{ "items": [ "\n\n
AbstractA key aim in epidemiological neuroscience is identification of markers to assess brain health and monitor therapeutic interventions. Quantitative susceptibility mapping (QSM) is an emerging magnetic resonance imaging technique that measures tissue magnetic susceptibility and has been shown to detect pathological changes in tissue iron, myelin and calcification. We present an open resource of QSM-based imaging measures of multiple brain structures in 35,273 individuals from the UK Biobank prospective epidemiological study. We identify statistically significant associations of 251 phenotypes with magnetic susceptibility that include body iron, disease, diet and alcohol consumption. Genome-wide associations relate magnetic susceptibility to 76 replicating clusters of genetic variants with biological functions involving iron, calcium, myelin and extracellular matrix. These patterns of associations include relationships that are unique to QSM, in particular being complementary to T2* signal decay time measures. These new imaging phenotypes are being integrated into the core UK Biobank measures provided to researchers worldwide, creating the potential to discover new, non-invasive markers of brain health.
\n \n\n \n \nAbstract\nHuntington\u2019s and Parkinson\u2019s disease are two movement disorders representing mainly opposite states of the basal ganglia inhibitory function. Despite being an integral part of the cortico-subcortico-cortical circuitry, the subthalamic nucleus function has been studied at the level of detail required to isolate its signal only through invasive studies in Huntington\u2019s and Parkinson\u2019s disease. Here, we tested whether the subthalamic nucleus exhibited opposite functional signatures in early Huntington\u2019s and Parkinson\u2019s disease. We included both movement disorders in the same whole-brain imaging study, and leveraged ultra-high-field 7T MRI to achieve the very fine resolution needed to investigate the smallest of the basal ganglia nuclei. Eleven of the 12 Huntington\u2019s disease carriers were recruited at a premanifest stage, while 16 of the 18 Parkinson\u2019s disease patients only exhibited unilateral motor symptoms (15 were at Stage I of Hoehn and Yahr off medication). Our group comparison interaction analyses, including 24 healthy controls, revealed a differential effect of Huntington\u2019s and Parkinson\u2019s disease on the functional connectivity at rest of the subthalamic nucleus within the sensorimotor network, i.e. an opposite effect compared with their respective age-matched healthy control groups. This differential impact in the subthalamic nucleus included an area precisely corresponding to the deep brain stimulation \u2018sweet spot\u2019\u2014the area with maximum overall efficacy\u2014in Parkinson\u2019s disease. Importantly, the severity of deviation away from controls\u2019 resting-state values in the subthalamic nucleus was associated with the severity of motor and cognitive symptoms in both diseases, despite functional connectivity going in opposite directions in each disorder. We also observed an altered, opposite impact of Huntington\u2019s and Parkinson\u2019s disease on functional connectivity within the sensorimotor cortex, once again with relevant associations with clinical symptoms. The high resolution offered by the 7T scanner has thus made it possible to explore the complex interplay between the disease effects and their contribution on the subthalamic nucleus, and sensorimotor cortex. Taken altogether, these findings reveal for the first time non-invasively in humans a differential, clinically meaningful impact of the pathophysiological process of these two movement disorders on the overall sensorimotor functional connection of the subthalamic nucleus and sensorimotor cortex.
\n \n\n \n \nAbstractA key aim in epidemiological neuroscience is identification of markers to assess brain health and monitor therapeutic interventions. Quantitative susceptibility mapping (QSM) is an emerging MRI technique that measures tissue magnetic susceptibility and has been shown to detect pathological changes in tissue iron, myelin and calcification. We developed a QSM processing pipeline to estimate magnetic susceptibility of multiple brain structures in 35,885 subjects from the UK Biobank prospective epidemiological study. We identified phenotypic associations of magnetic susceptibility that include body iron, disease, diet, and alcohol consumption. Genome-wide associations related magnetic susceptibility to genetic variants with biological functions involving iron, calcium, myelin, and extracellular matrix. These patterns of associations include relationships that are unique to QSM, in particular being complementary to T2* measures. These new imaging phenotypes are being integrated into the core UK Biobank measures provided to researchers world-wide, creating potential to discover novel, non-invasive markers of brain health.
