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Prof Robin Dunbar, Emeritus Professor of Evolutionary Psychology has been in conversation with Jim Al-Khalili on Radio 4's Life Scientific. This fascinating podcast gives takes us on a journey from his early beginnings in science, and his fascinating research and groundbreaking discoveries he's made deciphering the mysteries as to why humans and animals evolve the social habits to exist in friendship circles.
The missing pieces: an investigation into the parallels between Charles Bonnet, phantom limb and tinnitus syndromes.
Charles Bonnet syndrome (CBS) is a condition characterised by visual hallucinations of varying complexity on a background of vision loss. CBS research has gained popularity only in recent decades, despite evidence dating back to 1760. Knowledge of CBS among both the patient and professional populations unfortunately remains poor, and little is known of its underlying pathophysiology. CBS parallels two other better-known conditions that occur as a result of sensory loss: phantom limb syndrome (PLS) (aberrant sensation of the presence of a missing limb) and tinnitus (aberrant sensation of sound). As 'phantom' conditions, CBS, PLS and tinnitus share sensory loss as a precipitating factor, and, as subjective perceptual phenomena, face similar challenges to investigations. Thus far, these conditions have been studied separately from each other. This review aims to bridge the conceptual gap between CBS, PLS and tinnitus and seek common lessons between them. It considers the current knowledge base of CBS and explores the extent to which an understanding of PLS and tinnitus could provide valuable insights into the pathology of CBS (including the roles of cortical reorganisation, emotional and cognitive factors), and towards identifying effective potential management for CBS.
Ranked Importance of Visual Function Outcome Measures in Choroideremia Clinical Trials.
PURPOSE: Clinical trials of novel therapies for choroideremia require robust and clinically meaningful visual function outcome measures. Best-corrected visual acuity (BCVA) is mostly insensitive to changes in disease state, until late stages, and hence also to potential therapeutic gains after gene therapies. While the insensitivity of BCVA as an effective outcome measure is common wisdom, its low importance has not been rigorously demonstrated in the literature. This work uses statistical techniques to rank the relative importance of potential functional outcome measures in choroideremia. METHODS: Retrospective dominance analysis was performed on data from a longitudinal interventional clinical trial performed at the Oxford Eye Hospital. Functional data from the untreated eye were analyzed and correlated with an anatomic measure of disease progression in the form of blue fundus autofluorescence area of the surviving outer retinal island. Each functional measure was then ranked in terms of variable importance. RESULTS: Microperimetry was the functional measure ranking first in terms of variable importance, followed by time since baseline visit, Pelli-Robson contrast sensitivity, high spatial frequency contrast sensitivity function, and low luminance visual acuity. Early Treatment Diabetic Screening chart BCVA under standard lighting conditions was ranked lowest among the panel of test modalities. CONCLUSIONS: Clinical trials in choroideremia for early and mid-stage disease would be justified in moving away from using standard BCVA as a clinical trial outcome measure as we have shown its sensitivity to be relatively low compared to microperimetry. We have also demonstrated how functional measures rank in terms of importance.
Quantitative Contribution of Clinical Attacks to Residual Disability in Patients With AQP4-Antibody Neuromyelitis Optica Spectrum Disorder.
