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NHS England has announced a programme to provide NHS staff with evidence-based digital programmes to protect their mental health during the COVID-19 response. The apps are designed to help maintain healthy sleep, and reduce anxiety.
A service-user digital intervention to collect real-time safety information on acute, adult mental health wards: the WardSonar mixed-methods study.
BACKGROUND: Acute inpatient mental health services report high levels of safety incidents. The application of patient safety theory has been sparse, particularly concerning interventions that proactively seek patient perspectives. OBJECTIVE(S): Develop and evaluate a theoretically based, digital monitoring tool to collect real-time information from patients on acute adult mental health wards about their perceptions of ward safety. DESIGN: Theory-informed mixed-methods study. A prototype digital monitoring tool was developed from a co-design approach, implemented in hospital settings, and subjected to qualitative and quantitative evaluation. SETTING AND METHODS: Phase 1: scoping review of the literature on patient involvement in safety interventions in acute mental health care; evidence scan of digital technology in mental health contexts; qualitative interviews with mental health patients and staff about perspectives on ward safety. This, alongside stakeholder engagement with advisory groups, service users and health professionals, informed the development processes. Most data collection was virtual. Phase 1 resulted in the technical development of a theoretically based digital monitoring tool that collected patient feedback for proactive safety monitoring. Phase 2: implementation of the tool in six adult acute mental health wards across two UK NHS trusts; evaluation via focused ethnography and qualitative interviews. Statistical analysis of WardSonar data and routine ward data involving construction of an hour-by-hour data set per ward, permitting detailed analysis of the use of the WardSonar tool. PARTICIPANTS: A total of 8 patients and 13 mental health professionals participated in Phase 1 interviews; 33 staff and 34 patients participated in Phase 2 interviews. INTERVENTIONS: Patients could use a web application (the WardSonar tool) to record real-time perceptions of ward safety. Staff could access aggregated, anonymous data to inform timely interventions. RESULTS: Coronavirus disease 2019 restrictions greatly impacted the study. Stakeholder engagement permeated the project. Phase 1 delivered a theory-based, collaboratively designed digital tool for proactive patient safety monitoring. Phase 2 showed that the tool was user friendly and broadly acceptable to patients and staff. The aggregated safety data were infrequently used by staff. Feasibility depended on engaged staff and embedding use of the tool in ward routines. There is strong evidence that an incident leads to increased probability of further incidents within the next 4 hours. This puts a measure on the extent to which social/behavioural contagion persists. There is weak evidence to suggest that an incident leads to a greater use of the WardSonar tool in the following hour, but none to suggest that ward atmosphere predicts future incidents. Therefore, how often patients use the tool seems to send a stronger signal about potential incidents than patients' real-time reports about ward atmosphere. LIMITATIONS: Implementation was limited to two NHS trusts. Coronavirus disease 2019 impacted design processes including stakeholder engagement; implementation; and evaluation of the monitoring tool in routine clinical practice. Higher uptake could enhance validity of the results. CONCLUSIONS: WardSonar has the potential to provide a valuable route for patients to communicate safety concerns. The WardSonar monitoring tool has a strong patient perspective and uses proactive real-time safety monitoring rather than traditional retrospective data review. FUTURE WORK: The WardSonar tool can be refined and tested further in a post Coronavirus disease 2019 context. STUDY REGISTRATION: This study is registered as ISRCTN14470430. FUNDING: This award was funded by the National Institute for Health and Care Research (NIHR) Health and Social Care Delivery Research programme (NIHR award ref: NIHR128070) and is published in full in Health and Social Care Delivery Research; Vol. 12, No. 14. See the NIHR Funding and Awards website for further award information.
