisted, Longitudinal Studies, Magnetic Resonance Imaging, Male, Organ Size, Prospective Studies, Schizophrenia diagnostic imaging, Social Work, Stress, Psychological genetics, Young Adult, Adult Survivors of Child Adverse Events psychology, Amygdala diagnostic imaging, Genetic Predisposition to Disease, Hippocampus diagnostic imaging, Schizophrenia genetics, Stress, Psychological diagnostic imaging
- Abstract
Background: There is an established link between childhood adversity (CA) and schizophrenia. Hippocampus and amygdala abnormalities pre-date onset in those at high familial risk (fHR) of schizophrenia, but it is not clear whether these alterations are associated with CA in those at elevated risk of schizophrenia., Methods: We examined hippocampal and amygdala volumes in those at fHR who had been referred to a social worker or the Children's Panel compared to those who had not., Results: The right hippocampus and left amygdala were significantly smaller in those that had been referred to social work and Children's Panel., Conclusions: Our findings suggest that CA can influence structural changes in the brain in a cohort at fHR of schizophrenia. These findings provide further evidence that while genetic factors contribute to the structural changes found in schizophrenia, environmental factors such as CA can have a lasting impact on specific brain regions., (Copyright © 2016 Elsevier B.V. All rights reserved.)
- Published
- 2016
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39. Negative symptoms and longitudinal grey matter tissue loss in adolescents at risk of psychosis: preliminary findings from a 6-year follow-up study.
- Author
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McKechanie AG, Moorhead TW, Stanfield AC, Whalley HC, Johnstone EC, Lawrie SM, and Owens DG
- Subjects
- Adolescent, Adult, Cerebellum diagnostic imaging, Cerebral Cortex diagnostic imaging, Female, Follow-Up Studies, Gray Matter diagnostic imaging, Humans, Magnetic Resonance Imaging, Male, Psychotic Disorders diagnostic imaging, Schizophrenia diagnostic imaging, Temporal Lobe diagnostic imaging, Young Adult, Cerebellum pathology, Cerebral Cortex pathology, Disease Progression, Gray Matter pathology, Psychotic Disorders pathology, Psychotic Disorders physiopathology, Schizophrenia pathology, Schizophrenia physiopathology, Temporal Lobe pathology
- Abstract
Background: Negative symptoms are perhaps the most disabling feature of schizophrenia. Their pathogenesis remains poorly understood and it has been difficult to assess their development over time with imaging techniques., Aims: To examine, using tensor-based structural imaging techniques, whether there are regions of progressive grey matter volume change associated with the development of negative symptoms., Method: A total of 43 adolescents at risk of psychosis were examined using magnetic resonance imaging and whole brain tensor-based morphometry at two time points, 6 years apart., Results: When comparing the individuals with significant negative symptoms with the remaining participants, we identified five regions of significant grey matter tissue loss over the 6-year period. These regions included the left temporal lobe, the left cerebellum, the left posterior cingulate and the left inferior parietal sulcus., Conclusions: Negative symptoms are associated with longitudinal grey matter tissue loss. The regions identified include areas associated with psychotic symptoms more generally but also include regions uniquely associated with negative symptoms., (© The Royal College of Psychiatrists 2016.)
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- 2016
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40. Longitudinal changes in hippocampal volume in the Edinburgh High Risk Study of Schizophrenia.
