Virtuous violence : a social identity approach to understanding the politics of prejudice in inter-group relations

The aim of the thesis is to provide a social identity account of the politics of mobilisation: based on hatred mostly, in contrast with accounts of solidarity. The bulk of the thesis concentrates on exploring how and why is prejudice in the form of hatred mobilised in inter-group relations. Three studies parse the structure of hate discourse of Hindu right-wing groups in India. Study 1 and study 2 are qualitative studies that analyse the production of hate in two mediums of communication, while study 3 is an experimental study demonstrating the reception of hate. The studies analyse the structure of hate discourse with the theoretical lens of a social identity framework to explicate a context of categories and category-relations, while colouring in the contents of the categories with data from India. The first contention is, if a virtuous in-group can be construed as under threat from an out-group, then, the annihilation of the other can be justified as the defence of virtue. In the other words, violence becomes virtuous. The second contention is, the process that motivates out-group hate discourse derives from struggles over intra-group authority. That is, out-group threats are invoked in order to condemn political rivals for in-group power as not representing the group and not defending group interests. This sets up the foil for the leader to position ‘self’ as the ideal leader who protects and represents the in-group, while undermining the credibility of the political rival. Study 4 is a qualitative study analysing counter-hegemonic discourse on mobilisations against the rhetoric of hatred. Taken together, the first 3 studies argue that hatred is not an inherent feature of individuals or a natural fall-out of inter-group processes, it is mobilised for specific political aims. The fourth study looks at the dimensions with which other leaders counteract the politics of hate; when hatred can be mobilised, so can solidarity. The theoretical implications and limitations have been discussed

Social cognition in children with epilepsy in mainstream education

AIM To establish whether deficits in social cognition are present in children with generalised or focal epilepsy in mainstream education, and whether any relation exists between social cognition, communication, and behaviour measures. METHOD In a cross-sectional study, children with an epilepsy-only diagnoses in mainstream education (n=20 with generalized epilepsy; eight males, 12 females; mean age 11y 6mo, SD 2y 6mo; and n=27 with focal epilepsy; 12 males, 15 females; mean age 11y 8mo, SD 2y 2mo) and comparison participants (n=57; 28 males, 29 females; mean age 11y 2mo, SD 2y 4mo) were administered the Strange Stories task and the Mind in the Eyes task, as well as an IQ assessment. Parents completed the Children’s Communication Checklist-2 and the Child Behavior Checklist (CBCL). RESULTS Both groups of children with epilepsy performed more poorly than control children on the Mental Stories component of the Strange Stories task, F(2,101)=3.2, p<0.001. Performance on Mental Stories was related to pragmatic communication, but only in the generalized epilepsy group (r=0.51, p=0.03, 95% CI=0.2–0.8). There were no differences between epilepsy groups or control participants in the Mind in the Eyes task, F(2,101)=0.4, p=0.4. INTERPRETATION Children with ‘epilepsy only’ are at risk of deficits in social cognition and may require appropriate support

Parkinson's disease and dopaminergic therapy—differential effects on movement, reward and cognition

Cognitive deficits are very common in Parkinson's disease particularly for ‘executive functions’ associated with frontal cortico-striatal networks. Previous work has identified deficits in tasks that require attentional control like task-switching, and reward-based tasks like gambling or reversal learning. However, there is a complex relationship between the specific cognitive problems faced by an individual patient, their stage of disease and dopaminergic treatment. We used a bimodality continuous performance task during fMRI to examine how patients with Parkinson's disease represent the prospect of reward and switch between competing task rules accordingly. The task-switch was not separately cued but was based on the implicit reward relevance of spatial and verbal dimensions of successive compound stimuli. Nineteen patients were studied in relative ‘on’ and ‘off’ states, induced by dopaminergic medication withdrawal (Hoehn and Yahr stages 1–4). Patients were able to successfully complete the task and establish a bias to one or other dimension in order to gain reward. However the lateral prefrontal cortex and caudate nucleus showed a non-linear U-shape relationship between motor disease severity and regional brain activation. Dopaminergic treatment led to a shift in this U-shape function, supporting the hypothesis of differential neurodegeneration in separate motor and cognitive cortico–striato–thalamo–cortical circuits. In addition, anterior cingulate activation associated with reward expectation declined with more severe disease, whereas activation following actual rewards increased with more severe disease. This may facilitate a change in goal-directed behaviours from deferred predicted rewards to immediate actual rewards, particularly when on dopaminergic treatment. We discuss the implications for investigation and optimal treatment of this common condition at different stages of disease

Radiofármacos PET

Dada la tasa actual de evolución de la biología molecular de los receptores del SNC, la diferencia entre el número de radiotrazadores disponibles y las drogas potenciales va creciendo rápidamente99. Debemos por tanto insistir en que la utilidad de la tecnología PET en la búsqueda de nuevos agentes terapéuticos descansa sin duda en la obtención de compuestos marcados, por lo que la potenciación de la radioquímica y la radiofarmacia van a ser puntos clave en el desarrollo de este apasionante campo