Are we designed to be happy?: The neuroscience of making sense of pleasure
The science of happiness is still in its infancy; there is little consensus on how happiness might be best defined, let alone studied. Still, the pursuit of happiness was inscribed in the American Constitution as a fundamental right, and recently governments around the world have started to measure the happiness and well-being of people as a measure on par with gross national product. Whatever it is, happiness is clearly desirable, yet worryingly fleeting. In this chapter, we will describe some of the scientific progress that has been made. We will take our lead from Aristotle, who was interested in the good life; a life lived embedded in meaningful values (Aristotle, 350 BC/1976). He divided the main ingredients into hedonia and eudaimonia. The former is perhaps best translated as "pleasure" (derived from hedus, the sweet taste of honey), while eudaimonia is often translated as "well-being," although it is probably better captured by "flourishing" or "meaningful pleasure.".
Expedient Access to 18F-Fluoroheteroarenes via Deaminative Radiofluorination of Aniline-Derived Pyridinium Salts.
Herein, we disclose that pyridinium salts derived from abundant (hetero)anilines represent a novel precursor class for nucleophilic aromatic substitution reactions with [18F]fluoride. The value of this new 18F-fluorodeamination is demonstrated with the synthesis of over 30 structurally diverse and complex heteroaryl 18F-fluorides, several derived from scaffolds that were yet to be labelled with fluorine-18. The protocol tolerates heteroarenes and functionalities commonly found in drug discovery libraries, and is amenable to scale-up and automation on a commercial radiosynthesiser.
Multi-dynamic modelling reveals strongly time-varying resting fMRI correlations.
The activity of functional brain networks is responsible for the emergence of time-varying cognition and behaviour. Accordingly, time-varying correlations (Functional Connectivity) in resting fMRI have been shown to be predictive of behavioural traits, and psychiatric and neurological conditions. Typically, methods that measure time varying Functional Connectivity (FC), such as sliding windows approaches, do not separately model when changes occur in the mean activity levels from when changes occur in the FC, therefore conflating these two distinct types of modulation. We show that this can bias the estimation of time-varying FC to appear more stable over time than it actually is. Here, we propose an alternative approach that models changes in the mean brain activity and in the FC as being able to occur at different times to each other. We refer to this method as the Multi-dynamic Adversarial Generator Encoder (MAGE) model, which includes a model of the network dynamics that captures long-range time dependencies, and is estimated on fMRI data using principles of Generative Adversarial Networks. We evaluated the approach across several simulation studies and resting fMRI data from the Human Connectome Project (1003 subjects), as well as from UK Biobank (13301 subjects). Importantly, we find that separating fluctuations in the mean activity levels from those in the FC reveals much stronger changes in FC over time, and is a better predictor of individual behavioural variability.
An ALS-associated mutation dysregulates microglia-derived extracellular microRNAs in a sex-specific manner.
Evidence suggests the presence of microglial activation and microRNA (miRNA) dysregulation in amyotrophic lateral sclerosis (ALS), the most common form of adult motor neuron disease. However, few studies have investigated whether the miRNA dysregulation originates from microglia. Furthermore, TDP-43 (encoded by TARDBP), involved in miRNA biogenesis, aggregates in tissues of ∼98% of ALS cases. Thus, this study aimed to determine whether expression of the ALS-linked TDP-43M337V mutation in a transgenic mouse model dysregulates microglia-derived miRNAs. RNA sequencing identified several dysregulated miRNAs released by transgenic microglia and a differential miRNA release by lipopolysaccharide-stimulated microglia, which was more pronounced in cells from female mice. We validated the downregulation of three candidate miRNAs, namely, miR-16-5p, miR-99a-5p and miR-191-5p, by reverse transcription quantitative polymerase chain reaction (RT-qPCR) and identified their predicted targets, which primarily include genes involved in neuronal development and function. These results suggest that altered TDP-43 function leads to changes in the miRNA population released by microglia, which may in turn be a source of the miRNA dysregulation observed in the disease. This has important implications for the role of neuroinflammation in ALS pathology and could provide potential therapeutic targets.
Acute neural effects of the mood stabiliser lamotrigine on emotional processing in healthy volunteers: a randomised control trial.