BACKGROUND AND OBJECTIVES: Disease-related disability in aquaporin-4 antibody-positive neuromyelitis optica spectrum disorder (AQP4-NMOSD) is solely attributed to clinical attacks. However, few studies have assessed the relationship between attacks and residual disability in NMOSD. Thus, we aimed to quantify the contribution of clinical attacks to the residual disability in patients with AQP4-NMOSD. METHODS: This retrospective observational single-center study enrolled patients from the Oxford National NMO Service, with the inclusion criteria as (1) AQP4-NMOSD diagnosis and (2) availability of at least 1 disability score (Expanded Disability Status Scale [EDSS] or logarithm of the minimum angle of resolution [LogMAR] score) recorded ≥6 months after attack (defined as residual disability). The outcome measures were EDSS and LogMAR scores. Univariable and multivariable linear mixed-effect models were used to quantify the effect of clinical relapses on the outcomes. RESULTS: A total of 165 patients with AQP4-NMOSD (median onset age, 43 years, range 2-84; women, 140 [84.8%]; White European patients, 92 [55.8%]; African or African British patients, 40 [24.2%]; Asian or Asian British patients, 20 [12.1%]; multiracial or unknown racial patients, 13 [7.9%]) were included, with the median time of disability measurement since the last attack being 32 months (range 6-197). The mean increase in the EDSS score per relapse was 0.304 (95% CI 0.074-0.553, p < 0.001), with individual relapse phenotypes showing different effects: the transverse myelitis (TM) + optic neuritis (ON) phenotype contributed most, with an increase of 1.290 (95% CI 0.233-2.207, p = 0.017) per relapse, followed by brain plus other phenotypes (β = 0.782, 95% CI 0.029-1.03, p < 0.001) and isolated TM (β = 0.295, 95% CI 0.074-0.549, p < 0.001), while neither brain nor optic nerve relapse alone was associated with a residual change in the EDSS score. Older onset age was correlated with more severe motor disability where this mainly occurred early in the disease course while younger patients exhibited mild initial disability that worsened more significantly with relapses. Each ON attack led to a mean increase of 0.464 (95% CI 0.199-0.741, p < 0.001) in the LogMAR score. Race, sex, and timing of acute treatment did not significantly affect these disability outcomes (EDSS and LogMAR scores). DISCUSSION: The quantitative contribution of relapse to the residual disability in patients with AQP4-NMOSD varies across phenotypes, and this relapse-related disability progression may also vary by the onset age. Although this retrospective single-center study may need validation in other data sets, these findings may help predict disability and provide a modeling tool for longer term disability in the cost-effective analysis of newer interventions.
Translated and culturally adapted internet-delivered cognitive therapy for social anxiety disorder in Japanese clinical settings: study protocol for a randomised controlled trial.
BACKGROUND: Cognitive therapy for social anxiety disorder (CT-SAD) has extensive empirical support and is recommended in several national guidelines. However, ensuring access to evidence-based psychological therapies such as CT-SAD remains a global challenge. An internet-delivered version of this treatment protocol (iCT-SAD) has recently been developed in the UK as a way to overcome this challenge, demonstrating comparable outcomes to face-to-face CT-SAD whilst requiring less therapist time per client. Initial findings also suggest its cross-cultural transferability, but the previous studies in other cultural settings used the English language programme and only included English-fluent participants as a second language. It is not yet known what outcomes can be achieved once the programme has been translated and adapted for a different cultural context. Therefore, this trial aims to evaluate the clinical efficacy of Japanese iCT-SAD when combined with treatment as usual (TAU) in clients with SAD. METHODS: This two-arm, parallel-group, superiority randomised controlled trial will recruit 60 Japanese participants with SAD, randomly assigning them to either Japanese iCT-SAD + TAU or TAU alone at a ratio of 1:1. The primary outcome measure is the self-report Liebowitz Social Anxiety Scale, and secondary.outcomes include other measures of social anxiety symptoms and processes, general mood and functioning, and response to treatment. We will also assess treatment acceptability and gather participant feedback. Assessments will take place at baseline (week 0), mid-treatment (week 8), and post-treatment (week 15), with a further 3-month follow-up (week 27) for the iCT-SAD + TAU arm. The primary analyses will be conducted on an intent-to-treat basis, comparing the primary and secondary outcome measures between groups using linear mixed-effect models, along with additional mediation analysis. DISCUSSION: Investigating the efficacy of translated and culturally adapted iCT-SAD in different cultural contexts is an important step in evaluating the global reach of internet interventions. This trial will provide valuable insights into the effects of iCT-SAD combined with usual care, and how this treatment could be delivered in routine clinical settings in Japan. TRIAL REGISTRATION: International Standard Randomized Controlled Trials (ISRCTN), ISRCTN82859645, registered on January 19, 2024. UMIN Clinical Trials Registry (UMIN-CTR), UMIN000052702, registered on November 6, 2023.