The SANAD II study of the effectiveness and cost-effectiveness of levetiracetam, zonisamide, or lamotrigine for newly diagnosed focal epilepsy: an open-label, non-inferiority, multicentre, phase 4, randomised controlled trial

Background: Levetiracetam and zonisamide are licensed as monotherapy for patients with focal epilepsy, but there is uncertainty as to whether they should be recommended as first-line treatments because of insufficient evidence of clinical effectiveness and cost-effectiveness. We aimed to assess the long-term clinical effectiveness and cost-effectiveness of levetiracetam and zonisamide compared with lamotrigine in people with newly diagnosed focal epilepsy. Methods: This randomised, open-label, controlled trial compared levetiracetam and zonisamide with lamotrigine as first-line treatment for patients with newly diagnosed focal epilepsy. Adult and paediatric neurology services across the UK recruited participants aged 5 years or older (with no upper age limit) with two or more unprovoked focal seizures. Participants were randomly allocated (1:1:1) using a minimisation programme with a random element utilising factor to receive lamotrigine, levetiracetam, or zonisamide. Participants and investigators were not masked and were aware of treatment allocation. SANAD II was designed to assess non-inferiority of both levetiracetam and zonisamide to lamotrigine for the primary outcome of time to 12-month remission. Anti-seizure medications were taken orally and for participants aged 12 years or older the initial advised maintenance doses were lamotrigine 50 mg (morning) and 100 mg (evening), levetiracetam 500 mg twice per day, and zonisamide 100 mg twice per day. For children aged between 5 and 12 years the initial daily maintenance doses advised were lamotrigine 1·5 mg/kg twice per day, levetiracetam 20 mg/kg twice per day, and zonisamide 2·5 mg/kg twice per day. All participants were included in the intention-to-treat (ITT) analysis. The per-protocol (PP) analysis excluded participants with major protocol deviations and those who were subsequently diagnosed as not having epilepsy. Safety analysis included all participants who received one dose of any study drug. The non-inferiority limit was a hazard ratio (HR) of 1·329, which equates to an absolute difference of 10%. A HR greater than 1 indicated that an event was more likely on lamotrigine. The trial is registered with the ISRCTN registry, 30294119 (EudraCt number: 2012-001884-64). Findings: 990 participants were recruited between May 2, 2013, and June 20, 2017, and followed up for a further 2 years. Patients were randomly assigned to receive lamotrigine (n=330), levetiracetam (n=332), or zonisamide (n=328). The ITT analysis included all participants and the PP analysis included 324 participants randomly assigned to lamotrigine, 320 participants randomly assigned to levetiracetam, and 315 participants randomly assigned to zonisamide. Levetiracetam did not meet the criteria for non-inferiority in the ITT analysis of time to 12-month remission versus lamotrigine (HR 1·18; 97·5% CI 0·95–1·47) but zonisamide did meet the criteria for non-inferiority in the ITT analysis versus lamotrigine (1·03; 0·83–1·28). The PP analysis showed that 12-month remission was superior with lamotrigine than both levetiracetam (HR 1·32 [97·5% CI 1·05 to 1·66]) and zonisamide (HR 1·37 [1·08–1·73]). There were 37 deaths during the trial. Adverse reactions were reported by 108 (33%) participants who started lamotrigine, 144 (44%) participants who started levetiracetam, and 146 (45%) participants who started zonisamide. Lamotrigine was superior in the cost-utility analysis, with a higher net health benefit of 1·403 QALYs (97·5% central range 1·319–1·458) compared with 1·222 (1·110–1·283) for levetiracetam and 1·232 (1·112, 1·307) for zonisamide at a cost-effectiveness threshold of £20 000 per QALY. Cost-effectiveness was based on differences between treatment groups in costs and QALYs. Interpretation: These findings do not support the use of levetiracetam or zonisamide as first-line treatments for patients with focal epilepsy. Lamotrigine should remain a first-line treatment for patients with focal epilepsy and should be the standard treatment in future trials. Funding: National Institute for Health Research Health Technology Assessment programme

The SANAD II study of the effectiveness and cost-effectiveness of valproate versus levetiracetam for newly diagnosed generalised and unclassifiable epilepsy: an open-label, non-inferiority, multicentre, phase 4, randomised controlled trial

