The pathological role of acrolein in experimental autoimmune encephalomyelitis and multiple sclerosis

Multiple sclerosis (MS) is an autoimmune demyelinating neuropathy that affects nearly 2.5 million people worldwide. Despite substantial efforts, few treatments are currently available largely due to limited knowledge of pathogenic mechanisms underlying the disease. The immune-inflammatory nature of the pathology has prompted investigation of the role of oxidative stress in disease development and progression; however targeting reactive oxygen species for neutralization has had marginal success therapeutically, suggesting that an alternate oxidative stress-related target would prove beneficial. Recently, our lab has implicated acrolein, a highly reactive aldehyde that is both a byproduct and catalyst of lipid peroxidation, as a potential therapeutic target and biomarker for MS diagnosis and symptom monitoring. We have shown that acrolein is elevated in clinical MS cases and experimental autoimmune encephalomyelitis (EAE), a murine model of MS. Furthermore, pharmacological sequestering of acrolein afforded a neuroprotective effect by suppressing tissue acrolein level, slowing disease progression, and decreasing symptom severity. Acrolein can also be produced exogenously as a pollutant from combustion engine exhaust, industrial processing, burning of tobacco and overheated cooking oil vapors. The pathogenic role of endogenous acrolein in MS raises the possibility that environmental exposure to acrolein could potentially increase MS risk or exacerbate MS symptoms. Using a respiratory exposure model in combination with urinary detection of an acrolein metabolite and immunoblotting assessment of tissue acrolein-lysine adducts, we have ascertained that inhalation of acrolein can cause accumulation of acrolein in mice systemically and locally within the CNS. Additionally clinical acrolein assessment using urine and serum samples revealed that MS patients who self-reported as smokers demonstrated higher systemic acrolein levels and demonstrated greater motor deficit compared to MS patients that did not smoke. These observations indicate that acrolein is likely contributing to the mechanisms underlying symptom development in EAE and MS and may serve as a therapeutic target and biomarker for diagnosis, guiding treatment regimens and monitoring relapses

Who Is Exposed to News? It Depends on How You Measure: Examining Self-Reported Versus Behavioral News Exposure Measures

Despite the importance of news exposure to political outcomes, news consumption is notoriously difficult to measure, and misreporting news exposure is common. In this study, we compare participants' news behaviors measured on a news aggregator website with their self-reported story selection immediately after exposure. We find that both individual and contextual characteristics - especially the presence of political cues in news headlines - influence reporting of news story selection. As a result, the news audience profiles differ using self-reported versus behavioral measures, creating two different pictures of news exposure. More attention is needed to improve news measurement strategies to address misreporting and to improve the accuracy of news audience profiles

Empowering Users to Respond to Misinformation about Covid-19

The World Health Organization has declared that misinformation shared on social media about Covid-19 is an “infodemic” that must be fought alongside the pandemic itself. We reflect on how news literacy and science literacy can provide a foundation to combat misinformation about Covid-19 by giving social media users the tools to identify, consume, and share high-quality information. These skills can be put into practice to combat the infodemic by amplifying quality information and actively correcting misinformation seen on social media. We conclude by considering the extent to which what we know about these literacies and related behaviors can be extended to less-researched areas like the Global South

Systemic Acrolein Elevations in Mice With Experimental Autoimmune Encephalomyelitis and Patients With Multiple Sclerosis

Demyelination and axonal injury are the key pathological processes in multiple sclerosis (MS), driven by inflammation and oxidative stress. Acrolein, a byproduct and instigator of oxidative stress, has been demonstrated as a neurotoxin in experimental autoimmune encephalomyelitis (EAE), an animal model of MS. However, due to the invasive nature of acrolein detection using immunoblotting techniques, the investigation of acrolein in MS has been limited to animal models. Recently, detection of a specific acrolein-glutathione metabolite, 3-HPMA, has been demonstrated in urine, enabling the noninvasive quantification of acrolein for the first time in humans with neurological disorders. In this study, we have demonstrated similar elevated levels of acrolein in both urine (3-HPMA) and in spinal cord tissue (acrolein-lysine adduct) in mice with EAE, which can be reduced through systemic application of acrolein scavenger hydralazine. Furthermore, using this approach we have demonstrated an increase of 3-HPMA in both the urine and serum of MS patients relative to controls. It is expected that this noninvasive acrolein detection could facilitate the investigation of the role of acrolein in the pathology of MS in human. It may also be used to monitor putative therapies aimed at suppressing acrolein levels, reducing severity of symptoms, and slowing progression as previously demonstrated in animal studies

