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Conducting public involvement in dementia research: The contribution of the European Working Group of People with Dementia to the ROADMAP project.
BACKGROUND: Dementia outcomes include memory loss, language impairment, reduced quality of life and personality changes. Research suggests that outcomes selected for dementia clinical trials might not be the most important to people affected. OBJECTIVE: One of the goals of the 'Real world Outcomes across the Alzheimer's Disease spectrum for better care: Multi-modal data Access Platform' (ROADMAP) project was to identify important outcomes from the perspective of people with dementia and their caregivers. We review how ROADMAP's Public Involvement shaped the programme, impacted the research process and gave voice to people affected by dementia. DESIGN: The European Working Group of People with Dementia (EWGPWD) were invited to participate. In-person consultations were held with people with dementia and caregivers, with advance information provided on ROADMAP activities. Constructive criticism of survey content, layout and accessibility was sought, as were views and perspectives on terminology and key concepts around disease progression. RESULTS: The working group provided significant improvements to survey accessibility and acceptability. They promoted better understanding of concepts around disease progression and how researchers might approach measuring and interpreting findings. They effectively expressed difficult concepts through real-world examples. CONCLUSIONS: The role of the EWGPWD in ROADMAP was crucial, and its impact was highly influential. Involvement from the design stage helped shape the ethos of the programme and ultimately its meaningfulness. PUBLIC CONTRIBUTION: People with dementia and their carers were involved through structured consultations and invited to provide feedback on project materials, methods and insight into terminology and relevant concepts.
Governing AI-Driven Health Research: Are IRBs Up to the Task?
Many are calling for concrete mechanisms of oversight for health research involving artificial intelligence (AI). In response, institutional review boards (IRBs) are being turned to as a familiar model of governance. Here, we examine the IRB model as a form of ethics oversight for health research that uses AI. We consider the model's origins, analyze the challenges IRBs are facing in the contexts of both industry and academia, and offer concrete recommendations for how these committees might be adapted in order to provide an effective mechanism of oversight for health-related AI research.
Magnitude and variability of structural brain abnormalities in neuropsychiatric disease: protocol for a network meta-analysis of MRI studies.
INTRODUCTION: Structural MRI is the most frequently used method to investigate brain volume alterations in neuropsychiatric disease. Previous meta-analyses have typically focused on a single diagnosis, thereby precluding transdiagnostic comparisons. METHODS AND ANALYSIS: We will include all structural MRI studies of adults that report brain volumes for participants from at least two of the following diagnostic groups: healthy controls, schizophrenia, schizoaffective disorder, delusional disorder, psychotic depression, clinical high risk for psychosis, schizotypal personality disorder, psychosis unspecified, bipolar disorder, autism spectrum disorder, major depressive disorder, attention deficit hyperactivity disorder, obsessive compulsive disorder, post-traumatic stress disorder, emotionally unstable personality disorder, 22q11 deletion syndrome, generalised anxiety disorder, social anxiety disorder, panic disorder, mixed anxiety and depression. Network meta-analysis will be used to synthesise eligible studies. The primary analysis will examine standardised mean difference in average volume, a secondary analysis will examine differences in variability of volumes. DISCUSSION: This network meta-analysis will provide a transdiagnostic integration of structural neuroimaging studies, providing researchers with a valuable summary of a large literature. PROSPERO REGISTRATION NUMBER: CRD42020221143.
Retinal microvascular parameters are not significantly associated with mild cognitive impairment in the Northern Ireland Cohort for the Longitudinal Study of Ageing.
