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To understand how pharmacological interventions can exert their powerful effects on brain function, we need to understand how they engage the brain's rich neurotransmitter landscape. Here, we bridge microscale molecular chemoarchitecture and pharmacologically induced macroscale functional reorganization, by relating the regional distribution of 19 neurotransmitter receptors and transporters obtained from positron emission tomography, and the regional changes in functional magnetic resonance imaging connectivity induced by 10 different mind-altering drugs: propofol, sevoflurane, ketamine, lysergic acid diethylamide (LSD), psilocybin, N,N-Dimethyltryptamine (DMT), ayahuasca, 3,4-methylenedioxymethamphetamine (MDMA), modafinil, and methylphenidate. Our results reveal a many-to-many mapping between psychoactive drugs' effects on brain function and multiple neurotransmitter systems. The effects of both anesthetics and psychedelics on brain function are organized along hierarchical gradients of brain structure and function. Last, we show that regional co-susceptibility to pharmacological interventions recapitulates co-susceptibility to disorder-induced structural alterations. Collectively, these results highlight rich statistical patterns relating molecular chemoarchitecture and drug-induced reorganization of the brain's functional architecture.

The purpose of this study is to determine whether there is a higher dislocation rate when postoperative hip precautions are not used for primary total hip arthroplasty (THA).A survey was conducted of the hip precautions used by orthopaedic departments in England performing elective primary THA. From the responses to the survey an interrupted time series analysis was performed using the hospital admissions data from the Hospital Episode Statistics (HES) database during the period April 1, 2011 to December 31, 2019 and subsequent dislocations of these prostheses up to June 30, 2020. These were used to determine dislocations within 180 days of primary surgery and emergency readmissions within 30 days of discharge.Records were reviewed from 229,057 patients receiving primary, elective THA across 114 hospitals. In total, 1,807 (0.8%) dislocations were recorded within 180 days of surgery. There were 12,416 (5.4%) emergency readmissions within 30 days of surgery. Within hospitals where hip precautions were stopped, the proportion of patients having a dislocation was 0.8% both before and after stopping precautions, with a significant postintervention trend towards fewer dislocations (P.001). There was also a significant immediate change in median length of stay from 4 to 3 days (P.001) but no significant trend in the proportion of emergency readmissions within 30 days.There is no evidence of an increase in early dislocation or 30-day readmission rates after stopping traditional postoperative hip precautions in primary THA. Potential reductions in length of stay will reduce the risks associated with an extended hospital admission, improve service efficiency, and reduce costs.

A central question in neuroscience is how consciousness arises from the dynamic interplay of brain structure and function. Here we decompose functional MRI signals from pathological and pharmacologically-induced perturbations of consciousness into distributed patterns of structure-function dependence across scales: the harmonic modes of the human structural connectome. `We show that structure-function coupling is a generalisable indicator of consciousness that is under bi-directional neuromodulatory control. We find increased structure-function coupling across scales during loss of consciousness, whether due to anaesthesia or brain injury, capable of discriminating between behaviourally indistinguishable sub-categories of brain-injured patients, tracking the presence of covert consciousness. The opposite harmonic signature characterises the altered state induced by LSD or ketamine, reflecting psychedelic-induced decoupling of brain function from structure and correlating with physiological and subjective scores. Overall, connectome harmonic decomposition reveals how neuromodulation and the network architecture of the human connectome jointly shape consciousness and distributed functional activation across scales., AIL, JV and PAMM would like to thank Lena Dorfschmidt for co-organising OxBridge BrainHack 2019, where this work began. We also thank all volunteers and patients who provided data. This work was supported by grants from The Wellcome Trust Research Training Fellowship (grant no. 083660/Z/07/Z), Raymond and Beverly Sackler Studentship, and the Cambridge Commonwealth Trust [RA]; the UK Medical Research Council (U.1055.01.002.00001.01) [JDP]; The James S. McDonnell Foundation [JDP]; the Canadian Institute for Advanced Research (CIFAR; grant RCZB/072 RG93193) [to DKM and EAS]; The National Institute for Health Research (NIHR, UK), Cambridge Biomedical Research Centre and NIHR Senior Investigator Awards [JDP and DKM]; The British Oxygen Professorship of the Royal College of Anaesthetists [DKM]; The Stephen Erskine Fellowship, Queens’ College, University of Cambridge [EAS]; The Evelyn Trust, Cambridge and the EoE CLAHRC fellowship [JA]; The Gates Cambridge Trust [AIL]; The Cambridge International Trust and the Howard Sidney Sussex Studentship [MMC]; The Oon Khye Beng Ch'Hia Tsio Studentship for Research in Preventive Medicine, Downing College, University of Cambridge [IP]; The Wellcome Trust (grant no. 210920/Z/18/Z) [PAMM]; The European Research Council Consolidator Grant CAREGIVING (615539) [MLK and SA]; The Center for Music in the Brain, funded by the Danish National Research Foundation (DNRF117) [MLK, SA and JV]; The Centre for Eudaimonia and Human Flourishing, funded by the Pettit and Carlsberg Foundations [MLK]; The Imperial College President’s Scholarship [LR]; The Alex Mosley Charitable Trust [RLCH]; The ketamine study was funded by the Bernard Wolfe Health Neuroscience Fund and the Wellcome Trust. The original LSD study received support from a Crowd Funding Campaign and the Beckley Foundation, as part of the Beckley-Imperial Research Programme. The research was also supported by the NIHR Brain Injury Healthcare Technology Co-operative based at Cambridge University Hospitals NHS Foundation Trust and University of Cambridge. Data used to obtain the human connectome were provided by the Human Connectome Project, WU-Minn Consortium (Principal Investigators: David Van Essen and Kamil Ugurbil; 1U54MH091657) funded by the 16 NIH Institutes and Centers that support the NIH Blueprint for Neuroscience Research; and by the McDonnell Center for Systems Neuroscience at Washington University. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.