Background: Valproate is a first-line treatment for patients with newly diagnosed idiopathic generalised or difficult to classify epilepsy, but not for women of child-bearing potential because of teratogenicity. Levetiracetam is increasingly prescribed for these patient populations despite scarcity of evidence of clinical effectiveness or cost-effectiveness. We aimed to compare the long-term clinical effectiveness and cost-effectiveness of levetiracetam compared with valproate in participants with newly diagnosed generalised or unclassifiable epilepsy. Methods: We did an open-label, randomised controlled trial to compare levetiracetam with valproate as first-line treatment for patients with generalised or unclassified epilepsy. Adult and paediatric neurology services (69 centres overall) across the UK recruited participants aged 5 years or older (with no upper age limit) with two or more unprovoked generalised or unclassifiable seizures. Participants were randomly allocated (1:1) to receive either levetiracetam or valproate, using a minimisation programme with a random element utilising factors. Participants and investigators were aware of treatment allocation. For participants aged 12 years or older, the initial advised maintenance doses were 500 mg twice per day for levetiracetam and valproate, and for children aged 5–12 years, the initial daily maintenance doses advised were 25 mg/kg for valproate and 40 mg/kg for levetiracetam. All drugs were administered orally. SANAD II was designed to assess the non-inferiority of levetiracetam compared with valproate for the primary outcome time to 12-month remission. The non-inferiority limit was a hazard ratio (HR) of 1·314, which equates to an absolute difference of 10%. A HR greater than 1 indicated that an event was more likely on valproate. All participants were included in the intention-to-treat (ITT) analysis. Per-protocol (PP) analyses excluded participants with major protocol deviations and those who were subsequently diagnosed as not having epilepsy. Safety analyses included all participants who received one dose of any study drug. This trial is registered with the ISRCTN registry, 30294119 (EudraCt number: 2012-001884-64). Findings: 520 participants were recruited between April 30, 2013, and Aug 2, 2016, and followed up for a further 2 years. 260 participants were randomly allocated to receive levetiracetam and 260 participants to receive valproate. The ITT analysis included all participants and the PP analysis included 255 participants randomly allocated to valproate and 254 randomly allocated to levetiracetam. Median age of participants was 13·9 years (range 5·0–94·4), 65% were male and 35% were female, 397 participants had generalised epilepsy, and 123 unclassified epilepsy. Levetiracetam did not meet the criteria for non-inferiority in the ITT analysis of time to 12-month remission (HR 1·19 [95% CI 0·96–1·47]); non-inferiority margin 1·314. The PP analysis showed that the 12-month remission was superior with valproate than with levetiracetam. There were two deaths, one in each group, that were unrelated to trial treatments. Adverse reactions were reported by 96 (37%) participants randomly assigned to valproate and 107 (42%) participants randomly assigned to levetiracetam. Levetiracetam was dominated by valproate in the cost-utility analysis, with a negative incremental net health benefit of −0·040 (95% central range −0·175 to 0·037) and a probability of 0·17 of being cost-effectiveness at a threshold of £20 000 per quality-adjusted life-year. Cost-effectiveness was based on differences between treatment groups in costs and quality-adjusted life-years. Interpretation: Compared with valproate, levetiracetam was found to be neither clinically effective nor cost-effective. For girls and women of child-bearing potential, these results inform discussions about benefit and harm of avoiding valproate. Funding: National Institute for Health Research Health Technology Assessment Programme

Striatal and extra-striatal dopaminergic function in Parkinson's disease and the effect of dopamine agonist therapy on PD progression studies with 3D[¹â¸F]-dopa PET

This thesis has implemented three dimensional (3D) acquisition, reconstruction and analysis of dynamic 18F-dopa PET datasets. This has resulted in a marked improvement in sensitivity and reconstructed resolution leading to superior data quality compared with 2D acquired PET data and consequently, greater precision in the assessment of the functional integrity of the presynaptic dopaminergic system. In comparing 3D with 2D acquired 18F-dopa PET datasets in normal subjects, the mean putamen and caudate Ki° values in the 3D group (n=12) were 0.017 ± 0.002 min-1 and 0.016 ± 0.002 min-1, respectively, compared with the 2D group (n=8) values of 0.012 ± 0.003 min-1 and 0.013 ± 0.003 min-1.  The average coefficient of variation in the Ki° estimates of putamen and caudate values, were 12.7% and 11.7% for 3D and 24.8% and 25.0% for 2D, respectively. 3D 18F-dopa PET reproducibility, expressed as the mean Ki° difference (the mean difference in the Ki° values between the first and second scans) in the same normal subject, was 2.4% for putamen and 5.0% for caudate (n=5), compared with a previously reported 10% reproducibility for putamen data in 2D mode. Employing 3D 18F-dopa PET and contrary to all previously reported 2D PET studies, we have demonstrated bilateral putamen dopaminergic dysfunction in early hemi-PD (H;Y -1) with all individual putamen Ki° values contralateral to the clinically unaffected side falling below the normal range. This thesis has applied statistical parametric mapping (SPM) to 3D 18F-dopa PET datasets to localise focal changes in striatal and extrastriatal dopaminergic function in early and advanced PD and in progressing from early to advanced disease.  In early left hemi-PD, significant extra-striatal increases in Ki° were observed in the left anterior cingulate gyrus and dorsal midbrain region (p18F-dopa PET the relative rates of progression of early Parkinson’s disease (PD) in patients started on a dopamine agonist (ropinirole), or L-dopa therapy.EThOS - Electronic Theses Online ServiceGBUnited Kingdo