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"Freeman, Daniel"
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Optimizing oncolytic virotherapy in cancer treatment
In the wake of the success of modern immunotherapy, oncolytic viruses (OVs) are currently seen as a potential therapeutic option for patients with cancer who do not respond or fail to achieve durable responses following treatment with immune checkpoint inhibitors. OVs offer a multifaceted therapeutic platform because they preferentially replicate in tumour cells, can be engineered to express transgenes that augment their cytotoxic and immunostimulatory activities, and modulate the tumour microenvironment to optimize immune-mediated tumour eradication, both at locoregional and systemic sites of disease. Lysis of tumour cells releases tumour-specific antigens that trigger both the innate and adaptive immune systems. OVs also represent attractive combination partners with other systemically delivered agents by virtue of their highly favourable safety profiles. Rational combinations of OVs with different immune modifiers and/or antitumour agents, based on mechanisms of tumour resistance to immune-mediated attack, may benefit the large, currently underserved, population of patients who respond poorly to immune checkpoint inhibition.
Journal Article
Paranoia : my life understanding and treating extreme mistrust
What is paranoia? What makes us mistrustful? How can this be overcome? In this book, Daniel Freeman, a Professor of Clinical Psychology at Oxford, shows how suspicion is rife, how conspiracy theories circulate like never before and how all too often emotion trumps evidence.
Book
Head-mounted central venous access during optical recordings and manipulations of neural activity in mice
Establishing reliable intravenous catheterization in mice with optical implants allows the combination of neural manipulations and recordings with rapid, time-locked delivery of pharmacological agents. Here we present a procedure for handmade jugular vein catheters designed for head-mounted intravenous access and provide surgical and postoperative guidance for improved survival and patency. A head-mounted vascular access point eliminates the need for a back-mounted button in animals already receiving neural implants, thereby reducing sites of implantation. This protocol, which is readily adoptable by experimenters with previous training and experience in mouse surgery, enables repeated fiber photometry recordings or optogenetic manipulation during drug delivery in adult mice that are awake and behaving, whether head fixed or freely moving. With practice, an experienced surgeon requires ~30 min to perform catheterization on each mouse. Altogether, these techniques facilitate the reliable and repeated delivery of pharmacological agents in mouse models while simultaneously recording at high temporal resolution and/or manipulating neural populations.
Key points
This protocol details how to gain head-mounted access to the bloodstream to easily combine recording and/or manipulation of neuronal activity with the reliable delivery of pharmacological agents.
Compared with other drug delivery methods, the intravenous technique explored here eliminates the stress and pain caused by needle pokes. The surgical and postoperative guidance provided in the protocol improves animal survival and catheter patency, increasing the reliability and reproducibility of results.
A protocol describing how to implant head-mounted jugular vein catheters in mice. This procedure facilitates systemic drug administration in a variety of experimental settings, including optical recording and manipulation of neuronal activities and behavioral tests.
Journal Article
Now you see me 2 : the closer you look, the less you'll see
The Four Horsemen are on a new mission to steal a chip that can decrypt any electronic device in the world.
DVD
Injection fears and COVID-19 vaccine hesitancy
When vaccination depends on injection, it is plausible that the blood-injection-injury cluster of fears may contribute to hesitancy. Our primary aim was to estimate in the UK adult population the proportion of COVID-19 vaccine hesitancy explained by blood-injection-injury fears.
In total, 15 014 UK adults, quota sampled to match the population for age, gender, ethnicity, income and region, took part (19 January-5 February 2021) in a non-probability online survey. The Oxford COVID-19 Vaccine Hesitancy Scale assessed intent to be vaccinated. Two scales (Specific Phobia Scale-blood-injection-injury phobia and Medical Fear Survey-injections and blood subscale) assessed blood-injection-injury fears. Four items from these scales were used to create a factor score specifically for injection fears.