COVID-19 is associated with neurological complications including stroke, delirium and encephalitis. Furthermore, a post-viral syndrome dominated by neuropsychiatric symptoms is common, and is seemingly unrelated to COVID-19 severity. The true frequency and underlying mechanisms of neurological injury are unknown, but exaggerated host inflammatory responses appear to be a key driver of COVID-19 severity. We investigated the dynamics of, and relationship between, serum markers of brain injury [neurofilament light (NfL), glial fibrillary acidic protein (GFAP) and total tau] and markers of dysregulated host response (autoantibody production and cytokine profiles) in 175 patients admitted with COVID-19 and 45 patients with influenza. During hospitalization, sera from patients with COVID-19 demonstrated elevations of NfL and GFAP in a severity-dependent manner, with evidence of ongoing active brain injury at follow-up 4 months later. These biomarkers were associated with elevations of pro-inflammatory cytokines and the presence of autoantibodies to a large number of different antigens. Autoantibodies were commonly seen against lung surfactant proteins but also brain proteins such as myelin associated glycoprotein. Commensurate findings were seen in the influenza cohort. A distinct process characterized by elevation of serum total tau was seen in patients at follow-up, which appeared to be independent of initial disease severity and was not associated with dysregulated immune responses unlike NfL and GFAP. These results demonstrate that brain injury is a common consequence of both COVID-19 and influenza, and is therefore likely to be a feature of severe viral infection more broadly. The brain injury occurs in the context of dysregulation of both innate and adaptive immune responses, with no single pathogenic mechanism clearly responsible.

Background/Aims Acute coronary syndromes include unstable angina and myocardial infarction, of which occlusive myocardial infarction is a high-risk subset that is often missed because of a lack of ST elevation. Pre-hospital electrocardiograms may be able to identify myocardial infarction early and reduce mortality. However, it is unclear whether pre-hospital electrocardiograms can accurately detect occlusive myocardial infarction and how this affects outcomes. This study will analyse the outcomes of patients with occlusive myocardial infarction who had a pre-hospital electrocardiogram. Method Electrocardiograms transmitted to the coronary care unit triage service were identified, along with data regarding patient demographics, referrals and mortality. Data were analysed for correlations between demographic and clinical factors and type of myocardial infarction. Results A total of 838 electrocardiograms were identified; 69 (8.2%) showed myocardial infarction and eight (1.0%) showed occlusive myocardial infarction, of which 50% had ST elevation. Patients with occlusive myocardial infarction were more likely to be triaged to the coronary care unit than patients with non-occlusive myocardial infarction (P=0.04). However, 38 (55.1%) of the patients with myocardial infarction and four (50.0%) of the patients with occlusive myocardial infarction were not directed to a coronary care unit or the catheterisation laboratory. Patients with occlusive myocardial infarction had higher index episode mortality rates (P=0.03) and 30-day mortality rates (PConclusions Despite pre-hospital electrocardiogram transmission and adherence to the guidelines, triage of myocardial infarction and occlusive myocardial infarction is imperfect. Refinement of risk scores and adaptation of new technology is required to help identify patients with occlusive myocardial infarction so they can be prioritised for immediate reperfusion therapy.