- Author
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Bois C, Levita L, Ripp I, Owens DCG, Johnstone EC, Whalley HC, and Lawrie SM
- Subjects
- Adolescent, Adult, Aged, Aging pathology, Amygdala diagnostic imaging, Corpus Striatum diagnostic imaging, Female, Follow-Up Studies, Genetic Predisposition to Disease, Humans, Linear Models, Longitudinal Studies, Magnetic Resonance Imaging, Male, Middle Aged, Organ Size, Risk, Thalamus diagnostic imaging, Young Adult, Hippocampus diagnostic imaging, Schizophrenia diagnostic imaging
- Abstract
Schizophrenia is associated with structural brain abnormalities that are likely to be present before disease onset. It remains unclear to what extent these represent general vulnerability indicators or are associated with the developing clinical state itself. It also remains unclear whether such state or trait alterations may be evident at any given time-point, or whether they progress over time. To investigate this, structural brain scans were acquired at two time-points (mean scan-interval 1.87years) in a cohort of young unaffected individuals at high familial risk of schizophrenia (baseline, n=142; follow-up, n=64) and healthy controls (baseline, n=36; follow-up, n=18). Sub-cortical reconstructions of the hippocampus and amygdala were generated using the longitudinal pipeline available with Freesurfer. The high risk cohort was subdivided into individuals that remained well during the study (HR[well], baseline, n=68; follow-up, n=30), transient and/or partial symptoms that were insufficient to support a formal diagnosis (HR[symp], baseline, n=57; follow-up, n=26) and individuals that subsequently developed schizophrenia according to ICD-10 criteria (HR[ill], baseline, n=17; follow-up, n=8). Longitudinal change in the hippocampus and amygdala was compared, focusing first on overall differences between high-risk individuals and controls and then on sub-group differences within the high-risk cohort. We found a significantly altered developmental trajectory for all high risk individuals compared to controls, with controls showing a significant increase in hippocampal volume over time compared to those at high risk. We did not find evidence of altered longitudinal trajectories based on clinical outcome within the high risk cohort. These results suggest that an altered developmental trajectory of hippocampal volume is associated with a general familial predisposition to develop schizophrenia, as this alteration was not related to subsequent clinical outcome., (Copyright © 2014. Published by Elsevier B.V.)
- Published
- 2016
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41. Childhood adversity and cortical thickness and surface area in a population at familial high risk of schizophrenia.
- Author
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Barker V, Bois C, Johnstone EC, Owens DG, Whalley HC, McIntosh AM, and Lawrie SM
- Subjects
- Adolescent, Adult, Cerebral Cortex diagnostic imaging, Female, Genetic Predisposition to Disease, Gray Matter diagnostic imaging, Humans, Image Processing, Computer-Assisted, Magnetic Resonance Imaging, Male, Organ Size, Risk, Schizophrenia diagnostic imaging, Schizophrenia genetics, Young Adult, Adult Survivors of Child Adverse Events, Cerebral Cortex pathology, Gray Matter pathology, Schizophrenia pathology
- Abstract
Background: There is now a well-established link between childhood adversity (CA) and schizophrenia. Similar structural abnormalities to those found in schizophrenia including alterations in grey-matter volume have also been shown in those who experience CA., Method: We examined whether global estimates of cortical thickness or surface area were altered in those familial high-risk subjects who had been referred to a social worker or the Children's Panel compared to those who had not., Results: We found that the cortical surface area of those who were referred to the Children's Panel was significantly smaller than those who had not been referred, but cortical thickness was not significantly altered. There was also an effect of social work referral on cortical surface area but not on thickness., Conclusions: Cortical surface area increases post-natally more than cortical thickness. Our findings suggest that CA can influence structural changes in the brain and it is likely to have a greater impact on cortical surface area than on cortical thickness.
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- 2016
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42. Charting the landscape of priority problems in psychiatry, part 2: pathogenesis and aetiology.
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Stephan KE, Binder EB, Breakspear M, Dayan P, Johnstone EC, Meyer-Lindenberg A, Schnyder U, Wang XJ, Bach DR, Fletcher PC, Flint J, Frank MJ, Heinz A, Huys QJM, Montague PR, Owen MJ, and Friston KJ
- Subjects
- Humans, Mental Disorders etiology, Mental Disorders pathology, Psychiatry, Research
- Abstract
This is the second of two companion papers proposing priority problems for research on mental disorders. Whereas the first paper focuses on questions of nosology and diagnosis, this Personal View concerns pathogenesis and aetiology of psychiatric diseases. We hope that this (non-exhaustive and subjective) list of problems, nominated by scientists and clinicians from different fields and institutions, provides guidance and perspectives for choosing future directions in psychiatric science., (Copyright © 2016 Elsevier Ltd. All rights reserved.)
- Published
- 2016
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43. Charting the landscape of priority problems in psychiatry, part 1: classification and diagnosis.
