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Circadian Therapeutics has been established to identify and bring to market pharmaceutical and diagnostic platforms for the effective management of physiological and pathological conditions through their ability to modify the body's circadian rhythms.
Learning How to Improve the Treatment of Persecutory Delusions: Using a Principal Trajectories Analysis to Examine Differential Effects of Two Psychological Interventions (Feeling Safe, Befriending) in Distinct Groups of Patients.
BACKGROUND: A theory-driven cognitive therapy (Feeling Safe) has produced much better outcomes for patients with persecutory delusions. There are four distinct response classes: very high delusion conviction with large improvement, very high delusion conviction with no response, high delusion conviction with large improvement, and high delusion conviction with modest improvement. Our objective was to apply principal trajectories analysis, a novel statistical method, to original trial data to estimate whether these groups may have responded differently to a different intervention: befriending. DESIGN: One hundred and thirty patients with persistent persecutory delusions were randomised to six months of Feeling Safe or befriending. Baseline assessments were used to assign patients allocated to befriending (who did not receive Feeling Safe) into the four Feeling Safe response classes. The treatment effect, including on potential mediators, was then estimated for these classes. RESULTS: Patients in two treatment response classes (Very high conviction/large improvement, High conviction/large improvement) benefited more from Feeling Safe, patients in one group (Very high conviction/no improvement) benefited more from befriending, and patients in the remaining group (High conviction/moderate improvement) benefited equally from the interventions. Mechanism differences were detected when Feeling Safe was superior to befriending, but not when befriending was superior. CONCLUSIONS: There may be patients with psychosis who benefit more from one type of therapy than another, likely due to different change mechanisms. The application of principal trajectories has generated testable hypotheses and a potential step toward personalised treatment. We recommend an investigation of whether sequential provision of the treatment types could enhance patient outcomes. Keywords: persecutory, delusions, outcome trajectories, psychosis, cognitive therapy.
Retinal microvascular phenotypes can track small vessel disease burden and CPAP treatment effectiveness in obstructive sleep apnea.
Optical coherence tomography angiography (OCT-A) retinal imaging enables in vivo visualization of the retinal microvasculature that is developmentally related to the brain and can offer insight on cerebrovascular health. We investigated retinal phenotypes and neuroimaging markers of small vessel disease (SVD) in individuals with obstructive sleep apnoea (OSA). We enrolled 44 participants (mean age 50.1 ± SD 9.1 years) and performed OCT-A imaging before and after continuous positive airway pressure (CPAP) therapy. Pre-treatment analyses using a generalized estimating equations model adjusted for relevant covariates, revealed perivascular spaces (PVS) volume in basal ganglia associated with greater foveal vessel density (fVD) (p-value
Sleep-disordered breathing in children and adults with intellectual disability: mind the gap!
BackgroundIn adults and children with intellectual disability (ID), sleep -disordered breathing (SDB) is thought to be common. However, large epidemiological studies are lacking, and there are few studies on optimal methods of investigation and even fewer randomised, controlled intervention trials of treatment.MethodPeer-reviewed publications from various databases were examined in line with search terms relevant to ID and SDB spanning the years 200-2024.ResultsFindings suggest that, due to comorbid conditions, children and adults with ID may experience both an increased risk of SDB, as well as lower frequency of diagnosis. SDB can compromise the emotional, physical and mental health of individuals with ID. Appropriate treatment when tolerated leads to an improvement in health and well-being and several studies emphasized the importance of consistent follow-up of people with ID - something that is not universally occurring during childhood, in the transition to adulthood and during adulthood itself. As the most frequently occurring form of ID worldwide, we use Down syndrome as a specific example of how diagnosing and treating SDB can lead to improved outcomes.ConclusionsThis review highlights the importance of identifying SDB in this heterogenous population, recognising the multi-faceted, deleterious consequences of untreated SDB in people with ID, and presents some strategies that can be harnessed to improve diagnosis and management. Until further ID-specific research is available, we urge flexibility in the approach to people with ID and SDB based in guidelines and standard practice developed for the typically developing population.
Prevalence of obstructive sleep apnea (OSA) among preschool aged children in the general population: A systematic review.
Untreated pediatric obstructive sleep apnea (OSA) is associated with significant morbidities affecting behavior, neurocognitive development, endocrine and metabolic health. This systematic review evaluated prevalence of OSA reported in population-based studies among preschoolers as early intervention may have positive effects on health and quality of life. Thirty studies were included. High degrees of heterogeneity in methods and definitions were observed between the studies. Seven studies confirmed OSA by implementing objective methods after screening for habitual snoring with only two studies utilizing polysomnography, the reference standard, testing 1.2% of the combined cohorts (n = 82/4575) to confirm disease. Diagnosis of OSA was based on utilizing retired thresholds of the apnea-hypopnea-index (AHI), AHI4%≥5/hour of sleep (hrSleep), reporting prevalence of 1.8% and 6.4%, respectively. The remaining five studies implemented relatively insensitive objective recording methods to confirm disease in a limited number of children (n = 449/2486; 18.0%), estimating prevalence in the range of 0.7%-13.0%. The remaining literature is based on implementing questionnaires only to evaluate OSA. Studies published before 2014 reported 3.3%-9.4% prevalence, while more recent studies published 2016-2023 report higher prevalence, 12.8%-20.4%, when excluding outliers. This trend suggests that prevalence of OSA may possibly have been increasing in preschoolers over the past decade.
