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As part of its Mental Health Season, BBC 1 showed their documentary on anxiety presented by Great British Bake Off Winner, Nadiya Hussain. the show featured Professor of Experimental Psychology, David Clark, who discusses with Nadiya the various features of anxiety.
P21-Activated Kinase 2 as a Novel Target for Ventricular Tachyarrhythmias Associated with Cardiac Adrenergic Stress and Hypertrophy.
Ventricular arrhythmias associated with cardiac adrenergic stress and hypertrophy pose a significant clinical challenge. We explored ventricular anti-arrhythmic effects of P21-activated kinase 2 (Pak2), comparing in vivo and ex vivo cardiomyocyte-specific Pak2 knockout (Pak2cko) or overexpression (Pak2ctg) murine models, under conditions of acute adrenergic stress, and hypertrophy following chronic transverse aortic constriction (TAC). Pak2 was downregulated 5 weeks following the latter TAC challenge. Cellular physiological, optical action potential and Ca2+ transient, measurements, demonstrated increased incidences of triggered ventricular arrhythmias, and prolonged action potential durations (APD) and altered Ca2+ transients with increases in their beat-to beat variations, in Pak2cko hearts. Electron microscopic, proteomic, and molecular biological methods revealed a mitochondrial localization of stress-related proteins on proteomic and phosphoproteomic analyses, particularly in TAC stressed Pak2cko mice. They further yielded accompanying evidence for mitochondrial oxidative stress, increased reactive oxygen species (ROS) biosynthesis, reduced mitochondrial complexes I-V, diminished ATP synthesis and elevated NADPH oxidase 4 (NOX4) levels. Pak2 overexpression and the novel Pak2 activator JB2019A ameliorated these effects, enhanced cardiac function and decreased the frequencies of triggered ventricular arrhythmias. Pak2 activation thus protects against ventricular arrhythmia associated with cardiac stress and hypertrophy, through unique mechanisms offering potential novel therapeutic anti-arrhythmic targets.
p21-Activated Kinases Present a New Drug Target for Hypertrophic Cardiomyopathy
Hypertrophic cardiomyopathy (HCM), primarily involving mutations in sarcomeric proteins, is the most common form of inherited heart disease and a leading cause of sudden death in young adults and athletes. HCM patients present with cardiac hypertrophy, fibrosis, and diastolic dysfunction often in a progressive manner. Despite significant progress made in understanding the molecular genetic basis of HCM, there remains a lack of effective and specific treatment for preventing disease progression in HCM. This article first provides an overview of recent progress in understanding the pathogenic basis of disease progression in HCM, in particular dysfunctional calcium handling, mitochondrial impairment, and endoplasmic reticulum stress. This article then analyses the evidence for critical roles of the multifunctional enzymes P21-activated kinase-1 and 2 (Pak1/2) in the heart and our opinion on their therapeutic value as a promising druggable target in pathological hypertrophy and associated ventricular arrhythmias.
The immunology and neuropathology of the autoimmune nodopathies
The autoimmune nodopthies have recently emerged as a discrete subtype of inflammatory neuropathy. They are characterised by the presence of IgG class autoantibodies directed against structural components of the node of Ranvier, such as the axonal isoform of neurofascin (NF186), or flanking paranodes, where NF155, on the glial membrane, and the axonal complex of contactin-1 and contactin-associated protein-1 (Caspr1), are established targets. Although initially proposed to be atypical forms of chronic inflammatory demyelinating polyradiculoneuropathy (CIDP), many patients initially present with a clinical picture in keeping with the acute inflammatory neuropathy Guillain-Barré syndrome (GBS). Furthermore, compared to seronegative CIDP and GBS, the autoimmune nodopathies have distinct underlying immunological and neuropathogenic mechanisms. Crucially, the treatment response profile is also different, and patients often fail to respond to immunotherapies typically used in seronegative cases, such as immunoglobulin infusions and corticosteroids. However, responses to anti-CD20 B-cell depleting therapies are frequent and often long-lasting. This review provides on overview of the antigenic landscape of the node of Ranvier, and the broad concept of nodopathies, and summarises the immunology, neuropathology and clinical features of these disabling yet treatable disorders.
Cost-utility analysis of the DREAMS START intervention for people living with dementia and their carers: a within-trial economic evaluation.