- Author
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Stephan KE, Bach DR, Fletcher PC, Flint J, Frank MJ, Friston KJ, Heinz A, Huys QJM, Owen MJ, Binder EB, Dayan P, Johnstone EC, Meyer-Lindenberg A, Montague PR, Schnyder U, Wang XJ, and Breakspear M
- Subjects
- Humans, Mental Disorders classification, Mental Disorders diagnosis, Psychiatry, Research
- Abstract
Contemporary psychiatry faces major challenges. Its syndrome-based disease classification is not based on mechanisms and does not guide treatment, which largely depends on trial and error. The development of therapies is hindered by ignorance of potential beneficiary patient subgroups. Neuroscientific and genetics research have yet to affect disease definitions or contribute to clinical decision making. In this challenging setting, what should psychiatric research focus on? In two companion papers, we present a list of problems nominated by clinicians and researchers from different disciplines as candidates for future scientific investigation of mental disorders. These problems are loosely grouped into challenges concerning nosology and diagnosis (this Personal View) and problems related to pathogenesis and aetiology (in the companion Personal View). Motivated by successful examples in other disciplines, particularly the list of Hilbert's problems in mathematics, this subjective and eclectic list of priority problems is intended for psychiatric researchers, helping to re-focus existing research and providing perspectives for future psychiatric science., (Copyright © 2016 Elsevier Ltd. All rights reserved.)
- Published
- 2016
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44. Grey matter networks in people at increased familial risk for schizophrenia.
- Author
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Tijms BM, Sprooten E, Job D, Johnstone EC, Owens DG, Willshaw D, Seriès P, and Lawrie SM
- Subjects
- Adolescent, Brain Mapping, Female, Humans, Image Processing, Computer-Assisted, Magnetic Resonance Imaging, Male, Prodromal Symptoms, Psychiatric Status Rating Scales, Risk, Schizophrenia genetics, Young Adult, Brain pathology, Gray Matter pathology, Nerve Net pathology, Schizophrenia pathology
- Abstract
Grey matter brain networks are disrupted in schizophrenia, but it is still unclear at which point during the development of the illness these disruptions arise and whether these can be associated with behavioural predictors of schizophrenia. We investigated if single-subject grey matter networks were disrupted in a sample of people at familial risk of schizophrenia. Single-subject grey matter networks were extracted from structural MRI scans of 144 high risk subjects, 32 recent-onset patients and 36 healthy controls. The following network properties were calculated: size, connectivity density, degree, path length, clustering coefficient, betweenness centrality and small world properties. People at risk of schizophrenia showed decreased path length and clustering in mostly prefrontal and temporal areas. Within the high risk sample, the path length of the posterior cingulate cortex and the betweenness centrality of the left inferior frontal operculum explained 81% of the variance in schizotypal cognitions, which was previously shown to be the strongest behavioural predictor of schizophrenia in the study. In contrast, local grey matter volume measurements explained 48% of variance in schizotypy. The present results suggest that single-subject grey matter networks can quantify behaviourally relevant biological alterations in people at increased risk for schizophrenia before disease onset., (Copyright © 2015 Elsevier B.V. All rights reserved.)
- Published
- 2015
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45. Cortical Surface Area Differentiates Familial High Risk Individuals Who Go on to Develop Schizophrenia.