Lamotrigine is an effective mood stabiliser, largely used for the management and prevention of depression in bipolar disorder. The neuropsychological mechanisms by which lamotrigine acts to relieve symptoms as well as its neural effects on emotional processing remain unclear. The primary objective of this current study was to investigate the impact of an acute dose of lamotrigine on the neural response to a well-characterised fMRI task probing implicit emotional processing relevant to negative bias. 31 healthy participants were administered either a single dose of lamotrigine (300 mg, n = 14) or placebo (n = 17) in a randomized, double-blind design. Inside the 3 T MRI scanner, participants completed a covert emotional faces gender discrimination task. Brain activations showing significant group differences were identified using voxel-wise general linear model (GLM) nonparametric permutation testing, with threshold free cluster enhancement (TFCE) and a family wise error (FWE)-corrected cluster significance threshold of p
Hypoxic pulmonary vasoconstriction does not limit maximal exercise capacity in healthy volunteers breathing 12% oxygen at sea level.
Maximal exercise capacity is reduced at altitude or during hypoxia at sea level. It has been suggested that this might reflect increased right ventricular afterload due to hypoxic pulmonary vasoconstriction. We have shown previously that the pulmonary vascular sensitivity to hypoxia is enhanced by sustained isocapnic hypoxia, and inhibited by intravenous iron. In this study, we tested the hypothesis that elevated pulmonary artery pressure contributes to exercise limitation during acute hypoxia. Twelve healthy volunteers performed incremental exercise tests to exhaustion breathing 12% oxygen, before and after sustained (8-h) isocapnic hypoxia at sea level. Intravenous iron sucrose (n = 6) or saline placebo (n = 6) was administered immediately before the sustained hypoxia. In the placebo group, there was a substantial (12.6 ± 1.5 mmHg) rise in systolic pulmonary artery pressure (SPAP) during sustained hypoxia, but no associated fall in maximal exercise capacity breathing 12% oxygen. In the iron group, the rise in SPAP during sustained hypoxia was markedly reduced (3.4 ± 1.0 mmHg). There was a small rise in maximal exercise capacity following sustained hypoxia within the iron group, but no overall effect of iron, compared with saline. These results do not support the hypothesis that elevated SPAP inhibits maximal exercise capacity during acute hypoxia in healthy volunteers.
Compensatory enhancement of input maintains aversive dopaminergic reinforcement in hungry Drosophila.
Hungry animals need compensatory mechanisms to maintain flexible brain function, while modulation reconfigures circuits to prioritize resource seeking. In Drosophila, hunger inhibits aversively reinforcing dopaminergic neurons (DANs) to permit the expression of food-seeking memories. Multitasking the reinforcement system for motivation potentially undermines aversive learning. We find that chronic hunger mildly enhances aversive learning and that satiated-baseline and hunger-enhanced learning require endocrine adipokinetic hormone (AKH) signaling. Circulating AKH influences aversive learning via its receptor in four neurons in the ventral brain, two of which are octopaminergic. Connectomics revealed AKH receptor-expressing neurons to be upstream of several classes of ascending neurons, many of which are presynaptic to aversively reinforcing DANs. Octopaminergic modulation of and output from at least one of these ascending pathways is required for shock- and bitter-taste-reinforced aversive learning. We propose that coordinated enhancement of input compensates for hunger-directed inhibition of aversive DANs to preserve reinforcement when required.
Human ventromedial prefrontal cortex is necessary for prosocial motivation.
Ventromedial prefrontal cortex (vmPFC) is vital for decision-making. Functional neuroimaging links vmPFC to processing rewards and effort, while parallel work suggests vmPFC involvement in prosocial behaviour. However, the necessity of vmPFC for these functions is unknown. Patients with rare focal vmPFC lesions (n = 25), patients with lesions elsewhere (n = 15) and healthy controls (n = 40) chose between rest and exerting effort to earn rewards for themselves or another person. vmPFC damage decreased prosociality across behavioural and computational measures. vmPFC patients earned less, discounted rewards by effort more, and exerted less force when another person benefited, compared to both control groups. Voxel-based lesion mapping revealed dissociations between vmPFC subregions. While medial damage led to antisocial behaviour, lateral damage increased prosocial behaviour relative to patients with damage elsewhere. vmPFC patients also showed reduced effort sensitivity overall, but reward sensitivity was limited to specific subregions. These results reveal multiple causal contributions of vmPFC to prosocial behaviour, effort and reward.