BACKGROUND: People living at home with dementia frequently have disturbed sleep. The multicomponent, non-pharmacological intervention DREAMS START has shown to be effective at improving sleep in this population. We aimed to conduct a cost-utility analysis of DREAMS START compared with treatment as usual (TAU). METHODS: This economic evaluation within a single-masked, phase 3, parallel-arm, superiority randomised controlled trial involved dyads of people with dementia and sleep disturbance and their family carer. Participants were recruited from the National Health Service and the Join Dementia Research service in England. Dyads were randomly assigned (1:1) to receive the DREAMS START intervention (plus TAU) or TAU. Randomisation was blocked, with stratification by site, and a web-based system was used for allocation. Researchers collecting outcome data were masked to allocation group. The primary outcome was sleep disturbance measured by the Sleep Disorders Inventory (SDI) at 8 months. At baseline, 4 months, and 8 months, family carers completed the 5-level EuroQoL 5 dimensions (EQ-5D-5L) proxy, the Dementia Quality of Life Instrument (DEMQOL)-Proxy, and EQ-5D-5L questionnaires, and resource use for the patient and family carer was measured. We calculated the probability that the DREAMS START intervention is cost-effective from a health and personal social services perspective and from a wider societal perspective for a range of decision thresholds per quality-adjusted life-year (QALY) gained using the EQ-5D-5L scores to calculate QALYs and imputing missing data, reported with a cost-effectiveness acceptability curve. This trial was registered with ISRCTN, 13072268, and is complete. FINDINGS: From Feb 24, 2021, to March 5, 2023, we randomly assigned 377 dyads: 188 to the intervention group and 189 to the TAU group. The mean age of participants with dementia was 79⋅4 years (SD 9⋅0), 206 (55%) of whom were women and 171 (45%) were men. As previously reported, the mean SDI score at 8 months was lower in the intervention group than in the TAU group (adjusted difference in means -4·70 [95% CI -7·65 to -1·74], p=0·002). The mean incremental difference in health and personal social services costs was £59 less per dyad (95% CI -5168 to 5050) and, when incorporating wider societal costs, was £116 less per dyad (-5769 to 5536) for the intervention group than the TAU group, although these figures were non-significant. The mean incremental difference in QALYs per person with dementia was 0·016 more (95% CI 0·000 to 0·033) for the intervention group than for the TAU group, indicating no significant difference in quality of life. At a £20 000 per QALY gained decision threshold, there was a 78% probability that DREAMS START is cost-effective, compared with TAU. INTERPRETATION: DREAMS START is likely to be cost-effective. Given its clinical effectiveness, we recommend that this intervention forms part of routine care for people with dementia and disturbed sleep. FUNDING: National Institute for Health and Care Research Health Technology Assessment.
The impact of autoimmune comorbidities on the onset attack recovery in adults with AQP4-NMOSD and MOGAD.
BACKGROUND: Aquaporin-4 neuromyelitis optica spectrum disorder (AQP4-NMOSD) often coexists with other autoimmune diseases (AIDs), whereas such comorbidities are less common in myelin oligodendrocyte glycoprotein antibody disease (MOGAD). This study investigates the impact of additional AIDs on early relapse recovery and disability in patients with AQP4-NMOSD and MOGAD. METHODS: This retrospective study included patients aged > 16 years with AQP4-NMOSD (n = 175) or MOGAD (n = 221), who were followed at a nationally commissioned Oxford service and categorized based on the presence of at least one AID. Outcomes included recovery from the onset attack, visual recovery after the first optic neuritis (ON) attack (≥ 6 months post attack), time to first relapse and time to death. Incomplete visual recovery was defined as visual acuity worse than LogMAR 0.1. Optical coherence tomography (OCT) assessed retinal nerve fiber layer thickness and ganglion cell-inner plexiform layer volume in a subset. RESULTS: In the AQP4-NMOSD cohort, 28% (n = 49) had at least one AID, compared to 11.3% (n = 25) in the MOGAD cohort (p
Increased Sensitivity to Effort and Perception of Effort in People with Schizophrenia.