Can I Trust You? Negative Affective Priming Influences Social Judgments in Schizophrenia

Successful social interactions rely on the ability to make accurate judgments based on social cues as well as the ability to control the influence of internal or external affective information on those judgments. Prior research suggests that individuals with schizophrenia misinterpret social stimuli and this misinterpretation contributes to impaired social functioning. We tested the hypothesis that for people with schizophrenia, social judgments are abnormally influenced by affective information. Twenty-three patients with schizophrenia and 35 healthy control participants rated the trustworthiness of faces following the presentation of neutral, negative (threat-related), or positive affective primes. Results showed that all participants rated faces following negative affective primes as less trustworthy than faces following neutral or positive primes. Importantly, this effect was significantly more pronounced for participants with schizophrenia, suggesting that schizophrenia may be characterized by an exaggerated influence of negative affective information on social judgment. Furthermore, the extent that the negative affective prime influenced trustworthiness judgments was significantly associated with patients' severity of positive symptoms, particularly feelings of persecution. These findings suggest that for people with schizophrenia, negative affective information contributes to an interpretive bias, consistent with paranoid ideation, when judging the trustworthiness of others. This bias may contribute to social impairments in schizophrenia.Psycholog

Do media literacies approach equity and justice?

It is often assumed that media literacy serves to protect and uphold democratic practice and that media literate citizens are the best safeguards for democracy. However, little attention is paid to defining this practice and its relationship to ongoing inequities within democratic societies. In this essay, we argue media literacy operates from three core assumptions; media literacy creates knowledgeable individuals, empowers communities, and encourages democratic participation. The first assumption draws out an individual’s skills and critical thinking in media literacy practices. The second assumption focuses on the community aspect of media literacy, specifically which communities are best served by media literacy and why. Finally, the connection between media literacy and democratic practices is evaluated to understand how the democratic ideals of equity and justice are situated within the existing literature. Through an exploration of these assumptions, this essay provokes a discussion into the assumptions that media literacy scholarship and practice addresses to highlight some of the gaps in constructing impactful practice that centers on equity and social justice

Do Media Literacies Approach Equity and Justice?

It is often assumed that media literacy serves to protect and uphold democratic practice and that media literate citizens are the best safeguards for democracy. However, little attention is paid to defining this practice and its relationship to ongoing inequities within democratic societies. In this essay, we argue media literacy operates from three core assumptions; media literacy creates knowledgeable individuals, empowers communities, and encourages democratic participation. The first assumption draws out an individual’s skills and critical thinking in media literacy practices. The second assumption focuses on the community aspect of media literacy, specifically which communities are best served by media literacy and why. Finally, the connection between media literacy and democratic practices is evaluated to understand how the democratic ideals of equity and justice are situated within the existing literature. Through an exploration of these assumptions, this essay provokes a discussion into the assumptions that media literacy scholarship and practice addresses to highlight some of the gaps in constructing impactful practice that centers on equity and social justice

The beliefs about paranoia scale:Confirmatory factor analysis and tests of a metacognitive model of paranoia in a clinical sample

This study aimed to confirm the factor structure of the Beliefs about Paranoia Scale (BaPS), a self-report measure to assess metacognitive beliefs about paranoia, and to test hypotheses of a metacognitive model. We hypothesised that positive and negative beliefs about paranoia would be associated with severity of suspiciousness, and that the co-occurrence of positive and negative beliefs would be associated with increased suspiciousness. A total of 335 patients meeting criteria for a schizophrenia spectrum disorder completed the BaPS, the Positive and Negative Syndromes Scale (PANSS), and the Psychotic Symptom Rating Scales (PSYRATS). Confirmatory factor analysis verified that the three BaPS subscales (negative beliefs about paranoia, paranoia as a survival strategy, and normalizing beliefs) were an adequate fit of the data. Ordinal regression showed that positive beliefs about paranoia as a survival strategy and negative beliefs were both associated with severity of suspiciousness. This was the first study to show that the co-occurrence of positive and negative beliefs was associated with increased suspiciousness. All hypotheses were confirmed, suggesting that a metacognitive approach has utility for the conceptualization of paranoia. Clinical implications suggest a role for metacognitive therapy, including strategies such as detached mindfulness and worry postponement

Measuring common responses to psychosis:Assessing the psychometric properties of a new measure