Measurement Invariance of the Higher-Order Model of Preschool Anxiety Scale (PAS) across Child Age, Gender, Parental Anxiety, and Pandemic Period in England
The Preschool Anxiety Scale (PAS) is a parent-report scale measuring young children’s anxiety symptoms involving five specific anxiety symptoms (separation anxiety, physical injury fears, social phobia, obsessive-compulsive disorder, generalised anxiety) that load on a higher-order factor representing general anxiety shared by all specific anxiety symptom subtypes. Although the PAS has been widely used to assess anxiety symptoms in young children, few studies have tested its measurement invariance for group comparisons. Using data from a sample of 2,221 children and their parents/carers in England, this study investigated the measurement invariance of the higher-order model of the PAS across child age (4-6 years vs. 6-7 years), gender (girls vs. boys), parental anxiety (low vs. high level), and children’s living circumstances (before vs. after the removal of COVID-19 restrictions). Our findings demonstrated the good factor structure, internal consistency, and convergent validity of the higher-order model of the PAS in all subgroups and supported its configural, metric, scalar invariance across these subgroups. Therefore, the findings suggest that the PAS is a reliable and valid instrument for assessing specific anxiety symptoms and general anxiety among young children in England, and that comparisons can be made between the subgroups under examination. Keywords: Anxiety symptoms, Preschool anxiety scale, Measurement invariance, Group comparisons, Early childhood
Dorsal Striatal Functional Connectivity and Repetitive Behavior Dimensions in Children and Youths With Neurodevelopmental Disorders.
BACKGROUND: Impairing repetitive behaviors are one of the core diagnostic symptoms in autism spectrum disorder and obsessive-compulsive disorder, but they also manifest in attention-deficit/hyperactivity disorder. Although the dorsal striatal circuit has been implicated in repetitive behaviors, extensive heterogeneity in and cross-diagnostic manifestations of these behaviors have suggested phenotypic and likely neurobiological heterogeneity across neurodevelopmental disorders (NDDs). METHODS: Intrinsic dorsal striatal functional connectivity was examined in 3 NDDs (autism spectrum disorder, obsessive-compulsive disorder, and attention-deficit/hyperactivity disorder) and typically developing control participants in a large single-cohort sample (N = 412). To learn how diagnostic labels and overlapping behaviors manifest in dorsal striatal functional connectivity measured with functional magnetic resonance imaging, the main and interaction effects of diagnosis and behavior were examined in 8 models (2 seed functional connectivity [caudate and putamen] × 4 sub-behavioral domains [sameness/ritualistic, self-injury, stereotypy, and compulsions]). RESULTS: The obsessive-compulsive disorder group demonstrated distinctive patterns in visual and visuomotor coordination regions compared with the other diagnostic groups. Lower-order repetitive behaviors (self-injury and stereotypy) manifesting across all participants were implicated in regions involved in motor and cognitive control, although the findings did not survive effects of multiple comparisons, suggesting heterogeneity in these behavioral domains. An interaction between self-injurious behavior and an attention-deficit/hyperactivity disorder diagnosis were observed on caudate-cerebellum functional connectivity. CONCLUSIONS: These findings confirmed high heterogeneity and overlapping behavioral manifestations in NDDs and their complex underlying neural mechanisms. A call for diagnosis-free symptom measures that can capture not only observable symptoms and severity across NDDs but also the underlying functions and motivations of such behaviors across diagnoses is needed.
Organization of thalamocortical structural covariance and a corresponding 3D atlas of the mouse thalamus.