Identifying falsified COVID-19 vaccines by analysing vaccine vial label and excipient profiles using MALDI-ToF mass spectrometry
The rapid development and worldwide distribution of COVID-19 vaccines is a remarkable achievement of biomedical research and logistical implementation. However, these developments are associated with the risk of a surge of substandard and falsified (SF) vaccines, as illustrated by the 184 incidents with SF and diverted COVID-19 vaccines which have been reported during the pandemic in 48 countries, with a paucity of methods for their detection in supply chains. In this context, matrix assisted laser desorption ionisation-time of flight (MALDI-ToF) mass spectrometry (MS) is globally available for fast and accurate analysis of bacteria in patient samples, offering a potentially accessible solution to identify SF vaccines. We analysed the COVISHIELD™ COVID-19 vaccine; falsified versions of which were found in India, Myanmar and Uganda. We demonstrate for the first time that analysis of spectra from the vaccine vial label and its adhesive could be used as a novel approach to detect falsified vaccines. Vials tested by this approach could be retained in the supply chain since it is non-invasive. We also assessed whether MALDI-ToF MS could be used to distinguish the COVISHIELD™ vaccine from surrogates of falsified vaccines and the effect of temperature on vaccine stability. Both polysorbate 80 and L-histidine excipients of the genuine vaccine could be detected by the presence of a unique combination of MALDI-ToF MS peaks which allowed us to distinguish between the genuine vaccines and falsified vaccine surrogates. Furthermore, even if a falsified product contained polysorbate 80 at the same concentration as used in the genuine vaccine, the characteristic spectral profile of polysorbate 80 used in genuine products is a reliable internal marker for vaccine authenticity. Our findings demonstrate that MALDI-ToF MS analysis of extracts from vial labels and the vaccine excipients themselves can be used independently to detect falsified vaccines. This approach has the potential to be integrated into the national regulatory standards and WHO’s Prevent, Detect, and Respond strategy as a novel effective tool for detecting falsified vaccines.
The relevance of the unique anatomy of the human prefrontal operculum to the emergence of speech.
Identifying the evolutionary origins of human speech remains a topic of intense scientific interest. Here we describe a unique feature of adult human neuroanatomy compared to chimpanzees and other primates that may provide an explanation of changes that occurred to enable the capacity for speech. That feature is the Prefrontal extent of the Frontal Operculum (PFOp) region, which is located in the ventrolateral prefrontal cortex, adjacent and ventromedial to the classical Broca's area. We also show that, in chimpanzees, individuals with the most human-like PFOp, particularly in the left hemisphere, have greater oro-facial and vocal motor control abilities. This critical discovery, when combined with recent paleontological evidence, suggests that the PFOp is a recently evolved feature of human cortical structure (perhaps limited to the genus Homo) that emerged in response to increasing selection for cognitive and motor functions evident in modern speech abilities.
Neural responses in macaque prefrontal cortex are linked to strategic exploration.
Humans have been shown to strategically explore. They can identify situations in which gathering information about distant and uncertain options is beneficial for the future. Because primates rely on scarce resources when they forage, they are also thought to strategically explore, but whether they use the same strategies as humans and the neural bases of strategic exploration in monkeys are largely unknown. We designed a sequential choice task to investigate whether monkeys mobilize strategic exploration based on whether information can improve subsequent choice, but also to ask the novel question about whether monkeys adjust their exploratory choices based on the contingency between choice and information, by sometimes providing the counterfactual feedback about the unchosen option. We show that monkeys decreased their reliance on expected value when exploration could be beneficial, but this was not mediated by changes in the effect of uncertainty on choices. We found strategic exploratory signals in anterior and mid-cingulate cortex (ACC/MCC) and dorsolateral prefrontal cortex (dlPFC). This network was most active when a low value option was chosen, which suggests a role in counteracting expected value signals, when exploration away from value should to be considered. Such strategic exploration was abolished when the counterfactual feedback was available. Learning from counterfactual outcome was associated with the recruitment of a different circuit centered on the medial orbitofrontal cortex (OFC), where we showed that monkeys represent chosen and unchosen reward prediction errors. Overall, our study shows how ACC/MCC-dlPFC and OFC circuits together could support exploitation of available information to the fullest and drive behavior towards finding more information through exploration when it is beneficial.
