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The Past, Present, and Future of the Brain Imaging Data Structure (BIDS).
The Brain Imaging Data Structure (BIDS) is a community-driven standard for the organization of data and metadata from a growing range of neuroscience modalities. This paper is meant as a history of how the standard has developed and grown over time. We outline the principles behind the project, the mechanisms by which it has been extended, and some of the challenges being addressed as it evolves. We also discuss the lessons learned through the project, with the aim of enabling researchers in other domains to learn from the success of BIDS.
Why every lab needs a handbook.
A lab handbook is a flexible document that outlines the ethos of a research lab or group. A good handbook will outline the different roles within the lab, explain what is expected of all lab members, provide an overview of the culture the lab aims to create, and describe how the lab supports its members so that they can develop as researchers. Here we describe how we wrote a lab handbook for a large research group, and provide resources to help other labs write their own handbooks.
Association of multimorbidity with mortality after stroke stratified by age, severity, aetiology, and prior disability.
INTRODUCTION: Multimorbidity is common in patients with stroke, and is associated with increased medium to long-term mortality, but its value for clinical decision-making and case-mix adjustment will depend on other factors, such as age, stroke severity, aetiological subtype, prior disability, and vascular risk factors. AIMS: In the absence of previous studies, we related multimorbidity to long-term post-stroke mortality with stratification by these factors. METHODS: In patients ascertained in a population-based stroke incidence study (Oxford Vascular Study; 2002-2017), we related pre-stroke multimorbidity (weighted/unweighted Charlson Comorbidity Index-CCI) to all-cause/vascular/non-vascular mortality (1/5/10-years) using regression models adjusted/stratified by age, sex, predicted early outcome (THRIVE Score), stroke severity (NIH Stroke Scale-NIHSS), aetiology (TOAST), pre-morbid disability (modified Rankin Scale-mRS), and non-CCI risk factors (hypertension, hyperlipidaemia, atrial fibrillation, smoking, deprivation, anxiety/depression). RESULTS: Among 2454 stroke patients (mean/SD age 74.1/13.9; 48.9% male; mean/SD NIHSS 5.7/7.0), 1375/56.0% had ≥1 CCI comorbidity and 685/27.9% had ≥2. After age/sex adjustment, multimorbidity (unweighted CCI≥2vs0) predicted (all p<0.001) mortality at 1-year (aHR=1.57, 95%CI=1.38-1.78), 5-years (1.73, 1.53-1.96), and 10-years (1.79, 1.58-2.03). Although multimorbidity was independently associated with pre-morbid disability (mRS>2: aOR=2.76, 2.13-3.60) and non-CCI risk factors (hypertension-1.56, 1.25-1.95; hyperlipidaemia-2.58, 2.03-3.28; atrial fibrillation-2.31; 1.78-2.98; smoking-1.37, 1.01-1.86), it predicted death after adjustment for all measured confounders (10-year-aHR=1.56, 1.37-1.78, p<0.001), driven mainly by non-vascular death (aHR=1.89, 1.55-2.29). Predictive value for 10-year all-cause death was greatest in patients with lower expected early mortality: lower THRIVE Score (pint<0.001), age<75 (aHR=2.27, 1.71-3.00), NIHSS<5 (1.84, 1.53-2.21), and lacunar stroke (3.56, 2.14-5.91). Results were similar using the weighted CCI. CONCLUSIONS: Pre-stroke multimorbidity is highly prevalent and is an independent predictor of death after stroke, supporting its inclusion in case-mix adjustment models and in informing decision-making by patients, families, and carers. Prediction in younger patients and after minor stroke, particularly for non-vascular death, suggests potential clinical utility in targeting interventions that require survival for 5-10 years to achieve a favourable risk/benefit ratio. DATA ACCESS STATEMENT: Data requests will be considered by the OXVASC Study Director (PMR-peter.rothwell@ndcn.ox.ac.uk).