For information from sensory organs to be processed by the brain, it is usually passed to appropriate areas of the cerebral cortex. Almost all of this information passes through the thalamus, a relay structure that reciprocally connects to the vast majority of the cortex. The thalamus facilitates this information transfer through a set of thalamocortical connections that vary in cellular structure, molecular profiles, innervation patterns, and firing rates. Additionally, corticothalamic connections allow for intracortical information transfer through the thalamus. These efferent and afferent connections between the thalamus and cortex have been the focus of many studies, and the importance of cortical connectivity in defining thalamus anatomy is demonstrated by multiple studies that parcellate the thalamus based on cortical connectivity profiles. Here, we examine correlated morphological variation between the thalamus and cortex, or thalamocortical structural covariance. For each voxel in the thalamus as a seed, we construct a cortical structural covariance map that represents correlated cortical volume variation, and examine whether high structural covariance is observed in cortical areas that are functionally relevant to the seed. Then, using these cortical structural covariance maps as features, we subdivide the thalamus into six non-overlapping regions (clusters of voxels), and assess whether cortical structural covariance is associated with cortical connectivity that specifically originates from these regions. We show that cortical structural covariance is high in areas of the cortex that are functionally related to the seed voxel, cortical structural covariance varies along cortical depth, and sharp transitions in cortical structural covariance profiles are observed when varying seed locations in the thalamus. Subdividing the thalamus based on structural covariance, we additionally demonstrate that the six thalamic clusters of voxels stratify cortical structural covariance along the dorsal-ventral, medial-lateral, and anterior-posterior axes. These cluster-associated structural covariance patterns are prominently detected in cortical regions innervated by fibers projecting out of their related thalamic subdivisions. Together, these results advance our understanding of how the thalamus and the cortex couple in their volumes. Our results indicate that these volume correlations reflect functional organization and structural connectivity, and further provides a novel segmentation of the mouse thalamus that can be used to examine thalamic structural variation and thalamocortical structural covariation in disease models.
Disordered social cognition: Alexithymia and interoception
Alexithymia is a condition characterized by difficulties identifying and describing one's own emotional states (Nemiah, Freyberger, & Sifneos, 1976). Individuals with alexithymia are often aware that they are experiencing an emotion, but struggle to determine whether it is fear, excitement, or anger, for example. Alexithymia is therefore associated with difficulties describing how one would feel in particular emotional scenarios (Lane et al., 1990), as well as with difficulties regulating one's emotions (Stasiewicz et al., 2012; Venta, Hart, & Sharp, 2013). This chapter details the behavioral and neurological characteristics of alexithymia, its etiology (including whether it may be evolutionarily adaptive), and its role in emotional impairment across clinical populations. The relationship between alexithymia and interoception (the ability to perceive and recognize the internal state of one's body) is also discussed, alongside evidence that alexithymia may represent a general deficit of interoception.
Efficacy and effectiveness of antipsychotics in schizophrenia: network meta-analyses combining evidence from randomised controlled trials and real-world data.