BACKGROUND: The retinal and cerebral microvasculature share similar embryological origins and physiological characteristics. Improved imaging technologies provide opportunistic non-invasive assessment of retinal microvascular parameters (RMPs) against cognitive outcomes. We evaluated baseline measures for associations between RMPs and mild cognitive impairment (MCI) from participants of the Northern Ireland Cohort for the Longitudinal Study of Ageing (NICOLA). METHODS: RMPs (central retinal arteriolar / venular equivalents, arteriole to venular ratio, fractal dimension and tortuosity) were measured from optic disc centred fundus images and analysed using semi-automated software. Associations between RMPs and MCI were assessed by multivariable logistic regression with adjustment for potential confounders including age, sex, alcohol consumption, smoking status, educational attainment, physical activity, cardiovascular disease (CVD), hypertension, mean arterial blood pressure, triglycerides, diabetes, body mass index, and high density lipoprotein levels. P < 0.05 was considered statistically significant. RESULTS: Data were available for 1431 participants, of which 156 (10.9%) were classified with MCI defined by a Montreal Cognitive Assessment (MoCA) score ≤ 26, with subjective cognitive decline, in the absence of depression or problems with activities of daily living. Participants had a mean age of 62.4 ± 8.5 yrs. and 52% were female. As expected, individuals with MCI had a lower MoCA score than those without (23.5 ± 2.6 versus 26.3 ± 2.7, respectively), were more likely to be female, have a lower level of educational attainment, be less physically active, more likely to have CVD, have higher levels of triglycerides and lower levels of high density lipoprotein. No significant associations between RMPs and MCI were detected in unadjusted, minimally adjusted or fully adjusted regression models or subsequent sensitivity analyses. CONCLUSION: Previous studies have reported both increased retinal venular calibre and reduced fractal dimension in association with mild cognitive impairment. Our study failed to detect any associations between RMPs and those individuals at an early stage of cognitive loss in an older community-based cohort.
Correction: The genomic basis of mood instability: identification of 46 loci in 363,705 UK Biobank participants, genetic correlation with psychiatric disorders, and association with gene expression and function.
A correction to this paper has been published and can be accessed via a link at the top of the paper.
Deep clinical and biological phenotyping of the preterm birth and small for gestational age syndromes: The INTERBIO-21 st Newborn Case-Control Study protocol.
Background: INTERBIO-21 st is Phase II of the INTERGROWTH-21 st Project, the population-based, research initiative involving nearly 70,000 mothers and babies worldwide coordinated by Oxford University and performed by a multidisciplinary network of more than 400 healthcare professionals and scientists from 35 institutions in 21 countries worldwide. Phase I, conducted 2008-2015, consisted of nine complementary studies designed to describe optimal human growth and neurodevelopment, based conceptually on the WHO prescriptive approach. The studies generated a set of international standards for monitoring growth and neurodevelopment, which complement the existing WHO Child Growth Standards. Phase II aims to improve the functional classification of the highly heterogenous preterm birth and fetal growth restriction syndromes through a better understanding of how environmental exposures, clinical conditions and nutrition influence patterns of human growth from conception to childhood, as well as specific neurodevelopmental domains and associated behaviors at 2 years of age. Methods: In the INTERBIO-21 st Newborn Case-Control Study, a major component of Phase II, our objective is to investigate the mechanisms potentially responsible for preterm birth and small for gestational age and their interactions, using deep phenotyping of clinical, growth and epidemiological data and associated nutritional, biochemical, omic and histological profiles. Here we describe the study sites, population characteristics, study design, methodology and standardization procedures for the collection of longitudinal clinical data and biological samples (maternal blood, umbilical cord blood, placental tissue, maternal feces and infant buccal swabs) for the study that was conducted between 2012 and 2018 in Brazil, Kenya, Pakistan, South Africa, Thailand and the UK. Discussion: Our study provides a unique resource for the planned analyses given the range of potentially disadvantageous exposures (including poor nutrition, pregnancy complications and infections) in geographically diverse populations worldwide. The study should enhance current medical knowledge and provide new insights into environmental influences on human growth and neurodevelopment.
Unraveling Mechanisms of Patient-Specific NRXN1 Mutations in Neuropsychiatric Diseases Using Human Induced Pluripotent Stem Cells.
Rare heterozygous deletions in the neurexin 1 (NRXN1) gene robustly increase an individual's risk of developing neurological and psychiatric disorders. However, the molecular bases by which different mutations result in different clinical presentations, with variable penetrance, are unknown. To better understand the molecular and cellular consequences of heterozygous NRXN1 mutations, Flaherty and colleagues studied how patient mutations influence the NRXN1 isoform repertoire and neuronal phenotypes using induced pluripotent stem (iPS) cells. Advancing from disease association to mechanistic insights, the authors provide insight into how patient mutations might impinge on neuronal function. This research highlights the value of iPS cells for elucidating otherwise elusive links between molecular and neuronal function. In addition, they provide further evidence of the importance of alternative splicing in the pathophysiology of neuropsychiatric diseases.