- Author
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Bois C, Ronan L, Levita L, Whalley HC, Giles S, McIntosh AM, Fletcher PC, Owens DC, Johnstone EC, and Lawrie SM
- Subjects
- Adolescent, Adult, Family Health, Female, Genetic Predisposition to Disease, Humans, Male, Prognosis, Prospective Studies, Risk Factors, Schizophrenia etiology, Young Adult, Cerebral Cortex pathology, Schizophrenia pathology
- Abstract
Background: Schizophrenia is associated with structural brain abnormalities that may be present before disease onset. It remains unclear whether these represent general vulnerability indicators or are associated with the clinical state itself., Methods: To investigate this, structural brain scans were acquired at two time points (mean scan interval 1.87 years) in a cohort of individuals at high familial risk of schizophrenia (n = 142) and control subjects (n = 36). Cortical reconstructions were generated using FreeSurfer. The high-risk cohort was subdivided into individuals that remained well during the study, individuals that had transient psychotic symptoms, and individuals that subsequently became ill. Baseline measures and longitudinal change in global estimates of thickness and surface area and lobar values were compared, focusing on overall differences between high-risk individuals and control subjects and then on group differences within the high-risk cohort., Results: Longitudinally, control subjects showed a significantly greater reduction in cortical surface area compared with the high-risk group. Within the high-risk group, differences in surface area at baseline predicted clinical course, with individuals that subsequently became ill having significantly larger surface area than individuals that remained well during the study. For thickness, longitudinal reductions were most prominent in the frontal, cingulate, and occipital lobes in all high-risk individuals compared with control subjects., Conclusions: Our results suggest that larger surface areas at baseline may be associated with mechanisms that go above and beyond a general familial disposition. A relative preservation over time of surface area, coupled with a thinning of the cortex compared with control subjects, may serve as vulnerability markers of schizophrenia., (Copyright © 2015 Society of Biological Psychiatry. Published by Elsevier Inc. All rights reserved.)
- Published
- 2015
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46. Brief Report: The Association of Autistic Traits and Behavioural Patterns in Adolescents Receiving Special Educational Assistance.
- Author
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Paul AR, McKechanie AG, Johnstone EC, Owens DG, and Stanfield AC
- Subjects
- Adolescent, Aggression, Attention, Autistic Disorder psychology, Female, Humans, Male, Autistic Disorder rehabilitation, Early Intervention, Educational, Social Skills
- Abstract
Introduction: The study aim was to describe behaviours associated with autistic traits., Methods: The Childhood Behaviour Checklist (CBCL) and Social Communication Questionnaire (SCQ) were used as measures of behaviour and autistic traits respectively in 331 adolescents receiving educational support. CBCL scores were compared between three groups defined by SCQ score: autism, pervasive developmental disorder (PDD) and non-PDD., Results: The PDD and autism groups had significantly higher scores on the CBCL than the non-PDD group across all CBCL scales except Delinquent Behaviour. On seven of the eight scales, there was no difference between the autism and PDD groups., Conclusion: Those with PDD or autism display significantly higher levels of withdrawal, somatic complaints, anxiety/depression, social, thought and attention problems, and aggressive behaviour.
- Published
- 2015
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47. Differential Efficacy of Nicotine Replacement Among Overweight and Obese Women Smokers.
- Author
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Strong DR, David SP, Johnstone EC, Aveyard P, Murphy MF, and Munafò MR
- Subjects
- Administration, Cutaneous, Adult, Double-Blind Method, Female, Follow-Up Studies, Humans, Male, Middle Aged, Obesity drug therapy, Obesity epidemiology, Overweight epidemiology, Smoking epidemiology, Treatment Outcome, Body Mass Index, Nicotine administration & dosage, Overweight drug therapy, Smoking drug therapy, Smoking Cessation methods, Tobacco Use Cessation Devices
- Abstract
Introduction: Rates of obesity are higher among more dependent smokers and 37%-65% of smokers seeking cessation treatment are overweight or obese. Overweight or obese smokers may possess metabolic and neurobiological features that contribute to difficulty achieving cessation using front-line nicotine replacement products. Attention to factors that facilitate effective cessation treatment in this vulnerable population is needed to significantly reduce mortality risk among overweight and obese smokers., Method: This secondary analysis of 2 large trials of transdermal nicotine replacement in general medical practices evaluated the hypothesis that higher body mass index (BMI) would moderate the efficacy of the nicotine patch. We examined the potential for gender to further moderate the relationship between BMI and treatment efficacy., Results: In the placebo controlled trial (N = 1,621), 21-mg patch was no more effective than placebo for assisting biochemically verified point prevalence abstinence up to 1 year after quitting for women with higher BMI, but appeared to be effective for men at normal or high BMI (gender × BMI beta = -0.22, p = .004). We did not find differential long-term cessation outcomes among male or female smokers in the 15-mg patch trial (n = 705). However, we observed significantly higher rates of early lapse among women with higher BMI treated with nicotine patch across both trials., Conclusion: These results suggest that increased BMI may affect the efficacy of nicotine patch on reducing risk of early lapse in women. Additional research is needed to explore mechanisms of risk for decreased efficacy of this commonly used cessation aid., (© The Author 2014. Published by Oxford University Press on behalf of the Society for Research on Nicotine and Tobacco. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)
- Published
- 2015
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48. Hippocampal, amygdala and nucleus accumbens volume in first-episode schizophrenia patients and individuals at high familial risk: A cross-sectional comparison.