OBJECTIVE: Motivational deficits in schizophrenia are proposed to be attributable in part to abnormal effort-cost computations, calculations weighing the costs vs. the benefits of actions. Several reports have shown that people with schizophrenia display a reduced willingness to exert effort for monetary rewards when compared to controls. The primary goal of the current study was to further characterize reduced willingness to exert effort in schizophrenia by determining whether reduced willingness reflects (1) reduced sensitivity to reward, (2) increased sensitivity to effort, or (3) a combination of both. DESIGN: We assessed effort-cost decision-making in 30 controls and 30 people with schizophrenia, using 2 separate experimental tasks. Critically, one paradigm allowed for independent estimation of effects of reward and effort sensitivity on choice behavior. The other task isolated effort sensitivity by measuring effort in the absence of reward. Clinical interviews and self-report questionnaires were administered to people with schizophrenia to determine negative symptom severity. RESULTS: Across both tasks, we found evidence for reduced willingness to exert effort in people with schizophrenia compared to controls. Further, in both paradigms reduced willingness to exert effort was driven by increased sensitivity to effort in people with schizophrenia compared to controls. In contrast, measures of reward sensitivity did not significantly differ between groups. Surprisingly, we did not find correlations between task variables and measures of negative symptom severity. CONCLUSIONS AND RELEVANCE: These findings further specify prior work by identifying a specific contributory role for increased effort sensitivity in effort-cost decision-making deficits in schizophrenia.
Preferences for fat, sugar, and oral-sensory food qualities in monkeys and humans.
In humans and other primates, food intake depends on sophisticated, individualized preferences for nutrients and oral-sensory food qualities that guide decision-making and eating behavior. The neural and behavioral mechanisms for such primate-typical food preferences remain poorly understood, despite their importance for human health and their targeting by pharmacological obesity treatments. Here, we review a series of experiments that investigated how the biologically critical properties of foods-their nutrients (sugar, fat, protein) and oral-sensory qualities (viscosity, oral sliding friction)-influence food preferences in monkeys and humans. In an economic nutrient-choice paradigm, macaques flexibly trade nutrients and oral-sensory food qualities against varying food amounts, consistent with the assignment of subjective values. Nutrient-value functions that link objective nutrient content to subjective values accurately model these preferences, predict choices across contexts, and explain individual differences. The monkeys' aggregated choice patterns resulting from their nutrient preferences lead to daily nutrient balances that deviate from dietary reference points, resembling suboptimal human eating patterns when exposed to high-calorie foods. To investigate the sensory basis underlying nutrient values, we developed novel engineering tools that quantify food textures on oral surfaces, using fresh pig tongues. Oral-texture (i.e., mouthfeel) parameters, including viscosity and sliding friction, were shown to mediate monkeys' preferences for high-fat foods. When translated to human subjects, this approach revealed a neural mechanism for preferring high-fat foods from oral texture in the orbitofrontal cortex (OFC)-a key reward system of the brain. Importantly, human OFC responses to oral sliding friction in individual subjects-measured in the MRI scanner-predicted subsequent fat intake in a naturalistic, life-like eating test. These findings suggest that a primate nutrient-reward paradigm offers a promising approach for investigating the behavioral and neural mechanisms for human-typical food reward and food choice, to advance understanding of human eating behavior, overeating, and obesity.
Active information sampling in health and disease
Active information gathering is a fundamental cognitive process that enables organisms to navigate uncertainty and make adaptive decisions. Here we synthesise current knowledge on the behavioural, neural, and computational mechanisms underlying information sampling in healthy people and across several brain disorders. The role of cortical and subcortical regions spanning limbic, insular, fronto-parietal, and striatal systems is considered, along with the contributions of key neurotransmitters involving norepinephrine, dopamine, and serotonin. We also examine how various clinical conditions, including schizophrenia, obsessive-compulsive disorder, and Parkinson's disease have an impact on information gathering behaviours. To account for the findings, we outline a neuroeconomic perspective on how the brain may evaluate the costs and benefits of acquiring information to resolve uncertainty. This work highlights how active information gathering is a crucial brain process for adaptive behaviour in healthy individuals and how its breakdown is relevant to several psychiatric and neurological conditions. The findings have important implications for developing novel computational assays as well as targeted interventions in brain disorders.
Goal-directedness deficit in Huntington's disease.
Apathy and impulsive behaviour co-occur in Huntington's disease (HD), but these debilitating behavioural syndromes are multidimensional constructs, raising the question of which specific dimensions drive this relationship and the stability of the co-occurring dimensions across time. People with HD and controls completed multidimensional apathy and impulsive behaviour scales at baseline and 1-year follow-up. A principal component analysis was performed on pooled data (n = 109) to identify components and factor loadings of subscales. Linear mixed models were used to examine differences in components between groups and timepoints. Three meaningful components emerged. Component 1 comprised positive loading for dimensions of apathy and impulsive behaviour pertaining to goal-directedness, namely attention, planning, initiation, and perseverance. In contrast, other dimensions of apathy and impulsive behaviour loaded onto components two and three in opposite directions. People with HD only scored worse than controls on the goal-directedness component. All components remained stable over time and closely resembled factors from the five-factor personality model. Component 1 mapped onto the factor conscientiousness, component 2 to extraversion, and component 3 to neuroticism. The clinical overlap between apathy and impulsive behaviour in HD relates to goal-directedness, whilst other dimensions of these constructs did not overlap.