The randomised thoracoscopic talc poudrage+indwelling pleural catheters versus thoracoscopic talc poudrage only in malignant pleural effusion trial (TACTIC): study protocol for a randomised controlled trial
IntroductionMalignant pleural effusion (MPE) is common, with 50 000 new cases per year in the UK. MPE causes disabling breathlessness and indicates advanced disease with a poor prognosis. Treatment approaches focus on symptom relief and optimising quality of life (QoL). Patients who newly present with MPE commonly require procedural intervention for both diagnosis and therapeutic benefit.Thoracoscopic pleural biopsies are highly sensitive in diagnosing pleural malignancy. Talc poudrage may be delivered at thoracoscopy (TTP) to prevent effusion recurrence by effecting pleurodesis. Indwelling pleural catheters (IPCs) offer an alternative strategy for fluid control, enabling outpatient management and are often used as ‘rescue’ therapy following pleurodesis failure or in cases of ‘trapped lung’. It is unknown whether combining a TTP with IPC insertion will improve patient symptoms or reduce time spent in the hospital.The randomised thoracoscopic talc poudrage + indwelling pleural catheters versus thoracoscopic talc poudrage only in malignant pleural effusion trial (TACTIC) is the first randomised controlled trial (RCT) to examine the benefit of a combined TTP and IPC procedure, evaluating cost-effectiveness and patient-centred outcomes such as symptoms and QoL. The study remains in active recruitment and has the potential to radically transform the pathway for all patients presenting with MPE.Methods and analysisTACTIC is an unblinded, multicentre, RCT comparing the combination of TTP with an IPC to TTP alone. Co-primary outcomes are time spent in the hospital and mean breathlessness score over 4 weeks postprocedure. The study will recruit 124 patients and aims to define the optimal pathway for patients presenting with symptomatic MPE.Ethics and disseminationTACTIC is sponsored by North Bristol NHS Trust and has been granted ethical approval by the London-Brent Research Ethics Committee (REC ref: 21/LO/0495). Publication of results in a peer-reviewed journal and conference presentations are anticipated.Trial registrationISRCTN 11058680.
Economic burden of cardiovascular diseases in the European Union: a population-based cost study
Background & aims Cardiovascular disease (CVD) impacts significantly health and social care systems as well as society through premature mortality and disability, with patients requiring care from relatives. Previous pan-European estimates of the economic burden of CVD are now outdated. This study aims to provide novel, up-to-date evidence on the economic burden across the 27 European Union (EU) countries in 2021. Methods Aggregate country-specific resource use data on morbidity, mortality, and health, social and informal care were obtained from international sources, such as the Statistical Office of the European Communities, enhanced by data from the European Society of Cardiology Atlas programme and patient-level data from the Survey of Health, Ageing and Retirement in Europe. Country-specific unit costs were used, with cost estimates reported on a per capita basis, after adjustment for price differentials. Results CVD is estimated to cost the EU €282 billion annually, with health and long-term care accounting for €155 billion (55%), equalling 11% of EU-health expenditure. Productivity losses accounted for 17% (€48 billion), whereas informal care costs were €79 billion (28%). CVD represented a cost of €630 per person, ranging from €381 in Cyprus to €903 in Germany. Coronary heart disease accounted for 27% (€77 billion) and cerebrovascular diseases for 27% (€76 billion) of CVD costs. Conclusions This study provides contemporary estimates of the wide-ranging impact of CVD on all aspects of the economy. The data help inform evidence based polices to reduce the impact of CVD, promoting care access and better health outcomes and economic sustainability.
NHS reference costs: a history and cautionary note.
Historically, the NHS did not routinely collect cost data, unlike many countries with private insurance markets. In 1998, for the first time the government mandated NHS trusts to submit estimates of their costs of service, known as reference costs. These have informed a wide range of health economic evaluations and important functions in the health service, such as setting prices.Reference costs are collected by progressively disaggregating budgets top-down into disease and treatment groups. Despite ongoing improvements to methods and guidance, these submissions continued to suffer a lack of accuracy and comparability, fundamentally undermining their credibility for critical functions.To overcome these issues, there was a long-held ambition to collect "patient-level" cost data. Patient-level costs are estimated with a combination of disaggregating budgets but also capturing the patient-level "causality of costs" bottom-up in the allocation of resources to patient episodes. These not only aim to capture more of the drivers of costs, but also improve consistency of reporting between providers.The change in methods may confer improvements to data quality, though judgement is still required and achieving consistency between trusts will take further work. Estimated costs may also change in important ways that may take many years to fully understand. We end on a cautionary note that patient-level cost methods may unlock potential, they alone contribute little to our understanding of the complexities involved with service quality or need, while that potential will require substantial investment to realise. Many healthcare resources cannot be attributed to individual patients so the very notion of "patient-level" costs may be misplaced. High hopes have been put in these new data, though much more work is now necessary to understand their quality, what they show and how their use will impact the system.
Investigation of the genetic aetiology of Lewy body diseases with and without dementia.