BACKGROUND: There is debate about the generalisability of results from randomised clinical trials (RCTs) to real-world settings. Studying outcomes of treatments for schizophrenia can shed light on this issue and inform treatment guidelines. We therefore compared the efficacy and effectiveness of antipsychotics for relapse prevention in schizophrenia and estimated overall treatment effects using all available RCT and real-world evidence. METHODS: We conducted network meta-analyses using individual participant data from Swedish and Finnish national registries and aggregate data from RCTs. The target population was adults (age >18 and <65 years) with schizophrenia and schizoaffective disorder with stabilised symptoms. We analysed each registry separately to obtain hazard ratios (HRs) and 95% CIs for relapse within 6 months post-antipsychotic initiation as our main outcome. Interventions studied were antipsychotics, no antipsychotic use, and placebo. We compared HRs versus a reference drug (oral haloperidol) between registries, and between registry individuals who would be eligible and ineligible for RCTs, using the ratio of HRs. We synthesised evidence using network meta-analysis and compared results from our network meta-analysis of real-world data with our network meta-analysis of RCT data, including oral versus long-acting injectable (LAI) formulations. Finally, we conducted a joint real-world and RCT network meta-analysis. FINDINGS: We included 90 469 individuals from the Swedish and Finnish registries (mean age 45·9 [SD 14·6] years; 43 025 [47·5%] women and 47 467 [52·5%] men, ethnicity data unavailable) and 10 091 individuals from 30 RCTs (mean age 39·6 years [SD 11·7]; 3724 [36·9%] women and 6367 [63·1%] men, 6022 White [59·7%]). We found good agreement in effectiveness of antipsychotics between Swedish and Finnish registries (HR ratio 0·97, 95% CI 0·88-1·08). Drug effectiveness versus no antipsychotic was larger in RCT-eligible than RCT-ineligible individuals (HR ratio 1·40 [1·24-1·59]). Efficacy versus placebo in RCTs was larger than effectiveness versus no antipsychotic in real-world (HR ratio 2·58 [2·02-3·30]). We found no evidence of differences between effectiveness and efficacy for between-drug comparisons (HR ratio vs oral haloperidol 1·17 [0·83-1·65], where HR ratio >1 means superior effectiveness in real-world to RCTs), except for LAI versus oral comparisons (HR ratio 0·73 [0·53-0·99], indicating superior effectiveness in real-world data relative to RCTs). The real-world network meta-analysis showed clozapine was most effective, followed by olanzapine LAI. The RCT network meta-analysis exhibited heterogeneity and inconsistency. The joint real-world and RCT network meta-analysis identified olanzapine as the most efficacious antipsychotic amongst those present in both RCTs and the real world registries. INTERPRETATION: LAI antipsychotics perform slightly better in the real world than according to RCTs. Otherwise, RCT evidence was in line with real-world evidence for most between-drug comparisons, but RCTs might overestimate effectiveness of antipsychotics observed in routine care settings. Our results further the understanding of the generalisability of RCT findings to clinical practice and can inform preferential prescribing guidelines. FUNDING: None.
Treatment Outcomes With Licensed and Unlicensed Stimulant Doses for Adults With Attention-Deficit/Hyperactivity Disorder: A Systematic Review and Meta-Analysis.
IMPORTANCE: Stimulants (methylphenidate and amphetamines) are often prescribed at unlicensed doses for adults with attention-deficit/hyperactivity disorder (ADHD). Whether dose escalation beyond US Food and Drug Administration recommendations is associated with positive risk benefits is unclear. OBJECTIVE: To investigate the impact, based on averages, of stimulant doses on treatment outcomes in adults with ADHD and to determine, based on averages, whether unlicensed doses are associated with positive risk benefits compared with licensed doses. DATA SOURCES: Twelve databases, including published (PubMed, Cochrane Library, Embase, Web of Sciences) and unpublished (ClinicalTrials.gov) literature, up to February 22, 2023, without language restrictions. STUDY SELECTION: Two researchers independently screened records to identify double-blinded randomized clinical trials of stimulants against placebo in adults (18 years and older) with ADHD. DATA EXTRACTION AND SYNTHESIS: Aggregate data were extracted and synthesized in random-effects dose-response meta-analyses and network meta-analyses. MAIN OUTCOME MEASURES: Change in ADHD symptoms and discontinuations due to adverse events. RESULTS: A total of 47 randomized clinical trials (7714 participants; mean age, 35 (SD, 11) years; 4204 male [56%]) were included. For methylphenidate, dose-response curves indicated additional reductions of symptoms with increments in doses, but the gains were progressively smaller and accompanied by continued additional risk of adverse events dropouts. Network meta-analyses showed that unlicensed doses were associated with greater reductions of symptoms compared with licensed doses (standardized mean difference [SMD], -0.23; 95% CI, -0.44 to -0.02; very low certainty of evidence), but the additional gain was small and accompanied by increased risk of adverse event dropouts (odds ratio, 2.02; 95% CI, 1.19-3.43; moderate certainty of evidence). For amphetamines, the dose-response curve approached a plateau and increments in doses did not indicate additional reductions of symptoms, but there were continued increments in the risk of adverse event dropouts. Network meta-analysis did not identify differences between unlicensed and licensed doses for reductions of symptoms (SMD, -0.08; 95% CI, -0.24 to 0.08; very low certainty of evidence). CONCLUSIONS AND RELEVANCE: Based on group averages, unlicensed doses of stimulants may not have positive risk benefits compared with licensed doses for adults with ADHD. In general, practitioners should consider unlicensed doses cautiously. Practitioners may trial unlicensed doses if needed and tolerated but should be aware that there may not be large gains in the response to the medication with those further increments in dose. However, the findings are averages and will not generalize to every patient.