In total, 3927 (26.2%) screened positive for blood-injection-injury phobia. Individuals screening positive (22.0%) were more likely to report COVID-19 vaccine hesitancy compared to individuals screening negative (11.5%), odds ratio = 2.18, 95% confidence interval (CI) 1.97-2.40,
< 0.001. The population attributable fraction (PAF) indicated that if blood-injection-injury phobia were absent then this may prevent 11.5% of all instances of vaccine hesitancy, AF = 0.11; 95% CI 0.09-0.14,
< 0.001. COVID-19 vaccine hesitancy was associated with higher scores on the Specific Phobia Scale,
= 0.22,
< 0.001, Medical Fear Survey,
= 0.23,
= <0.001 and injection fears,
= 0.25,
< 0.001. Injection fears were higher in youth and in Black and Asian ethnic groups, and explained a small degree of why vaccine hesitancy is higher in these groups.
Across the adult population, blood-injection-injury fears may explain approximately 10% of cases of COVID-19 vaccine hesitancy. Addressing such fears will likely improve the effectiveness of vaccination programmes.
Journal Article
Explaining paranoia: cognitive and social processes in the occurrence of extreme mistrust
BackgroundParanoia—incorrectly thinking that others are deliberating trying to harm you—causes distress, undermines social interactions and leads to withdrawal. It presents across multiple psychiatric diagnoses.ObjectiveThe primary aim was to determine the extent that cognitive and social processes may explain paranoia. The secondary aim was to identify explanatory factors that distinguished paranoia and social anxiety.Methods10 382 UK adults, quota sampled to match the population for age, gender, ethnicity, income and region, participated in a non-probability survey. All participants completed a paranoia measure and assessments of cognitive and social processes. Structural equation modelling was conducted.Findings2586 (24.9%) participants described being mistrustful of other people. 1756 (16.9%) participants wanted help to trust more. 66.7% of variance in paranoia was explained by a model comprising (in descending order of importance): within-situation defence behaviours, negative images, negative self-beliefs, discrimination, dissociation, aberrant salience, anxiety sensitivity, agoraphobic distress, worry, less social support, agoraphobic avoidance, less analytical reasoning and alcohol use. All explanatory factors were associated with paranoia and social anxiety. Ten factors were more closely associated with paranoia than social anxiety, including discrimination, hallucinations, negative images, aberrant salience and alcohol use. Nine factors were more closely associated with social anxiety, including less positive self-belief, an external locus of control, worry and less analytical reasoning.ConclusionsMultiple causes are likely to be involved in paranoia. Cognitive and social processes may explain a high degree of paranoia.Clinical implicationsMultiple clear targets for intervention to reduce paranoia are identified.
Journal Article
COVID-19 vaccine hesitancy in the UK: the Oxford coronavirus explanations, attitudes, and narratives survey (Oceans) II
Our aim was to estimate provisional willingness to receive a coronavirus 2019 (COVID-19) vaccine, identify predictive socio-demographic factors, and, principally, determine potential causes in order to guide information provision.
A non-probability online survey was conducted (24th September-17th October 2020) with 5,114 UK adults, quota sampled to match the population for age, gender, ethnicity, income, and region. The Oxford COVID-19 vaccine hesitancy scale assessed intent to take an approved vaccine. Structural equation modelling estimated explanatory factor relationships.
71.7% (
=3,667) were willing to be vaccinated, 16.6% (
=849) were very unsure, and 11.7% (
=598) were strongly hesitant. An excellent model fit (RMSEA=0.05/CFI=0.97/TLI=0.97), explaining 86% of variance in hesitancy, was provided by beliefs about the collective importance, efficacy, side-effects, and speed of development of a COVID-19 vaccine. A second model, with reasonable fit (RMSEA=0.03/CFI=0.93/TLI=0.92), explaining 32% of variance, highlighted two higher-order explanatory factors: 'excessive mistrust' (
=0.51), including conspiracy beliefs, negative views of doctors, and need for chaos, and 'positive healthcare experiences' (
=-0.48), including supportive doctor interactions and good NHS care. Hesitancy was associated with younger age, female gender, lower income, and ethnicity, but socio-demographic information explained little variance (9.8%). Hesitancy was associated with lower adherence to social distancing guidelines.