Up to 80% of Parkinson's disease patients develop dementia, but time to dementia varies widely from motor symptom onset. Dementia with Lewy bodies presents with clinical features similar to Parkinson's disease dementia, but cognitive impairment precedes or coincides with motor onset. It remains controversial whether dementia with Lewy bodies and Parkinson's disease dementia are distinct conditions or represent part of a disease spectrum. The biological mechanisms underlying disease heterogeneity, in particular the development of dementia, remain poorly understood, but will likely be key to understanding disease pathways and ultimately therapy development. Previous genome-wide association studies in Parkinson's disease and dementia with Lewy bodies/Parkinson's disease dementia have identified risk loci differentiating patients from controls. We collated data for 7,804 patients of European ancestry from Tracking Parkinson's (PRoBaND), The Oxford Discovery Cohort, and AMP-PD. We conducted a discrete phenotype genome-wide association studies comparing Lewy body diseases with and without dementia to decode disease heterogeneity by investigating the genetic drivers of dementia in Lewy body diseases. We found that risk alleles rs429358 tagging APOEe4 and rs7668531 near the MMRN1 and SNCA-AS1 genes, increase the odds of developing dementia and that an intronic variant rs17442721 tagging LRRK2 G2019S, on chromosome 12 is protective against dementia. These results should be validated in autopsy confirmed cases in future studies.
Investigating gait-responsive somatosensory cueing from a wearable device to improve walking in Parkinson's disease.
Freezing-of-gait (FOG) and impaired walking are common features of Parkinson's disease (PD). Provision of external stimuli (cueing) can improve gait, however, many cueing methods are simplistic, increase task loading or have limited utility in a real-world setting. Closed-loop (automated) somatosensory cueing systems have the potential to deliver personalised, discrete cues at the appropriate time, without requiring user input. Further development of cue delivery methods and FOG-detection are required to achieve this. In this feasibility study, we aimed to test if FOG-initiated vibration cues applied to the lower-leg via wearable devices can improve gait in PD, and to develop real-time FOG-detection algorithms. 17 participants with Parkinson's disease and daily FOG were recruited. During 1 h study sessions, participants undertook 4 complex walking circuits, each with a different intervention: continuous rhythmic vibration cueing (CC), responsive cueing (RC; cues initiated by the research team in response to FOG), device worn with no cueing (NC), or no device (ND). Study sessions were grouped into 3 stages/blocks (A-C), separated by a gap of several weeks, enabling improvements to circuit design and the cueing device to be implemented. Video and onboard inertial measurement unit (IMU) data were analyzed for FOG events and gait metrics. RC significantly improved circuit completion times demonstrating improved overall performance across a range of walking activities. Step frequency was significantly enhanced by RC during stages B and C. During stage C, > 10 FOG events were recorded in 45% of participants without cueing (NC), which was significantly reduced by RC. A machine learning framework achieved 83% sensitivity and 80% specificity for FOG detection using IMU data. Together, these data support the feasibility of closed-loop cueing approaches coupling real-time FOG detection with responsive somatosensory lower-leg cueing to improve gait in PD.
FUS-NLS mutation causes neurodevelopmental and systemic metabolic alterations
Mutations in the ubiquitously expressed DNA/RNA binding protein FUS cause aggressive juvenile forms of amyotrophic lateral sclerosis (ALS). While most FUS mutation studies have focused on motor neuron degeneration, little is known about wider systemic or developmental effects. We studied pleiotropic phenotypes in a physiological knock-in mouse model carrying the pathogenic FUSDelta14 mutation in homozygosity. RNA sequencing of multiple organs aimed to identify pathways altered by the mutant protein in the systemic transcriptome, including metabolic tissues given the link between ALS-FTD and altered metabolism. Few genes were commonly altered across all tissues, and most genes and pathways affected were generally tissue-specific. Phenotypic assessment of mice revealed systemic metabolic alterations related to the pathway changes identified. MRI brain scans and histological characterisation revealed that homozygous FUSDelta14 brains were smaller and displayed significant morphological alterations including a thinner cortex, reduced neuronal number and increased gliosis, which correlated with early cognitive impairment and fatal seizures. We show that the disease aetiology of FUS mutations can include both neurodevelopmental and systemic alterations.
Harnessing the potential of data-driven strategies to optimise transfusion practice.
No one doubts the significant variation in the practice of transfusion medicine. Common examples are the variability in transfusion thresholds and the use of tranexamic acid for surgery with likely high blood loss despite evidence-based standards. There is a long history of applying different strategies to address this variation, including education, clinical guidelines, audit and feedback, but the effectiveness and cost-effectiveness of these initiatives remains unclear. Advances in computerised decision support systems and the application of novel electronic capabilities offer alternative approaches to improving transfusion practice. In England, the National Institute for Health and Care Research funded a Blood and Transplant Research Unit (BTRU) programme focussing on 'A data-enabled programme of research to improve transfusion practices'. The overarching aim of the BTRU is to accelerate the development of data-driven methods to optimise the use of blood and transfusion alternatives, and to integrate them within routine practice to improve patient outcomes. One particular area of focus is implementation science to address variation in practice.