\n \n\n \n \nAbstractBrain imaging can be used to study how individuals\u2019 brains are aging, compared against population norms. This can inform on aspects of brain health; for example, smoking and blood pressure can be seen to accelerate brain aging. Typically, a single \u201cbrain age\u201d is estimated per subject, whereas here we we identified 62 modes of subject variability, from 21,407 subjects\u2019 multimodal brain imaging data in UK Biobank. The modes represent different aspects of brain aging, showing distinct patterns of functional and structural brain change, and distinct patterns of association with genetics, lifestyle, cognition, physical measures and disease. While conventional brain-age modelling found no genetic associations, 34 modes had genetic associations. We suggest that it is important not to treat brain aging as a single homogeneous process, and that modelling of distinct patterns of structural and functional change will reveal more biologically meaningful markers of brain aging in health and disease.
\n \n\n \n \nResting-state fMRI studies have shown that multiple functional networks, which consist of distributed brain regions that share synchronised spontaneous activity, co-exist in the brain. As these resting-state networks (RSNs) have been thought to reflect the brain's intrinsic functional organization, intersubject variability in the networks' spontaneous fluctuations may be associated with individuals' clinical, physiological, cognitive, and genetic traits. Here, we investigated resting-state fMRI data along with extensive clinical, lifestyle, and genetic data collected from 37,842 UK Biobank participants, with the object of elucidating intersubject variability in the fluctuation amplitudes of RSNs. Functional properties of the RSN amplitudes were first examined by analyzing correlations with the well-established between-network functional connectivity. It was found that a network amplitude is highly correlated with the mean strength of the functional connectivity that the network has with the other networks. Intersubject clustering analysis showed the amplitudes are most strongly correlated with age, cardiovascular factors, body composition, blood cell counts, lung function, and sex, with some differences in the correlation strengths between sensory and cognitive RSNs. Genome-wide association studies (GWASs) of RSN amplitudes identified several significant genetic variants reported in previous GWASs for their implications in sleep duration. We provide insight into key factors determining RSN amplitudes and demonstrate that intersubject variability of the amplitudes primarily originates from differences in temporal synchrony between functionally linked brain regions, rather than differences in the magnitude of raw voxelwise BOLD signal changes. This finding additionally revealed intriguing differences between sensory and cognitive RSNs with respect to sex effects on temporal synchrony and provided evidence suggesting that synchronous coactivations of functionally linked brain regions, and magnitudes of BOLD signal changes, may be related to different genetic mechanisms. These results underscore that intersubject variability of the amplitudes in health and disease need to be interpreted largely as a measure of the sum of within-network temporal synchrony and amplitudes of BOLD signals, with a dominant contribution from the former.
\n \n\n \n \nAbstractMagnetoencephalography (MEG) recordings are often contaminated by interference that can exceed the amplitude of physiological brain activity by several orders of magnitude. Furthermore, the activity of interference sources may spatially extend (known as source leakage) into the activity of brain signals of interest, resulting in source estimation inaccuracies. This problem is particularly apparent when using MEG to interrogate the effects of brain stimulation on large\u2010scale cortical networks. In this technical report, we develop a novel denoising approach for suppressing the leakage of interference source activity into the activity representing a brain region of interest. This approach leverages spatial and temporal domain projectors for signal arising from prespecified anatomical regions of interest. We apply this denoising approach to reconstruct simulated evoked response topographies to deep brain stimulation (DBS) in a phantom recording. We highlight the advantages of our approach compared to the benchmark\u2014spatiotemporal signal space separation\u2014and show that it can more accurately reveal brain stimulation\u2010evoked response topographies. Finally, we apply our method to MEG recordings from a single patient with Parkinson's disease, to reveal early cortical\u2010evoked responses to DBS of the subthalamic nucleus.