COVID-19 vaccine hesitancy is relatively evenly spread across the population. Willingness to take a vaccine is closely bound to recognition of the collective importance. Vaccine public information that highlights prosocial benefits may be especially effective. Factors such as conspiracy beliefs that foster mistrust and erode social cohesion will lower vaccine up-take.
Journal Article
The revised Green et al., Paranoid Thoughts Scale (R-GPTS): psychometric properties, severity ranges, and clinical cut-offs
The Green et al., Paranoid Thoughts Scale (GPTS) - comprising two 16-item scales assessing ideas of reference (Part A) and ideas of persecution (Part B) - was developed over a decade ago. Our aim was to conduct the first large-scale psychometric evaluation.
In total, 10 551 individuals provided GPTS data. Four hundred and twenty-two patients with psychosis and 805 non-clinical individuals completed GPTS Parts A and B. An additional 1743 patients with psychosis and 7581 non-clinical individuals completed GPTS Part B. Factor analysis, item response theory, and receiver operating characteristic analyses were conducted.
The original two-factor structure of the GPTS had an inadequate model fit: Part A did not form a unidimensional scale and multiple items were locally dependant. A Revised-GPTS (R-GPTS) was formed, comprising eight-item ideas of reference and 10-item ideas of persecution subscales, which had an excellent model fit. All items in the new Reference (a = 2.09-3.67) and Persecution (a = 2.37-4.38) scales were strongly discriminative of shifts in paranoia and had high reliability across the spectrum of severity (a > 0.90). The R-GPTS score ranges are: average (Reference: 0-9; Persecution: 0-4); elevated (Reference: 10-15; Persecution: 5-10); moderately severe (Reference: 16-20; Persecution:11-17); severe (Reference: 21-24; Persecution: 18-27); and very severe (Reference: 25+; Persecution: 28+). Recommended cut-offs on the persecution scale are 11 to discriminate clinical levels of persecutory ideation and 18 for a likely persecutory delusion.
The psychometric evaluation indicated a need to improve the GPTS. The R-GPTS is a more precise measure, has excellent psychometric properties, and is recommended for future studies of paranoia.
Journal Article
A randomised controlled test of emotional attributes of a virtual coach within a virtual reality (VR) mental health treatment
We set out to test whether positive non-verbal behaviours of a virtual coach can enhance people's engagement in automated virtual reality therapy. 120 individuals scoring highly for fear of heights participated. In a two-by-two factor, between-groups, randomised design, participants met a virtual coach that varied in warmth of facial expression (with/without) and affirmative nods (with/without). The virtual coach provided a consultation about treating fear of heights. Participants rated the therapeutic alliance, treatment credibility, and treatment expectancy. Both warm facial expressions (group difference = 7.44 [3.25, 11.62], p = 0.001,
eta
p
2
=0.10) and affirmative nods (group difference = 4.36 [0.21, 8.58], p = 0.040,
eta
p
2
= 0.04) by the virtual coach independently increased therapeutic alliance. Affirmative nods increased the treatment credibility (group difference = 1.76 [0.34, 3.11], p = 0.015,
eta
p
2
= 0.05) and expectancy (group difference = 2.28 [0.45, 4.12], p = 0.015,
eta
p
2
= 0.05) but warm facial expressions did not increase treatment credibility (group difference = 0.64 [− 0.75, 2.02], p = 0.363,
eta
p
2
= 0.01) or expectancy (group difference = 0.36 [− 1.48, 2.20], p = 0.700,
eta
p
2
= 0.001). There were no significant interactions between head nods and facial expressions in the occurrence of therapeutic alliance (p = 0.403,
eta
p
2
= 0.01), credibility (p = 0.072,
eta
p
2
= 0.03), or expectancy (p = 0.275,
eta
p
2
= 0.01). Our results demonstrate that in the development of automated VR therapies there is likely to be therapeutic value in detailed consideration of the animations of virtual coaches.
Journal Article