Non-coding Y RNA fragments in a complex with YBX1 modulate PARP1 residency at DNA double strand breaks.
To protect genome integrity from pervasive threats of damage and prevent diseases like cancer, cells employ an integrated network of signalling pathways called the DNA damage response. These pathways involve both protein and RNA components, which can act within the damaged cell or be transferred intercellularly to influence population-wide responses to damage. Here, we show that radioprotection can be conferred by damage-derived exosomes and is dependent on YBX1-packaged Y3-derived ysRNA. In recipient cells, ysRNAs are methylated on cytosine and bound by m5C reader, YBX1. YBX1/ysRNA localise at double strand break (DSB) sites to promote efficient DNA repair and cell survival through complex formation with PARP1. YBX1 modulates PARP1 auto-modification by facilitating ysRNA ADP-ribosylation, promoting increased PARP1 residency at DSBs. Our data highlight an unprecedented role for these under-studied species of small non-coding RNAs, identifying them as a novel substrate for PARP1 mediated ADP-ribosylation with a function in DNA repair.
An intensive weight loss programme with behavioural support for people with type 2 diabetes at risk of eating disorders in England (ARIADNE): a randomised, controlled, non-inferiority trial
Background: There are concerns that low-energy total diet replacement (TDR) programmes could trigger eating disorders, given their focus on weight and rigid dietary rules. We aimed to assess the effect of a TDR programme on eating disorder symptoms in people living with overweight or obesity and type 2 diabetes at high risk of developing an eating disorder. Methods: In this randomised, controlled, non-inferiority trial, participants with type 2 diabetes, overweight, and eating disorder symptoms across England were randomly assigned (1:1) to a low-energy TDR programme with formula products and behavioural support delivered remotely, or usual care. In brief, the intervention comprised 12 weeks of low-energy TDR in a nutritionally complete package of soups, shakes, and bars. After the 12 weeks, the intervention continued with stepped food reintroduction (around 8 weeks) based on a low-energy, nutrient-rich diet, followed by weight maintenance advice (around 4 weeks), personalised to an individual participant's circumstances and preferences. Participants allocated to the control group received usual care for their diabetes. The primary outcome was the change in eating disorder symptoms using the Eating Disorders Examination Questionnaire (EDE-Q) global score at 6 months (programme end). Safety was determined by the incidence of cases with high suspicion of a new eating disorder. The primary outcome analysis had an upper non-inferiority margin for EDE-Q of +1 SD (0·72). People with lived experience were involved throughout the trial and provided input on study conceptualisation, protocol development, delivery of the intervention, and intervention materials. The study was registered with ClinicalTrials.gov, NCT05744232. Findings: Between March 8, 2023, and Sept 12, 2023, 56 participants were randomly assigned to the intervention group (28 participants) or control group (28 participants). Participants had a mean age of 49·9 years (SD 8·1). 35 (63%) of 56 participants were women, 20 (36%) were men, and one (2%) was non-binary. 54 (96%) of participants were White and two (4%) were Asian. Participants had a mean BMI of 39·6 kg/m2 (SD 7·8) and a mean EDE-Q global score of 3·3 (0·4). 49 (88%) of 56 participants provided outcome data at 6 months and 45 (80%) at 1 year. At completion of the programme at 6 months, the mean weight loss was –13·9 kg (SD 11·2) in the intervention group and –3·7 kg (7·9) in the control group, with a between-group difference of –10·2 kg (95% CI –14·2 to –6·2). The between-group difference in the EDE-Q score was –0·8 points (–1·4 to –0·3) at 6 months, indicating non-inferiority. At 12 months, weight change was not different between groups, but non-inferiority and superiority in EDE-Q remained. No participants were suspected of having developed an eating disorder. 13 adverse events were documented, of which one, a cholecystectomy, was serious. Interpretation: Participation in a supported TDR programme did not worsen eating disorder symptoms in people with overweight or obesity and type 2 diabetes at high risk of developing an eating disorder. We found no evidence these programmes cause harm and a suggestion of benefit on eating disorder symptoms, independent of weight loss. Funding: Novo Nordisk UK Research Foundation.