A Virtual Reality (VR) based Comprehensive Freezing of Gait (FOG) Neuro-electrophysiologic Evaluation System for People with Parkinson's Disease (PD).
Although Freezing of gait (FOG) is one of the most frustrating phenomena for people with Parkinson's Disease (PD), especially in their advanced stage, it is one of the least explained syndromes. The current studies only showed beta oscillations existed in frontal cortex-basal ganglia networks. Further studies need to be carried out. However, simultaneously recording neuro-electrophysiologic signals during walking is always a challenge, especially for Electroencephalogram (EEG) and Local Field Potential (LFP). This paper demonstrated a Virtual Reality (VR) based system which can trigger FOG and record biological signals at the same time. Moreover, the utilisation of VR will significantly decrease space requirements. It will provide a safer and more convenient evaluation environment for future participants. One participant with PD helped to validate the feasibility of the system. The result showed that both EEG and LFP could be recorded at the same time with trigger markers. This system design can be used to trigger freezing episodes in the controlled environment, differentiate subtypes of gait difficulties, and identify neural signatures associated with freezing episodes.Clinical relevance - This paper proposed a VR-based comprehensive FOG neuro-electrophysiologic evaluation system for people with PD. It had the advantages of minimum space requirement and wireless LFP data collection without externalised leads. This paper was to indicate a larger study which would formally recruit larger populations with PD and FOG. Future studies would explore FOG-related brain network coherence.
‘A commitment to Equality, Diversity and Inclusion’: a conceptual framework for equality of opportunity in Patient and Public Involvement in research
Many research institutions and funders have recently stated their commitment to actively support and promote ‘Equality, Diversity and Inclusion’ (EDI) in various aspects of health research including Patient and Public Involvement (PPI). However, translating this commitment into specific research projects presents significant challenges that existing approaches, practical guidelines and initiatives have not adequately addressed. In this paper, we explore how the lack of clear justifications for the EDI commitment in existing guidelines inadvertently complicates the work of those involved with PPI and we stress the need for conceptual clarity for any EDI effort to yield meaningful results. Our focus centres on the first principle of the EDI discourse, ‘equality’, particularly in the form of ‘equality of opportunity’ as outlined in current guidance provided by the National Institute of Health Research in the United Kingdom. We examine challenges related to justifying and implementing a general, unspecified commitment to equality of opportunity and explain that this reflects a lack of consensus regarding the moral value of PPI in research – a profound problem that remains unaddressed. We then discuss how the presence of several opposing moral perspectives on PPI, makes determining the most appropriate way of addressing barriers to involvement complex and controversial, raising ethical implications for the work of health researchers, PPI specialists and coordinators. Finally we make suggestions on how future research can enrich the concept of ‘equality of opportunity’ in PPI and improve practice. While our primary focus is on the NIHR, a strong advocate of PPI in research, this analysis will point to normative and ethical considerations that may be relevant to other research institutions and funding organisations aiming to promote equality of opportunity in their public and patient involvement strategies.