\n \n\n \n \nBACKGROUND: Appropriate care escalation requires the detection and communication of in-hospital patient deterioration. Although deterioration in the ward environment is common, there continue to be patient deaths where problems escalating care have occurred. Learning from the everyday work of health care professionals (work-as-done) and identifying performance variability may provide a greater understanding of the escalation challenges and how they overcome these. The aims of this study were to i) develop a representative model detailing escalation of care ii) identify performance variability that may negatively or positively affect this process and iii) examine linkages between steps in the escalation process. METHODS: Thirty Applied Cognitive Task Analysis interviews were conducted with clinical experts (>4\u202fyears' experience) including Ward Nurses (n\u202f=\u202f7), Outreach or Sepsis Nurses (n\u202f=\u202f8), Nurse Manager or Consultant (n\u202f=\u202f6), Physiotherapists (n\u202f=\u202f4), Advanced Practitioners (n\u202f=\u202f4), and Doctor (n\u202f=\u202f1) from two National Health Service hospitals and analysed using Framework Analysis. Task-related elements of care escalation were identified and represented in a Functional Resonance Analysis Model. FINDINGS: The NEWS2's clinical escalation response constitutes eight unique tasks and illustrates work-as-prescribed, but our interview data uncovered an additional 24 tasks (n\u202f=\u202f32) pertaining to clinical judgement, decisions or processes reflecting work-as-done. Over a quarter of these tasks (9/32, 28\u202f%) were identified by experts as cognitively challenging with a high likelihood of performance variability. Three out of the nine variable tasks were closely coupled and interdependent within the Functional Resonance Analysis Model ('synthesising data points', 'making critical decision to escalate' and 'identifying interim actions') so representing points of potential escalation failure. Data assimilation from different clinical information systems with poor usability was identified as a key cognitive challenge. CONCLUSION: Our data support the emphasis on the need to retain clinical judgement and suggest that future escalation protocols and audit guidance require in-built flexibility, supporting staff to incorporate their expertise of the patient condition and the clinical environment. Improved information systems to synthesise the required data surrounding an unwell patient to reduce staff cognitive load, facilitate decision-making, support the referral process and identify actions are required. Fundamentally, reducing the cognitive load when assimilating core escalation data allows staff to provide better and more creative care. Study registration (ISRCTN 38850) and ethical approval (REC Ref 20/HRA/3828; CAG-20CAG0106).
\n \n\n \n \nAIM: To gain staff feedback on the implementation and impact of a novel ambulatory monitoring system to support coronavirus patient management on an isolation ward. DESIGN: Qualitative service evaluation. METHODS: Semi-structured interviews were conducted with 15 multidisciplinary isolation ward staff in the United Kingdom between July 2020 and May 2021. Interviews were audio-recorded, transcribed and analysed using thematic analysis. FINDINGS: Adopting Innovation to Assist Patient Safety was identified as the overriding theme. Three interlinked sub-themes represent facets of how the system supported patient safety. Patient Selection was developed throughout the pandemic, as clinical staff became more confident in choosing which patients would benefit most. Trust In the System described how nurses coped with discrepancies between the ambulatory system and ward observation machines. Finally, Resource Management examined how, once trust was built, staff perceived the ambulatory system assisted with caseload management. This supported efficient personal protective equipment resource use by reducing the number of isolation room entries. Despite these reported benefits, face-to-face contact was still highly valued, despite the risk of coronavirus exposure. CONCLUSION: Hospital wards should consider using ambulatory monitoring systems to support caseload management and patient safety. Patients in isolation rooms or at high risk of deterioration may particularly benefit from this additional monitoring. However, these systems should be seen as an adjunct to nursing care, not a replacement. IMPLICATIONS FOR THE PROFESSION AND/OR PATIENT CARE: Nurses valued ambulatory monitoring as a means of ensuring the safety of patients at risk of deterioration and prioritizing their workload. IMPACT: The findings of this research will be useful to all those developing or considering implementation of ambulatory monitoring systems in hospital wards. REPORTING METHOD: This manuscript follows the Consolidated criteria for Reporting Qualitative Research (COREQ) guidelines with inclusion of relevant SQUIRE guidelines for reporting quality improvement. PATIENT OR PUBLIC CONTRIBUTION: No Patient or Public Contribution.