A Comparison of Change Blindness and the Visual Perception of Museum Artefacts in Real-World and On-Screen Scenarios
The book is organized around 4 sections. The first deals with the creativity and its neural basis (responsible editor Emmanuelle Volle). The second section concerns the neurophysiology of aesthetics (responsible editor Zoï Kapoula).
A novel synergistic drug combination of a mitogen-activated extracellular signal-regulated kinase inhibitor with [177Lu]Lu-rhPSMA-10.1 for prostate cancer treatment: Results of a preclinical evaluation.
PURPOSE: The prostate-specific membrane antigen (PSMA)-targeted radiohybrid ligand [177Lu]Lu-rhPSMA-10.1 is a promising next-generation radiopharmaceutical therapy in prostate cancer. This preclinical evaluation comprised an in vitro screen of potential novel synergistic drug combinations with [177Lu]Lu-rhPSMA-10.1, and an in vivo efficacy analysis of the lead drug combination in PSMA-expressing prostate cancer xenografts. METHODS: In total, 177 anticancer drugs were screened in a clonogenic survival assay of 22Rv1 cells which used 5-fold serial dilutions of the test drug (≤ 20 μM) to determine the half-maximal inhibitory concentration (IC50), compared to incubations of the test drug plus [177Lu]Lu-rhPSMA-10.1 (15 MBq) after 10 days. A subsequent focused screen assessed the impact of [177Lu]Lu-rhPSMA-10.1 (0-25 MBq/mL) on drug IC50. Synergy scores were determined using the zero interaction potency (ZIP) reference model (ZIP scores >5 % indicate high synergistic potency) and the multidimensional synergy of combinations (MuSyC) platform (log α >0 indicates synergistic potency). Therapeutic efficacy of the lead drug combination was evaluated in vivo: intravenous [177Lu]Lu-rhPSMA-10.1 (30 MBq, single dose) and oral cobimetinib (0.25 mg/day for 21 days) (alone/in combination) were administered to 22Rv1 tumor-bearing NMRI nude mice (eight mice/group plus untreated controls). Tumor volume was measured twice weekly for 69 days (two-way ANOVA and Tukey's multiple comparisons test: data analyzed until three mice/group remained). KaplanMeier Log-rank survival analyses were performed. RESULTS: In vitro screening identified cobimetinib (a mitogen-activated extracellular signal-regulated kinase inhibitor) as a lead candidate for synergistic combination with [177Lu]Lu-rhPSMA-10.1 across a wide concentration range (ZIP score=13 %). MuSyC analysis suggested synergistic efficacy from enhanced potency of both drugs in the combination (both log α>3). Combination treatment significantly suppressed tumor growth in vivo versus untreated controls (from Day 13-30; p<0.01) and [177Lu]Lu-rhPSMA-10.1 (from Day 17-30; p<0.001). Median survival was significantly longer with combination treatment (49 days) versus untreated controls (23 days; p=0.001) and [177Lu]Lu-rhPSMA-10.1 monotherapy (36 days; p=0.002). No major compound-related toxicity for cobimetinib ± [177Lu]Lu-rhPSMA-10.1 was observed. CONCLUSIONS: The combination of cobimetinib and [177Lu]Lu-rhPSMA-10.1 demonstrated enhanced preclinical therapeutic efficacy versus single agents, supporting clinical investigation of this novel drug combination in prostate cancer.
Corrigendum: Proceedings of the 12th annual deep brain stimulation think tank: cutting edge technology meets novel applications.
[This corrects the article DOI: 10.3389/fnhum.2025.1544994.].
Death and the Doctor: the museum as a tool for understanding the needs of the dying
Over the past several years, the Ashmolean Museum at Oxford has been part of a multi- disciplinary team examining the question of how we train medical students to deal with those parts of their profession which are concerned primarily with the humanity of their patients. In collaboration with colleagues from Neuroscience, Psychiatry, History and Theology, the Museum has participated in an ongoing teaching experiment in which medical history, ethics and the visual arts are brought to bear on an understanding of medical professionalism - what it means to be a doctor and how to be a better one. Bringing together museum professionals, Expert Patient Tutors and doctors in curriculum planning and delivery, the work has been delivered online, using images from the museum’s collections, and live, using the Ashmolean galleries as spaces for the consideration of issues around death, dying and end-of-life care. This article and its preface reflect broadly on a decade of medical collaboration at the Ashmolean and specifically on the processes of both making and delivering teaching on dealing with death, in a cross-disciplinary, non-medical context, asking not only what the Museum can do for medical education but why medical education needs the museum.