Prior Expectations of Volatility Following Psychotherapy for Delusions: A Randomized Clinical Trial.
IMPORTANCE: Persecutory delusions are common, distressing, and difficult to treat. Testing computational neuroscience models of delusions can identify new therapeutic targets. OBJECTIVE: To determine whether change in delusion severity is associated with a corresponding change in volatility priors and brain activation estimated during a belief updating task. DESIGN, SETTING, AND PARTICIPANTS: This randomized clinical trial was conducted from April 9, 2021, to December 5, 2023, within the Vanderbilt University Medical Center Psychiatric Hospital and at a community mental health center in Nashville, Tennessee. Participants were adults (aged between 18 and 65 years) with schizophrenia spectrum or delusional disorder and an active, persistent (≥3 months) persecutory delusion with strong conviction (>50%). Participants were randomly assigned 1:1 to either cognitive behavioral therapy for psychosis (CBTp)-based intervention or befriending therapy. Intention-to-treat analysis was performed from June 1 to October 31, 2024. INTERVENTION: The CBTp was a manualized intervention targeting persecutory delusions. The befriending therapy involved engaging in conversations and activities focused on neutral topics. Both interventions were provided in person, lasted for 8 weeks, and included standard care. Standard care consisted of medication management and ancillary services. MAIN OUTCOMES AND MEASURES: Primary outcomes were volatility priors (ie, prior expectations of volatility) derived from a 3-option probabilistic reversal learning task; persecutory delusion severity measured by the Psychotic Symptom Rating Scales (PSYRATS delusion subscale; score range: 0-16, with the highest score indicating severe preoccupation, distress, conviction, and functioning impact); and brain activation in the striatum and prefrontal cortex measured by blood oxygenation level-dependent signal change. Associations between volatility priors, clinical improvement, and change in neural activation were examined. RESULTS: Sixty-two participants (median [range] age, 31 [19-63] years; 38 males [61%]) were randomly assigned to the CBTp (n = 32) or befriending therapy (n = 30) arms. A subgroup of 35 participants (57%) completed functional magnetic resonance imaging. Volatility priors decreased following treatment (F1,112 = 7.7 [P = .006]; Cohen d = 0.52 [95% CI, 0.15-0.90]), as did delusion severity (F1,112 = 59.7 [P
A systematic review of the performance of actigraphy in measuring sleep stages.
The accuracy of actigraphy for sleep staging is assumed to be poor, but examination is limited. This systematic review aimed to assess the performance of actigraphy in sleep stage classification of adults. A systematic search was performed using MEDLINE, Web of Science, Google Scholar, and Embase databases. We identified eight studies that compared sleep architecture estimates between wrist-worn actigraphy and polysomnography. Large heterogeneity was found with respect to how sleep stages were grouped, and the choice of metrics used to evaluate performance. Quantitative synthesis was not possible, so we performed a narrative synthesis of the literature. From the limited number of studies, we found that actigraphy-based sleep staging had some ability to classify different sleep stages compared with polysomnography.
Acute Plasmodium yoelii 17XNL Infection During BCG Vaccination Limits T Cell Responses and Mycobacterial Growth Inhibition.
Tuberculosis and malaria overlap in many sub-Saharan African countries where Bacillus Calmette Guérin (BCG) vaccination is routinely administered. The aim of this study was to determine whether the timing of BCG vaccination in relation to a malaria infection has implications for BCG vaccine efficacy. Mice were intradermally vaccinated with BCG either 4 weeks before infection with blood-stage Plasmodium yoelii 17XNL, at 13 days post-infection (during an acute blood-stage malaria infection) or 21 days post-infection (after clearance of P. yoelii 17XNL infection). Ex vivo control of mycobacterial growth by splenocytes was used as a surrogate of protective efficacy, and PPD-specific T-cell responses were quantified by flow cytometry. No differences in mycobacterial growth control were detected between BCG vaccinated mice and groups receiving vaccination prior to or after clearance of P. yoelii 17XNL infection. Poorer control of mycobacterial growth was observed following BCG vaccination administered during an acute malarial infection compared to BCG vaccination only or BCG vaccination after blood-stage malaria infection, and mycobacterial growth negatively correlated with the magnitude of total cytokine production from PPD-specific CD4+ T cells (p
Next-generation phenotyping of inherited retinal diseases from multimodal imaging with Eye2Gene.