\n \n\n \n \nAbstractIn a great partnership, the Federation of European Neuroscience Societies (FENS) and the Hertie Foundation organized the FENS\u2010Hertie 2022 Winter School on \u2018Neuro\u2010immune interactions in health and disease\u2019. The school selected 27 PhD students and 13 postdoctoral fellows from 20 countries and involved 14 faculty members experts in the field. The Winter School focused on a rising field of research, the interactions between the nervous and both innate and adaptive immune systems under pathological and physiological conditions. A fine\u2010tuned neuro\u2010immune crosstalk is fundamental for healthy development, while disrupted neuro\u2010immune communication might play a role in neurodegeneration, neuroinflammation and aging. However, much is yet to be understood about the underlying mechanisms of these neuro\u2010immune interactions in the healthy brain and under pathological scenarios. In addition to new findings in this emerging field, novel methodologies and animal models were presented to foment research on neuro\u2010immunology. The FENS\u2010Hertie 2022 Winter School provided an insightful knowledge exchange between students and faculty focusing on the latest discoveries in the biology of neuro\u2010immune interactions while fostering great academic and professional opportunities for early\u2010career neuroscientists from around the world.
\n \n\n \n \nA recent study by Suissa and colleagues explored the clinical relevance of a medical image segmentation metric (Dice metric) commonly used in the field of artificial intelligence (AI). They showed that pixel-wise agreement for physician identification of structures on ultrasound images is variable, and a relatively low Dice metric (0.34) correlated to a substantial agreement on subjective clinical assessment. We highlight the need to bring structure and clinical perspective to the evaluation of medical AI, which clinicians are best placed to direct.
\n \n\n \n \nAbstract\nBackground\nThere is a need to improve the treatment of prostate cancer (PCa) and reduce treatment side effects. Vascular-targeted photodynamic therapy (VTP) is a focal therapy for low-risk low-volume localised PCa, which rapidly disrupts targeted tumour vessels. There is interest in expanding the use of VTP to higher-risk disease. Tumour vasculature is characterised by vessel immaturity, increased permeability, aberrant branching and inefficient flow. FRT alters the tumour microenvironment and promotes transient \u2018vascular normalisation\u2019. We hypothesised that multimodality therapy combining fractionated radiotherapy (FRT) and VTP could improve PCa tumour control compared against monotherapy with FRT or VTP.\n\nMethods\nWe investigated whether sequential delivery of FRT followed by VTP 7 days later improves flank TRAMP-C1 PCa tumour allograft control compared to monotherapy with FRT or VTP.\n\nResults\nFRT induced \u2018vascular normalisation\u2019 changes in PCa flank tumour allografts, improving vascular function as demonstrated using dynamic contrast-enhanced magnetic resonance imaging. FRT followed by VTP significantly delayed tumour growth in flank PCa allograft pre-clinical models, compared with monotherapy with FRT or VTP, and improved overall survival.\n\nConclusion\nCombining FRT and VTP may be a promising multimodal approach in PCa therapy. This provides proof-of-concept for this multimodality treatment to inform early phase clinical trials.\n
\n \n\n \n \nIdentifying factors that are causes of disease progression, especially in neurodegenerative diseases, is of considerable interest. Disease progression can be described as a trajectory of outcome over time-for example, a linear trajectory having both an intercept (severity at time zero) and a slope (rate of change). A technique for identifying causal relationships between one exposure and one outcome in observational data whilst avoiding bias due to confounding is two sample Mendelian Randomisation (2SMR). We consider a multivariate approach to 2SMR using a multilevel model for disease progression to estimate the causal effect an exposure has on the intercept and slope. We carry out a simulation study comparing a na\u00efve univariate 2SMR approach to a multivariate 2SMR approach with one exposure that effects both the intercept and slope of an outcome that changes linearly with time since diagnosis. The simulation study results, across six different scenarios, for both approaches were similar with no evidence against a non-zero bias and appropriate coverage of the 95% confidence intervals (for intercept 93.4-96.2% and the slope 94.5-96.0%). The multivariate approach gives a better joint coverage of both the intercept and slope effects. We also apply our method to two Parkinson's cohorts to examine the effect body mass index has on disease progression. There was no strong evidence that BMI affects disease progression, however the confidence intervals for both intercept and slope were wide.