Aims Total hip arthroplasty (THA) is a very successful and cost-effective operation, yet debate continues about the optimum fixation philosophy in different age groups. The concept of the 'cementless paradox' and the UK 'Getting it Right First Time' initiative encourage increased use of cemented fixation due to purported lower revision rates, especially in elderly patients, and decreased cost. Methods In a high-volume, tertiary referral centre, we identified 10,112 THAs from a prospectively collected database, including 1,699 cemented THAs, 5,782 hybrid THAs, and 2,631 cementless THAs. The endpoint was revision for any reason. Secondary analysis included examination of implant survivorship in patients aged over 70 years, over 75 years, and over 80 years at primary THA. Results Cemented fixation had the lowest implant survival in all age groups, with a total ten-year survivorship of 97.0% (95% confidence interval (CI) 95.8 to 97.8) in the cemented group, 97.6% (95% CI 96.9 to 98.1) in the hybrid group, and 97.9% (95% CI 96.9 to 98.6) in the cementless group. This was not statistically significant (p = 0.092). There was no age group where cemented fixation outperformed hybrid or cementless fixation. Conclusion While all fixation techniques performed well at long-term follow-up, cemented fixation was associated with the lowest implant survival in all age groups, including in more elderly patients. We recommend that surgeons should carefully monitor their own outcomes and use fixation techniques that they are familiar with, and deliver the best outcomes in their own hands. Cite this article: Bone Joint J 2022;104-B(2):206–211.

Treatment decisions in myocardial infarction (MI) are currently stratified by ST elevation (ST-elevation myocardial infarction [STEMI]) or lack of ST elevation (non-ST elevation myocardial infarction [NSTEMI]) on the electrocardiogram. This arose from the assumption that ST elevation indicated acute coronary artery occlusion (OMI). However, one-quarter of all NSTEMI cases are an OMI, and have a higher mortality. The purpose of this study was to identify features that could help identify OMI.Prospectively collected data from patients undergoing percutaneous coronary intervention (PCI) was analyzed. Data included presentation characteristics, comorbidities, treatments, and outcomes. Latent class analysis was undertaken, to determine patterns of presentation and history associated with OMI.A total of 1412 patients underwent PCI for acute MI, and 263 were diagnosed as OMI. Compared to nonocclusive MI, OMI patients are more likely to have fewer comorbidities but no difference in cerebrovascular disease and increased acute mortality (4.2% vs. 1.1%; p .001). Of OMI, 29.5% had delays to their treatment such as immediate reperfusion therapy. With latent class analysis, while clusters of similar patients are observed in the data set, the data available did not usefully identify patients with OMI compared to non-OMI.Features between OMI and STEMI are broadly very similar. However, there was no difference in age and risk of cerebrovascular disease in the OMI/non-OMI group. There are no reliable characteristics therefore for identifying OMI versus non-OMI. Delays to treatment also suggest that OMI patients are still missing out on optimal treatment. An alternative strategy is required to improve the identification of OMI patients.

IntroductionCardiovascular diseases are highly prevalent amongst the UK population, and the quality of care is being reduced due to accessibility and resource issues. Increased implementation of digital technologies into the cardiovascular care pathway has enormous potential to lighten the load on the NHS, however, it is not possible to adopt this shift without embedding the perspectives of service users and clinicians.Methods and AnalysisA series of qualitative studies will be carried out with the aim of developing a stakeholder-led perspective on the implementation of digital technologies to improve holistic diagnosis of heart disease. Focus groups will be carried out with 20 people with lived experience of heart disease, and interviews will be carried out with 10 clinicians with experience of diagnosing heart diseases. The data will be analysed using an inductive thematic analysis approach.Ethics and DisseminationThis study received ethical approval from the Sciences and Technology Cross Research Council at the University of Sussex. The findings will be disseminated through conference presentations, peer-reviewed publications and to the study participants.Strengths and LimitationsThe study materials have been informed by patient advisory boards, meaning they are sensitive to the experiences of the participants and the clinicians that will be recruited.The study will allow an in-depth understanding of the attitudes and experience of people with lived experience of heart disease and clinicians with experience of diagnosing heart disease.The use of an online research platform for participant recruitment will disadvantage those less comfortable using online resources. This may include those living in deprived areas without access to high quality technologies (which disproportionately excludes ethnic minority groups) and clinical populations with comorbidities that prevent the use of certain technologies, such as visual, auditory, physical, or learning impairments.The use of thematic analysis will not be free from the influence of the researcher’s personal experience and knowledge