Increased chloroplast occupancy in bundle sheath cells of rice hap3H mutants revealed by Chloro-Count: a new deep learning-based tool.
There is an increasing demand to boost photosynthesis in rice to increase yield potential. Chloroplasts are the site of photosynthesis, and increasing their number and size is a potential route to elevate photosynthetic activity. Notably, bundle sheath cells do not make a significant contribution to overall carbon fixation in rice, and thus, various attempts are being made to increase chloroplast content specifically in this cell type. In this study, we developed and applied a deep learning tool, Chloro-Count, and used it to quantify chloroplast dimensions in bundle sheath cells of OsHAP3H gain- and loss-of-function mutants in rice. Loss of OsHAP3H increased chloroplast occupancy in bundle sheath cells by 50%. When grown in the field, mutants exhibited increased numbers of tillers and panicles. The implementation of Chloro-Count enabled precise quantification of chloroplasts in loss- and gain-of-function OsHAP3H mutants and facilitated a comparison between 2D and 3D quantification methods. Collectively, our observations revealed that a mechanism operates in bundle sheath cells to restrict chloroplast occupancy as cell dimensions increase. That mechanism is unperturbed in Oshap3H mutants but loss of OsHAP3H function leads to an increase in chloroplast numbers. The use of Chloro-Count also revealed that 2D quantification is compromised by the positioning of chloroplasts within the cell.
EXPRESS: How stable are taste-shape crossmodal correspondences over time?
The present research investigates the stability of taste-shape crossmodal correspondences (that is, how people non-randomly associate tastes and visual shapes, such as sweetness matched to roundness) over time, exploring the temporal dimension of crossmodal interactions. While previous research has established the existence of various taste-shape crossmodal correspondences, this study addresses their consistency over time through a test-retest paradigm. Drawing parallels with the concept of synesthesia, in which stability is used as a criterion, the research focuses on taste-shape associations, a domain not previously explored for temporal stability. Participants rated the perceived curvature and symmetry that they associated with taste words (sweet, umami, sour, salty, and bitter) and their liking of tastes and shapes. The same participants performed this task three times over a two-week period. The results consistently replicated previous findings, revealing that sweet tastes were perceived as significantly more curved and symmetrical than other tastes, and umami was rated as more curved and symmetrical than sour, salty, and bitter tastes. Notably, the study found moderate-to-substantial test-retest reliability for the majority of the taste-shape correspondences, indicating robust stability over time. Analyses suggested that differences in assessments between test and retest sessions were primarily due to random error, with no systematic biases. However, a small subset of participants showed significant differences from other participants in their associations, particularly for umami-related correspondences. This research contributes to our understanding of taste-shape correspondences by demonstrating their temporal stability, offering insights into the dynamics of taste, curvature, symmetry, and liking. We posit that consistency might be used as a criterion supporting the existence of a given crossmodal correspondence. The findings have implications for product design and marketing, emphasizing the importance of considering temporal aspects when capitalizing on crossmodal correspondences in creating product expectations and experiences.
Reduced neurovascular coupling is associated with increased cardiovascular risk without established cerebrovascular disease: A cross-sectional analysis in UK biobank.
Mid-life vascular risk factors predict late-life cerebrovascular diseases and poor global brain health. Although endothelial dysfunction is hypothesized to contribute to this process, evidence of impaired neurovascular function in early stages remains limited. In this cross-sectional study of 31,934 middle-aged individuals from UK Biobank without established cerebrovascular disease, the overall 10-year risk of cardiovascular events was associated with reduced neurovascular coupling (p
Suppression of ADP-ribosylation reversal triggers cell vulnerability to alkylating agents
The ADP-ribosyl hydrolases PARG and ARH3 counteract PARP enzymatic activity by removing ADP-ribosylation. PARG and ARH3 activities have a synthetic lethal effect; however, the specific molecular mechanisms underlying this response remain unknown. Here, we show that the PARG and ARH3 synthetic lethality is enhanced further in the presence of DNA alkylating agents, suggesting that the inability to revert ADP-ribosylation primarily affects the repair of alkylated DNA bases. ARH3 knockout cells, treated with PARG inhibitor and alkylating genotoxins, accumulated single-stranded DNA and DNA damage, resulting in G2/M cell cycle arrest and apoptosis. Furthermore, we reveal a reduction in PARP1/PARP2 levels in ARH3-deficient cells treated with PARG inhibitor due to excessive ADP-ribosylation, which may contribute to alkylating agents’ vulnerability. Collectively, these results uncover the potential of targeting ADP-ribosyl hydrolases in combination with alkylating agents for cancer therapy and provide insights into the mechanisms underlying the synthetic lethal effect.