\n \n\n \n \nThe International Parkinson and Movement Disorder Society (MDS) created a task force (TF) to provide a critical overview of the Parkinson's disease (PD) subtyping field and develop a guidance on future research in PD subtypes. Based on a literature review, we previously concluded that PD subtyping requires an ultimate alignment with principles of precision medicine, and consequently novel approaches were needed to describe heterogeneity at the individual patient level. In this manuscript, we present a novel purpose-driven framework for subtype research as a guidance to clinicians and researchers when proposing to develop, evaluate, or use PD subtypes. Using a formal consensus methodology, we determined that the key purposes of PD subtyping are: (1) to predict disease progression, for both the development of therapies (use in clinical trials) and prognosis counseling, (2) to predict response to treatments, and (3) to identify therapeutic targets for disease modification. For each purpose, we describe the desired product and the research required for its development. Given the current state of knowledge and data resources, we see purpose-driven subtyping as a pragmatic and necessary step on the way to precision medicine. \u00a9 2024 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.
\n \n\n \n \nCorrect placement of supraglottic airway devices (SGDs) is crucial for patient safety and of prime concern of anesthesiologists who want to provide effective and efficient airway management to their patients undergoing surgery or procedures requiring anesthesia care. In the majority of cases, blind insertion of SGDs results in less-than-optimal anatomical and functional positioning of the airway devices. Malpositioning can cause clinical malfunction and result in interference with gas exchange, loss-of-airway, gastric inflation, and aspiration of gastric contents. A close match is needed between the shape and profile of SGDs and the laryngeal inlet. An adequate first seal (with the respiratory tract) and a good fit at the second seal of the distal cuff and the gastrointestinal tract are most desirable. Vision-guided insertion techniques are ideal and should be the way forward. This article recommends the use of third-generation vision-incorporated-video SGDs, which allow for direct visualization of the insertion process, corrective maneuvers, and, when necessary, insertion of a nasogastric tube (NGT) and/or endotracheal tube (ETT) intubation. A videoscope embedded within the SGD allows a visual check of the glottis opening and position of the epiglottis. This design affords the benefit of confirming and/or correcting a SGD's position in the midline and rotation in the sagittal plane. The first clinically available video laryngeal mask airways (VLMAs) and multiple prototypes are being tested and used in anesthesia. Existing VLMAs are still not perfect, and further improvements are recommended. Additional modifications in multicamera technology, to obtain a panoramic view of the SGD sitting correctly in the hypopharynx and to prove that correct sizes have been used, are in the process of production. Ultimately, any device inserted orally-SGD, ETT, NGT, temperature probe, transesophageal scope, neural integrity monitor (NIM) tubes-could benefit from correct vision-guided positioning. VLMAs also allow for automatic recording, which can be documented in clinical records of patients, and could be valuable during teaching and research, with potential value in case of legal defence (with an airway incident). If difficulties occur with the airway, documentation in the patient's file may help future anesthesiologists to better understand the real-time problems. Both manufacturers and designers of SGDs may learn from optimally positioned SGDs to improve the design of these airway devices.
\n \n\n \n \n