The use of the lambda-mu-sigma (LMS) method for estimating centiles and producing reference ranges has received much interest in clinical practice, especially for assessing growth in childhood. However, this method may not be directly applicable where measures are based on a score calculated from question response categories that is bounded within finite intervals, for example, in psychometrics. In such cases, the main assumption of normality of the conditional distribution of the transformed response measurement is violated due to the presence of ceiling (and floor) effects, leading to biased fitted centiles when derived using the common LMS method. This paper describes the methodology for constructing reference intervals when the response variable is bounded and explores different distribution families for the centile estimation, using a score derived from a parent-completed assessment of cognitive and language development in 24 month-old children. Results indicated that the z-scores, and thus the extracted centiles, improved when kurtosis was also modeled and that the ceiling effect was addressed with the use of the inflated binomial distribution. Therefore, the selection of the appropriate distribution when constructing centile curves is crucial.

BACKGROUND: The growth in multi-center neuroimaging studies generated a need for methods that mitigate the differences in hardware and acquisition protocols across sites i.e., scanner effects. ComBat harmonization methods have shown promise but have not yet been tested on all the data types commonly studied with magnetic resonance imaging (MRI). This study aimed to validate neuroCombat, longCombat and gamCombat on both structural and diffusion metrics in both cross-sectional and longitudinal data. METHODS: We used a travelling subject design whereby 73 healthy volunteers contributed 161 scans across two sites and four machines using one T1 and five diffusion MRI protocols. Scanner was defined as a composite of site, machine and protocol. A common pipeline extracted two structural metrics (volumes and cortical thickness) and two diffusion tensor imaging metrics (mean diffusivity and fractional anisotropy) for seven regions of interest including gray and (except for cortical thickness) white matter regions. RESULTS: Structural data exhibited no significant scanner effect and therefore did not benefit from harmonization in our particular cohort. Indeed, attempting harmonization obscured the true biological effect for some regions of interest. Diffusion data contained marked scanner effects and was successfully harmonized by all methods, resulting in smaller scanner effects and better detection of true biological effects. LongCombat less effectively reduced the scanner effect for cross-sectional white matter data but had a slightly lower probability of incorrectly finding group differences in simulations, compared to neuroCombat and gamCombat. False positive rates for all methods and all metrics did not significantly exceed 5%. CONCLUSIONS: Statistical harmonization of structural data is not always necessary and harmonization in the absence of a scanner effect may be harmful. Harmonization of diffusion MRI data is highly recommended with neuroCombat, longCombat and gamCombat performing well in cross-sectional and longitudinal settings.

COVID-19 is associated with neurological complications including stroke, delirium and encephalitis. Furthermore, a post-viral syndrome dominated by neuropsychiatric symptoms is common, and is seemingly unrelated to COVID-19 severity. The true frequency and underlying mechanisms of neurological injury are unknown, but exaggerated host inflammatory responses appear to be a key driver of COVID-19 severity. We investigated the dynamics of, and relationship between, serum markers of brain injury [neurofilament light (NfL), glial fibrillary acidic protein (GFAP) and total tau] and markers of dysregulated host response (autoantibody production and cytokine profiles) in 175 patients admitted with COVID-19 and 45 patients with influenza. During hospitalization, sera from patients with COVID-19 demonstrated elevations of NfL and GFAP in a severity-dependent manner, with evidence of ongoing active brain injury at follow-up 4 months later. These biomarkers were associated with elevations of pro-inflammatory cytokines and the presence of autoantibodies to a large number of different antigens. Autoantibodies were commonly seen against lung surfactant proteins but also brain proteins such as myelin associated glycoprotein. Commensurate findings were seen in the influenza cohort. A distinct process characterized by elevation of serum total tau was seen in patients at follow-up, which appeared to be independent of initial disease severity and was not associated with dysregulated immune responses unlike NfL and GFAP. These results demonstrate that brain injury is a common consequence of both COVID-19 and influenza, and is therefore likely to be a feature of severe viral infection more broadly. The brain injury occurs in the context of dysregulation of both innate and adaptive immune responses, with no single pathogenic mechanism clearly responsible.