Funding body agreements and policies The FOCUS Trial was funded by the National Institute for Health Research Health Technology Assessment (NIHR HTA) programme (project number 10/101/02) and will be published in full in Health Technology Assessment. Visit the HTA programme website for further project information. The views and opinions expressed therein are those of the authors and do not necessarily reflect those of the HTA programme, NIHR, NHS or the Department of Health. Acknowledgements The authors would like to acknowledge The Psychosis Research Unit (PRU) Service User Reference Group (SURG) for their support with the FOCUS Trial and for their contribution to designing the Measure of Common Responses. We also acknowledge The Mental Health Research Network, Scottish Mental Health Research Network, FOCUS Trial Steering Committee and Data Monitoring and Ethics Committee. Thanks also to Lizi Graves, Susan Irving, Toyah Lebert, Liesbeth Tip, Maggie Douglas-Bailey and the other Research Assistants who have worked on the FOCUS Trial.Peer reviewedPostprin

Cognitive behavioural therapy for clozapine-resistant schizophrenia: the FOCUS RCT

Background: Clozapine (clozaril, Mylan Products Ltd) is a first-choice treatment for people with schizophrenia who have a poor response to standard antipsychotic medication. However, a significant number of patients who trial clozapine have an inadequate response and experience persistent symptoms, called clozapine-resistant schizophrenia (CRS). There is little evidence regarding the clinical effectiveness of pharmacological or psychological interventions for this population. Objectives: To evaluate the clinical effectiveness and cost-effectiveness of cognitive–behavioural therapy (CBT) for people with CRS and to identify factors predicting outcome. Design: The Focusing on Clozapine Unresponsive Symptoms (FOCUS) trial was a parallel-group, randomised, outcome-blinded evaluation trial. Randomisation was undertaken using permuted blocks of random size via a web-based platform. Data were analysed on an intention-to-treat (ITT) basis, using random-effects regression adjusted for site, age, sex and baseline symptoms. Cost-effectiveness analyses were carried out to determine whether or not CBT was associated with a greater number of quality-adjusted life-years (QALYs) and higher costs than treatment as usual (TAU). Setting: Secondary care mental health services in five cities in the UK. Participants: People with CRS aged up to 16 years, with an International Classification of Diseases, Tenth Revision (ICD-10) schizophrenia spectrum diagnoses and who are experiencing psychotic symptoms. Interventions: Individual CBT included up to 30 hours of therapy delivered over 9 months. The comparator was TAU, which included care co-ordination from secondary care mental health services. Main outcome measures: The primary outcome was the Positive and Negative Syndrome Scale (PANSS) total score at 21 months and the primary secondary outcome was PANSS total score at the end of treatment (9 months post randomisation). The health benefit measure for the economic evaluation was the QALY, estimated from the EuroQol-5 Dimensions, five-level version (EQ-5D-5L), health status measure. Service use was measured to estimate costs. Results: Participants were allocated to CBT (n = 242) or TAU (n = 245). There was no significant difference between groups on the prespecified primary outcome [PANSS total score at 21 months was 0.89 points lower in the CBT arm than in the TAU arm, 95% confidence interval (CI) –3.32 to 1.55 points; p = 0.475], although PANSS total score at the end of treatment (9 months) was significantly lower in the CBT arm (–2.40 points, 95% CI –4.79 to –0.02 points; p = 0.049). CBT was associated with a net cost of £5378 (95% CI –£13,010 to £23,766) and a net QALY gain of 0.052 (95% CI 0.003 to 0.103 QALYs) compared with TAU. The cost-effectiveness acceptability analysis indicated a low likelihood that CBT was cost-effective, in the primary and sensitivity analyses (probability < 50%). In the CBT arm, 107 participants reported at least one adverse event (AE), whereas 104 participants in the TAU arm reported at least one AE (odds ratio 1.09, 95% CI 0.81 to 1.46; p = 0.58). Conclusions: Cognitive–behavioural therapy for CRS was not superior to TAU on the primary outcome of total PANSS symptoms at 21 months, but was superior on total PANSS symptoms at 9 months (end of treatment). CBT was not found to be cost-effective in comparison with TAU. There was no suggestion that the addition of CBT to TAU caused adverse effects. Future work could investigate whether or not specific therapeutic techniques of CBT have value for some CRS individuals, how to identify those who may benefit and how to ensure that effects on symptoms can be sustained. Trial registration: Current Controlled Trials ISRCTN99672552