- Author
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Bois C, Levita L, Ripp I, Owens DC, Johnstone EC, Whalley HC, and Lawrie SM
- Subjects
- Adolescent, Adult, Analysis of Variance, Cross-Sectional Studies, Female, Functional Laterality, Humans, Image Processing, Computer-Assisted, Magnetic Resonance Imaging, Male, Retrospective Studies, Young Adult, Amygdala pathology, Hippocampus pathology, Nucleus Accumbens pathology, Schizophrenia pathology
- Abstract
It is unknown whether brain changes occur prior to onset of schizophrenia or after it develops. Prospective familial high risk studies provide a good method to investigate this. In the Edinburgh High Risk Study, structural MRI scans of 150 young individuals at familial high risk of schizophrenia, 34 patients with first-episode schizophrenia and 36 matched controls were obtained. Of the high risk participants with scans suitable for analysis, 17 developed schizophrenia after the scans were taken, whilst 57 experienced isolated or sub-clinical psychotic symptoms, and 70 remained well. We used Freesurfer to extract volumetric measurements of the hippocampus, amygdala and nucleus accumbens with the aim of assessing whether any alterations found were present in all those at high risk, or selectively in the high risk cohort based on future clinical outcome, or only in those experiencing their first-episode of psychosis. We found no significant differences in any examined regions between controls and those at high risk, or between those at high risk who later developed schizophrenia and those who remained well. However, patients with first-episode schizophrenia demonstrated significant volumetric reductions in the bilateral hippocampus, left amygdala, and right nucleus accumbens compared to high risk individuals and healthy controls, which were not significantly associated with the intake of anti-psychotic medication or duration of illness. We found that patients had significantly smaller left amygdalae and bilateral hippocampus compared to HR[ill]. Our findings suggest that volumetric reductions of the hippocampus, amygdala and nucleus accumbens occur early in the first-episode of psychosis. The apparent absence of high risk versus control differences we found using Freesurfer is at odds with our previous studies conducted on the same sample, and possible methodological reasons for these apparent discrepancies are discussed., (Copyright © 2015 Elsevier B.V. All rights reserved.)
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- 2015
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49. Aberrant P53 expression lacks prognostic or predictive significance in colorectal cancer: results from the VICTOR trial.
- Author
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McGregor MJ, Fadhil W, Wharton R, Yanagisawa Y, Presz M, Pritchard A, Womack C, Dutton S, Kerr RS, Kerr DJ, Johnstone EC, and Ilyas M
- Subjects
- Biomarkers, Colorectal Neoplasms genetics, Colorectal Neoplasms mortality, Colorectal Neoplasms pathology, Genes, p53, Humans, Immunohistochemistry, Mutation, Neoplasm Staging, Prognosis, Colorectal Neoplasms drug therapy, Lactones therapeutic use, Sulfones therapeutic use, Tumor Suppressor Protein p53 analysis
- Abstract
Aim: Biomarkers with prognostic and predictive value can help stratify patients with colorectal cancer (CRC) into appropriate treatment groups. We sought to evaluate the clinical utility of P53 protein expression as a biomarker in VICTOR, a large phase III trial of rofecoxib in stage II and III CRC., Patients and Methods: Tissue micro arrays were constructed from 884 tumors and the expression of P53 was examined by immunohistochemistry. Tumors were dichotomised as either P53-positive (nuclear expression in >10% of cells or the 'absent' pattern, both representing TP53 mutation) or P53-negative (nuclear expression in <10% of cells)., Results: Aberrant P53 expression was found in 65% (482/740) of patients. It was associated with distal location (p<0.001) and stage III disease (p<0.001). No effect was observed on disease-free or overall survival, and there was no interaction with chemotherapy or radiotherapy., Conclusion: Analysis of P53 expression in the patients recruited to the VICTOR trial confirmed that P53 expression is associated with site and stage of CRC. However, independently, this biomarker has neither prognostic nor predictive utility in this cohort of patients., (Copyright© 2015 International Institute of Anticancer Research (Dr. John G. Delinassios), All rights reserved.)