Rare eye diseases such as inherited retinal diseases (IRDs) are challenging to diagnose genetically. IRDs are typically monogenic disorders and represent a leading cause of blindness in children and working-age adults worldwide. A growing number are now being targeted in clinical trials, with approved treatments increasingly available. However, access requires a genetic diagnosis to be established sufficiently early. Critically, the timely identification of a genetic cause remains challenging. We demonstrate that a deep learning algorithm, Eye2Gene, trained on a large multimodal imaging dataset of individuals with IRDs (n = 2,451) and externally validated on data provided by five different clinical centres, provides better-than-expert-level top-five accuracy of 83.9% for supporting genetic diagnosis for the 63 most common genetic causes. We demonstrate that Eye2Gene's next-generation phenotyping can increase diagnostic yield by improving screening for IRDs, phenotype-driven variant prioritization and automatic similarity matching in phenotypic space to identify new genes. Eye2Gene is accessible online (app.eye2gene.com) for research purposes.
The impact of estrogen deficiency on liver metabolism; implications for hormone replacement therapy
Abstract Metabolic dysfunction-associated steatotic liver disease (MASLD, previously NAFLD) is the most common chronic liver condition globally. It affects 1-in-3 individuals and is associated with increased liver and cardiovascular mortality. MASLD is a sexually dimorphic condition and in women the prevalence and severity of MASLD rises significantly following menopause. Preclinical data shows that lack of estrogen promotes multisystem metabolic dysfunction that is characteristic of MASLD. This not only includes hepatic lipid accumulation, insulin resistance and fibrosis, but also extra-hepatic metabolic processes in adipose and skeletal muscle. There are currently no available MASLD treatments tailored to women. The uptake of estrogen-based menopausal hormone replacement therapy (HRT) has seen a dramatic increase in recent years. Despite the changing attitudes to HRT and the strong evidence base implicating estrogen deficiency in the development of MASLD, the impact of HRT on MASLD in postmenopausal women is poorly studied. In this review, we discuss the burden of MASLD in women, the effect of estrogen deficiency on the processes that drive MASLD development and progression, and explore potential sex-specific therapeutic strategies that may prevent or limit MASLD development after menopause.
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 UNIVERSITY will be for the people’: arts, humanities and the founding of the civic universities
The paper addresses the current crisis in the Arts and Humanities by a foray into history, looking at the ideals and expectations that lay behind the founding of the civic universities in the late-19th and early-20th centuries. Focusing particularly on the case of the University of Sheffield, it explores what founding a university ‘for’ the people meant at that time, and the support from all sides for an education that was not only open to all, but encompassed Literature, Music Education (following the Hadow Reports) and Philosophy as well as the Sciences and more technical instruction. Public engagement, in multiple forms, lay at the heart of these conceptions of a civic university. Considering our current situation, the paper suggests it is time to overturn misplaced conceptions of a ‘useful’ education, and to return to earlier ideals of a university that was truly for the people. (This article is published in the thematic collection ‘The arts and humanities: rethinking value for today—views from Fellows of the British Academy’, edited by Isobel Armstrong.).
Subgrouping autism and ADHD based on structural MRI population modelling centiles.
BACKGROUND: Autism and attention deficit hyperactivity disorder (ADHD) are two highly heterogeneous neurodevelopmental conditions with variable underlying neurobiology. Imaging studies have yielded varied results, and it is now clear that there is unlikely to be one characteristic neuroanatomical profile of either condition. Parsing this heterogeneity could allow us to identify more homogeneous subgroups, either within or across conditions, which may be more clinically informative. This has been a pivotal goal for neurodevelopmental research using both clinical and neuroanatomical features, though results thus far have again been inconsistent with regards to the number and characteristics of subgroups. METHODS: Here, we use population modelling to cluster a multi-site dataset based on global and regional centile scores of cortical thickness, surface area and grey matter volume. We use HYDRA, a novel semi-supervised machine learning algorithm which clusters based on differences to controls and compare its performance to a traditional clustering approach. RESULTS: We identified distinct subgroups within autism and ADHD, as well as across diagnosis, often with opposite neuroanatomical alterations relatively to controls. These subgroups were characterised by different combinations of increased or decreased patterns of morphometrics. We did not find significant clinical differences across subgroups. LIMITATIONS: Crucially, however, the number of subgroups and their membership differed vastly depending on chosen features and the algorithm used, highlighting the impact and importance of careful method selection. CONCLUSIONS: We highlight the importance of examining heterogeneity in autism and ADHD and demonstrate that population modelling is a useful tool to study subgrouping in autism and ADHD. We identified subgroups with distinct patterns of alterations relative to controls but note that these results rely heavily on the algorithm used and encourage detailed reporting of methods and features used in future studies.