Better sexual acceptability of agomelatine (25 and 50 mg) compared to escitalopram (20 mg) in healthy volunteers. A 9-week, placebo-controlled study using the PRSexDQ scale.
UNLABELLED: The present double-blind, placebo-controlled study evaluates the effects of agomelatine and the selective serotonin reuptake inhibitor escitalopram on sexual dysfunction in healthy men and women. METHODS: A total of 133 healthy volunteers (67 men, 66 women) were randomly assigned to agomelatine (25 or 50 mg) or escitalopram (20 mg) or placebo for nine weeks. Sexual acceptability was evaluated by using the psychotropic-related sexual dysfunction questionnaire 5-items total score and sexual dysfunction relative to each sub-score (in 110 volunteers with sexual activity). Sexual dysfunction was evaluated at baseline and after two, five and eight weeks of treatment and one week after drug discontinuation. RESULTS: The psychotropic-related sexual dysfunction questionnaire 5-items total score was significantly lower in both agomelatine groups versus escitalopram at all visits (p < 0.01 to p < 0.0001) with no difference between agomelatine and placebo nor between both agomelatine doses. Similar results were observed after drug discontinuation. The total score was significantly higher in the escitalopram group than in the placebo group at each post-baseline visit (p < 0.01 to p < 0.001). Similar results were observed regardless of volunteers' gender. Compared to placebo, only escitalopram significantly impaired dysfunction relative to "delayed orgasm or ejaculation" (p < 0.01) and "absence of orgasm or ejaculation" (p < 0.05 to p < 0.01). The percentage of participants with a sexual dysfunction was higher in the escitalopram group than in agomelatine groups (p < 0.01 to p < 0.05) and placebo (p < 0.01). CONCLUSION: The study confirms the better sexual acceptability profile of agomelatine (25 or 50 mg) in healthy men and women, compared to escitalopram. TRIAL REGISTRATION NAME: Evaluation of the effect of agomelatine and escitalopram on emotions and motivation in healthy male and female volunteers. TRIAL REGISTRATION NUMBER: ISRCTN75872983.
Exploring the incidence of inadequate response to antidepressants in the primary care of depression.
Data from the UK suggests 13-55 % of depression patients experience some level of treatment resistance. However, little is known about how physicians manage inadequate response to antidepressants in primary care. This study aimed to explore the incidence of inadequate response to antidepressants in UK primary care. One-hundred-eighty-four medication-free patients with low mood initiated antidepressant treatment and monitored severity of depression symptoms, using the QIDS-SR16, for 48 weeks. Medication changes, visits to healthcare providers, and health-related quality of life were also recorded. Patients were classified into one of four response types based on their QIDS scores at three study timepoints: persistent inadequate responders (<50 % reduction in baseline QIDS at all timepoints), successful responders (≥50 % reduction in baseline QIDS at all timepoints), slow responders (≥50 % reduction in QIDS at week 48, despite earlier inadequate responses), and relapse (initial ≥50 % reduction in baseline QIDS, but inadequate response by week 48). Forty-eight weeks after initiating treatment 47 % of patients continued to experience symptoms of depression (QIDS >5), and 20 % of patients had a persistent inadequate response. Regardless of treatment response, 96 % (n = 176) of patients did not visit their primary care physician over the 40-week follow-up period. These results suggest that despite receiving treatment, a considerable proportion of patients with low mood remain unwell and fail to recover. Monitoring depression symptoms remotely can enable physicians to identify inadequate responders, allowing patients to be reassessed or referred to secondary services, likely improving patients' quality of life and reducing the socioeconomic impacts of chronic mental illness.