Utilising clinical parameters to improve the selection of nerve biopsy candidates
AbstractBackgroundPeripheral nerve biopsy is a valuable final diagnostic tool; however, histopathological results can be non‐diagnostic.AimsWe aim to identify quality improvement measures by evaluating the pre‐biopsy assessment and diagnostic yield of specific histopathological diagnosis.MethodsThis was a retrospective study based on 10 years of experience with peripheral nerve biopsies at a single centre. Clinical data were obtained regarding pre‐biopsy history, examination, serum and cerebrospinal fluid (CSF) investigations, neurophysiology and peripheral nerve imaging. Based upon a histopathological outcome, patients were grouped into vasculitis, granulomatous and infiltrative (diagnostic) group, or a comparison group of non‐specific axonal neuropathy and normal (non‐specific/normal) group.ResultsFrom a cohort of 64 patients, 21 (32.8%) were included in the diagnostic group and 30 (46.9%) in the non‐specific/normal group. Clinical parameters associated with the diagnostic group were shorter history (mean 10.2 months vs 38.1), stepwise progression (81% vs 20%), neuropathic pain (85.7% vs 56.7%), vasculitic rash (23.8% vs 0%), mononeuritis multiplex (57.1% vs 10%), asymmetry (90.5% vs 60%), raised white cell count (47.6% vs 16.7%), myeloperoxidase antibody (19.1% vs 0%) and abnormal peripheral nerve imaging (33.3% vs 10%).ConclusionSelection of patients undergoing nerve biopsy requires careful consideration of clinical parameters, including peripheral nerve imaging. Several quality improvement measures are proposed to improve yield of clinically actionable information from nerve biopsy.
Peripherin is a biomarker of axonal damage in peripheral nervous system disease
Abstract Valid, responsive blood biomarkers specific to peripheral nerve damage would improve management of peripheral nervous system (PNS) diseases. Neurofilament light chain (NfL) is sensitive for detecting axonal pathology but is not specific to PNS damage, as it is expressed throughout the PNS and CNS. Peripherin, another intermediate filament protein, is almost exclusively expressed in peripheral nerve axons. We postulated that peripherin would be a promising blood biomarker of PNS axonal damage. We demonstrated that peripherin is distributed in sciatic nerve, and to a lesser extent spinal cord tissue lysates, but not in brain or extra-neural tissues. In the spinal cord, anti-peripherin antibody bound only to the primary cells of the periphery (anterior horn cells, motor axons and primary afferent sensory axons). In vitro models of antibody-mediated axonal and demyelinating nerve injury showed marked elevation of peripherin levels only in axonal damage and only a minimal rise in demyelination. We developed an immunoassay using single molecule array technology for the detection of serum peripherin as a biomarker for PNS axonal damage. We examined longitudinal serum peripherin and NfL concentrations in individuals with Guillain-Barré syndrome (GBS, n = 45, 179 time points), chronic inflammatory demyelinating polyradiculoneuropathy (CIDP, n = 35, 70 time points), multiple sclerosis (n = 30), dementia (as non-inflammatory CNS controls, n = 30) and healthy individuals (n = 24). Peak peripherin levels were higher in GBS than all other groups (median 18.75 pg/ml versus < 6.98 pg/ml, P < 0.0001). Peak NfL was highest in GBS (median 220.8 pg/ml) and lowest in healthy controls (median 5.6 pg/ml), but NfL did not distinguish between CIDP (17.3 pg/ml), multiple sclerosis (21.5 pg/ml) and dementia (29.9 pg/ml). While peak NfL levels were higher with older age (rho = +0.39, P < 0.0001), peak peripherin levels did not vary with age. In GBS, local regression analysis of serial peripherin in the majority of individuals with three or more time points of data (16/25) displayed a rise-and-fall pattern with the highest value within the first week of initial assessment. Similar analysis of serial NfL concentrations showed a later peak at 16 days. Group analysis of serum peripherin and NfL levels in GBS and CIDP patients were not significantly associated with clinical data, but in some individuals with GBS, peripherin levels appeared to better reflect clinical outcome measure improvement. Serum peripherin is a promising new, dynamic and specific biomarker of acute PNS axonal damage.