Enhancing Tree Performance Through Species Mixing: Review of a Quarter-Century of TreeDivNet Experiments Reveals Research Gaps and Practical Insights
Purpose of Review: International ambitions for massive afforestation and restoration are high. To make these investments sustainable and resilient under future climate change, science is calling for a shift from planting monocultures to mixed forests. But what is the scientific basis for promoting diverse plantations, and what is the feasibility of their establishment and management? As the largest global network of tree diversity experiments, TreeDivNet is uniquely positioned to answer these pressing questions. Building on 428 peer-reviewed TreeDivNet studies, combined with the results of a questionnaire completed by managers of 32 TreeDivNet sites, we aimed to answer the following questions: (i) How and where have TreeDivNet experiments enabled the relationship between tree diversity and tree performance (including productivity, survival, and pathogen damage) to be studied, and what has been learned? (ii) What are the remaining key knowledge gaps in our understanding of the relationship between tree diversity and tree performance? and (iii) What practical insights can be gained from the TreeDivNet experiments for operational, real-world forest plantations? Recent Findings: We developed a conceptual framework that identifies the variety of pathways through which target tree performance is related to local neighbourhood diversity and mapped the research efforts for each of those pathways. Experimental research on forest mixtures has focused primarily on direct tree diversity effects on productivity, with generally positive effects of species and functional diversity on productivity. Fewer studies focused on indirect effects mediated via biotic growing conditions (e.g. soil microbes and herbivores) and resource availability and uptake. Most studies examining light uptake found positive effects of species diversity. For pests and diseases, the evidence points mostly towards lower levels of infection for target trees when growing in mixed plantations. Tree diversity effects on the abiotic growing conditions (e.g. microclimate, soil properties) and resource-use efficiency have been less well studied to date. The majority of tree diversity experiments are situated in temperate forests, while (sub)tropical forests, and boreal forests in particular, remain underrepresented. Summary: TreeDivNet provides evidence in favour of mixing tree species to increase tree productivity while identifying a variety of different processes that drive these diversity effects. The design, scale, age, and management of TreeDivNet experiments reflect their focus on fundamental research questions pertaining to tree diversity-ecosystem function relationships and this scientific focus complicates translation of findings into direct practical management guidelines. Future research could focus on (i) filling the knowledge gaps related to underlying processes of tree diversity effects to better design plantation schemes, (ii) identifying optimal species mixtures, and (iii) developing practical approaches to make experimental mixed plantings more management oriented.
Enabling nucleophilic reactivity in molecular calcium fluoride complexes.
Calcium fluoride is the ultimate source of all fluorochemicals. Current synthetic approaches rely on the use of HF, generated from naturally occurring fluorspar and sulfuric acid. Methods for constructing E-F bonds directly from CaF2 have long been frustrated by its high lattice energy, low solubility and impaired fluoride ion nucleophilicity. Little fundamental understanding of the reactivity of Ca-F moieties is available to guide methodology development; well-defined molecular species containing Ca-F bonds are extremely rare, and existing examples are strongly aggregated and evidence no nucleophilic fluoride delivery. Here, by contrast, we show that by targeting anionic systems of the type [Ln(X)2CaF]-, monomeric calcium fluoride complexes containing single Ca-F bonds can be synthesized, including via routes involving fluoride abstraction from existing C-F bonds. Comparative structural and spectroscopic studies of mono- and dinuclear systems allow us to define structure-activity relationships for E-F bond formation from molecular calcium fluorides.
The 18F-Difluoromethyl Group: Challenges, Impact and Outlook.
The difluoromethyl functionality has proven useful in drug discovery, as it can modulate the properties of bioactive molecules. For PET imaging, this structural motif has been largely underexploited in (pre)clinical radiotracers due to a lack of user-friendly radiosynthetic routes. This Minireview provides an overview of the challenges facing radiochemists and summarises the efforts made to date to access 18F-difluoromethyl-containing radiotracers. Two distinct approaches have prevailed, the first of which relies on 18F-fluorination. A second approach consists of a 18F-difluoromethylation process, which uses 18F-labelled reagents capable of releasing key reactive intermediates such as the [18F]CF2H radical or [18F]difluorocarbene. Finally, we provide an outlook for future directions in the radiosynthesis of [18F]CF2H compounds and their application in tracer radiosynthesis.