Sweet anticipation and positive emotions in music, groove, and dance
Across human cultures, music is an important source of emotion, including positive emotions and pleasurable experiences. Our brains and bodies are moved by music as part of an active process in which our brains are constantly generating predictions of what is likely to happen next. The constituent elements of music (melody, harmony, and rhythm) are processed in an active, sustained musical pleasure cycle that gives rise to action, emotion, and learning, led by activity in specific brain networks. The ‘sweet anticipation’ stage of this pleasure cycle is both highly motivating and pleasurable. Here, we highlight research on how music, groove and dance can generate positive emotion. Especially in the case of dance, an important element of this collective positive emotion arises from engagement with other people. Yet, most neuroscientific research on music to date has focused on an individual processing music passively, rather than interacting, and until now very little neuroscientific research has been undertaken on dance. We therefore argue that future research would do well to focus on the dynamics and underlying brain mechanisms of the collective experience of music making and dance.
Effectiveness as an outcome measure for treatment trials in psychiatry
There is at present some confusion about the relative value of clinical trials performed to investigate efficacy vs. those designed to investigate effectiveness. This is particularly challenging when studies performed as experiments for regulators by companies are used to shape and inform clinical practice, especially if studies conducted under more real life conditions fail to support predicted benefits. We review the field in relation to the new antipsychotics, in particular. Other indications, including mood disorders, which are also briefly touched upon, have so far received less definitive attention, but are likely to encounter the same difficulties. We conclude that, where the results of efficacy trials are positive and an effectiveness trial is negative, one should not necessarily prefer the effectiveness trial. it may simply have failed. Where efficacy trials and effectiveness trials point to similar conclusions, then the findings are mutually supportive. © 2009 wydanie polskie, Instytut Psychiatrii i Neurologii.
Psilocin acutely disrupts sleep and affects local but not global sleep homeostasis in laboratory mice
<jats:title>Abstract</jats:title><jats:p>Serotonergic psychedelic drugs, such as psilocin (4-hydroxy-N,N-dimethyltryptamine), profoundly alter the quality of consciousness through mechanisms which are incompletely understood. Growing evidence suggests that a single psychedelic experience can positively impact long-term psychological well-being, with relevance for the treatment of psychiatric disorders, including depression. A prominent factor associated with psychiatric disorders is disturbed sleep, and the sleep-wake cycle is implicated in the regulation of neuronal firing and activity homeostasis. It remains unknown to what extent psychedelic agents directly affect sleep, in terms of both acute arousal and homeostatic sleep regulation. Here, chronic <jats:italic>in vivo</jats:italic> electrophysiological recordings were obtained in mice to track sleep-wake architecture and cortical activity after psilocin injection. Administration of psilocin led to delayed REM sleep onset and reduced NREM sleep maintenance for up to approximately 3 hours after dosing, and the acute EEG response was associated primarily with an enhanced oscillation around 4 Hz. No long-term changes in sleep-wake quantity were found. When combined with sleep deprivation, psilocin did not alter the dynamics of homeostatic sleep rebound during the subsequent recovery period, as reflected in both sleep amount and EEG slow wave activity. However, psilocin decreased the recovery rate of sleep slow wave activity following sleep deprivation in the local field potentials of electrodes targeting medial prefrontal and surrounding cortex. It is concluded that psilocin affects both global vigilance state control and local sleep homeostasis, an effect which may be relevant for its antidepressant efficacy.</jats:p>
Linking the timing of a mother's and child's death: Comparative evidence from two rural South African population-based surveillance studies, 2000-2015.