- Published
- 2015
50. Investigating the possible causal association of smoking with depression and anxiety using Mendelian randomisation meta-analysis: the CARTA consortium.
- Author
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Taylor AE, Fluharty ME, Bjørngaard JH, Gabrielsen ME, Skorpen F, Marioni RE, Campbell A, Engmann J, Mirza SS, Loukola A, Laatikainen T, Partonen T, Kaakinen M, Ducci F, Cavadino A, Husemoen LLN, Ahluwalia TS, Jacobsen RK, Skaaby T, Ebstrup JF, Mortensen EL, Minica CC, Vink JM, Willemsen G, Marques-Vidal P, Dale CE, Amuzu A, Lennon LT, Lahti J, Palotie A, Räikkönen K, Wong A, Paternoster L, Wong AP, Horwood LJ, Murphy M, Johnstone EC, Kennedy MA, Pausova Z, Paus T, Ben-Shlomo Y, Nohr EA, Kuh D, Kivimaki M, Eriksson JG, Morris RW, Casas JP, Preisig M, Boomsma DI, Linneberg A, Power C, Hyppönen E, Veijola J, Jarvelin MR, Korhonen T, Tiemeier H, Kumari M, Porteous DJ, Hayward C, Romundstad PR, Smith GD, and Munafò MR
- Subjects
- Adolescent, Adult, Aged, Causality, Female, Humans, Male, Mendelian Randomization Analysis, Middle Aged, Nerve Tissue Proteins genetics, Receptors, Nicotinic genetics, Smoking genetics, Young Adult, Anxiety epidemiology, Anxiety Disorders epidemiology, Depression epidemiology, Depressive Disorder epidemiology, Smoking epidemiology, Stress, Psychological epidemiology
- Abstract
Objectives: To investigate whether associations of smoking with depression and anxiety are likely to be causal, using a Mendelian randomisation approach., Design: Mendelian randomisation meta-analyses using a genetic variant (rs16969968/rs1051730) as a proxy for smoking heaviness, and observational meta-analyses of the associations of smoking status and smoking heaviness with depression, anxiety and psychological distress., Participants: Current, former and never smokers of European ancestry aged ≥16 years from 25 studies in the Consortium for Causal Analysis Research in Tobacco and Alcohol (CARTA)., Primary Outcome Measures: Binary definitions of depression, anxiety and psychological distress assessed by clinical interview, symptom scales or self-reported recall of clinician diagnosis., Results: The analytic sample included up to 58 176 never smokers, 37 428 former smokers and 32 028 current smokers (total N=127 632). In observational analyses, current smokers had 1.85 times greater odds of depression (95% CI 1.65 to 2.07), 1.71 times greater odds of anxiety (95% CI 1.54 to 1.90) and 1.69 times greater odds of psychological distress (95% CI 1.56 to 1.83) than never smokers. Former smokers also had greater odds of depression, anxiety and psychological distress than never smokers. There was evidence for positive associations of smoking heaviness with depression, anxiety and psychological distress (ORs per cigarette per day: 1.03 (95% CI 1.02 to 1.04), 1.03 (95% CI 1.02 to 1.04) and 1.02 (95% CI 1.02 to 1.03) respectively). In Mendelian randomisation analyses, there was no strong evidence that the minor allele of rs16969968/rs1051730 was associated with depression (OR=1.00, 95% CI 0.95 to 1.05), anxiety (OR=1.02, 95% CI 0.97 to 1.07) or psychological distress (OR=1.02, 95% CI 0.98 to 1.06) in current smokers. Results were similar for former smokers., Conclusions: Findings from Mendelian randomisation analyses do not support a causal role of smoking heaviness in the development of depression and anxiety., (Published by the BMJ Publishing Group Limited. For permission to use (where not already granted under a licence) please go to http://group.bmj.com/group/rights-licensing/permissions.)
- Published
- 2014
- Full Text
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