BACKGROUND: The effect of the period before a mother's death on child survival has been assessed in only a few studies. We conducted a comparative investigation of the effect of the timing of a mother's death on child survival up to age five years in rural South Africa. METHODS: We used discrete time survival analysis on data from two HIV-endemic population surveillance sites (2000-2015) to estimate a child's risk of dying before and after their mother's death. We tested if this relationship varied between sites and by availability of antiretroviral therapy (ART). We assessed if related adults in the household altered the effect of a mother's death on child survival. FINDINGS: 3,618 children died from 2000-2015. The probability of a child dying began to increase in the 7-11 months prior to the mother's death and increased markedly in the 3 months before (2000-2003 relative risk = 22.2, 95% CI = 14.2-34.6) and 3 months following her death (2000-2003 RR = 20.1; CI = 10.3-39.4). This increased risk pattern was evident at both sites. The pattern attenuated with ART availability but remained even with availability at both sites. The father and maternal grandmother in the household lowered children's mortality risk independent of the association between timing of mother and child mortality. CONCLUSIONS: The persistence of elevated mortality risk both before and after the mother's death for children of different ages suggests that absence of maternal care and abrupt breastfeeding cessation might be crucial risk factors. Formative research is needed to understand the circumstances for children when a mother is very ill or dies, and behavioral and other risk factors that increase both the mother and child's risk of dying. Identifying families when a mother is very ill and implementing training and support strategies for other members of the household are urgently needed to reduce preventable child mortality.
Alcohol affordability: implications for alcohol price policies. A cross-sectional analysis in middle and older adults from UK Biobank
<jats:title>Abstract</jats:title> <jats:sec> <jats:title>Background</jats:title> <jats:p>Increasing the price of alcohol reduces alcohol consumption and harm. The role of food complementarity, transaction costs and inflation on alcohol demand are determined and discussed in relation to alcohol price policies.</jats:p> </jats:sec> <jats:sec> <jats:title>Methods</jats:title> <jats:p>UK Biobank (N = 502,628) was linked by region to retail price quotes for the years 2007 to 2010. The log residual food and alcohol prices, and alcohol availability were regressed onto log daily alcohol consumption. Model standard errors were adjusted for clustering by region.</jats:p> </jats:sec> <jats:sec> <jats:title>Results</jats:title> <jats:p>Associations with alcohol consumption were found for alcohol price (β = −0.56, 95% CI, −0.92 to −0.20) and availability (β = 0.06, 95% CI, 0.04 to 0.07). Introducing, food price reduced the alcohol price consumption association (β = −0.26, 95% CI, −0.50 to −0.03). Alcohol (B = 0.001, 95% CI, 0.0004 to 0.001) and food (B = 0.001, 95% CI, 0.0005 to 0.0006) price increased with time and were associated (ρ = 0.57, P &lt; 0.001).</jats:p> </jats:sec> <jats:sec> <jats:title>Conclusion</jats:title> <jats:p>Alcohol and food are complements, and the price elasticity of alcohol reduces when the effect of food price is accounted for. Transaction costs did not affect the alcohol price consumption relationship. Fixed alcohol price policies are susceptible to inflation.</jats:p> </jats:sec>
Large-scale societal dynamics are reflected in human mood and brain
<jats:title>Abstract</jats:title><jats:p>The stock market is a bellwether of socio-economic changes that may directly affect individual well-being. Using large-scale UK-biobank data generated over 14 years, we applied specification curve analysis to rigorously identify significant associations between the local stock market index (FTSE100) and 479,791 UK residents’ mood, as well as their alcohol intake and blood pressure adjusting the results for a large number of potential confounders, including age, sex, linear and non-linear effects of time, research site, other stock market indexes. Furthermore, we found similar associations between FTSE100 and volumetric measures of affective brain regions in a subsample (n=39,755; measurements performed over 5.5 years), which were particularly strong around phase transitions characterized by maximum volatility in the market. The main findings did not depend on applied effect-size estimation criteria (linear methods or mutual information criterion) and were replicated in two independent US-based studies (Parkinson’s Progression Markers Initiative; n=424; performed over 2,5 years and MyConnectome; n=1; 81 measurements over 1,5 years). Our results suggest that phase transitions in the society, indexed by stock market, exhibit close relationships with human mood, health and the affective brain from an individual to population level.</jats:p>