This study explores the relationship between extra-curricular opportunities offered by a UK higher education institution and participants' subsequent educational and occupational trajectories. We present a statistical analysis of the association between participation in a range of such interventions and undergraduate learner outcomes, including grade-based assessment scores, module pass/failure rates, final degree classifications and graduate progression rates to higher study or professional employment. We find strong statistical evidence that participation is positively correlated with improved student outcomes, which holds when controlling for other key factors that influence student success, including gender, ethnicity, disability, age, subject area and pre-entry qualifications. When student groups with an existing pre-disposition towards lower achievement participate in extracurricular activities, the evidence suggests that their participation helps to negate the existing socio-economic and demographic effects on educational outcomes. Engagement with 'out of classroom' pursuits is a critical element of the student experience, and increasing opportunities to those student groups who may not typically access them is likely to add value to the overarching student experience, both at university and beyond.

The Covid‐19 pandemic created the most urgent platform for change that the veterinary profession has ever seen. Every business in every sector throughout the world was forced to simultaneously redesign itself from the ground up against a singular overriding imperative – social distancing. As human safety became the priority, established systems, processes and operating models were torn apart and hastily replaced. This article illustrates how using efficiency models can help practices recover and redefine their working models following the pandemic.

To understand how pharmacological interventions can exert their powerful effects on brain function, we need to understand how they engage the brain’s rich neurotransmitter landscape. Here, we bridge microscale molecular chemoarchitecture and pharmacologically-induced macroscale functional reorganisation, by relating the regional distribution of 19 neurotransmitter receptors and transporters obtained from Positron Emission Tomography, and the regional changes in functional MRI connectivity induced by 10 different mind-altering drugs: propofol, sevoflurane, ketamine, LSD, psilocybin, DMT, ayahuasca, MDMA, modafinil, and methylphenidate. Our results reveal that psychoactive drugs exert their effects on brain function by engaging multiple neurotransmitter systems. The effects of both anaesthetics and psychedelics on brain function are organised along hierarchical gradients of brain structure and function. Finally, we show that regional co-susceptibility to pharmacological interventions recapitulates co-susceptibility to disorder-induced structural alterations. Collectively, these results highlight rich statistical patterns relating molecular chemoarchitecture and drug-induced reorganisation of the brain’s functional architecture.

Aims To determine mortality risk after first revision total hip arthroplasty (THA) for periprosthetic femoral fracture (PFF), and to compare this to mortality risk after primary and first revision THA for other common indications. Methods The study cohort consisted of THAs recorded in the National Joint Registry between 2003 and 2015, linked to national mortality data. First revision THAs for PFF, infection, dislocation, and aseptic loosening were identified. We used a flexible parametric model to estimate the cumulative incidence function of death at 90 days, one year, and five years following first revision THA and primary THA, in the presence of further revision as a competing risk. Analysis covariates were age, sex, and American Society of Anesthesiologists (ASA) grade. Results A total of 675,078 primary and 74,223 first revision THAs were included (of which 6,131 were performed for PFF). Following revision for PFF, mortality ranged from 9% at 90 days, 21% at one year, and 60% at five years in the highest risk group (males, ≥ 75 years, ASA ≥ 3) to 0.6%, 1.4%, and 5.5%, respectively, for the lowest risk group (females, < 75 years, ASA ≤ 2). Mortality was greater in all groups following first revision THA for PFF than for primary THA. Compared to mortality risk after first revision THA for infection, dislocation, or aseptic loosening, revision for PFF was associated with higher five-year mortality in all groups except males < 75 years with an ASA ≤ 2. Conclusion Mortality risk after revision THA for PFF is high, reaching 60% at five years in the highest risk patient group. In comparison to other common indications for revision, PFF demonstrated the highest overall risk of mortality at five years. These estimates can be used in the surgical decision-making process and when counselling patients and carers regarding surgical risk. Cite this article: Bone Joint J 2020;102-B(12):1670–1674.

Background An improved understanding of the trajectory of recovery after mild traumatic brain injury is important to be able to understand individual patient outcomes, for longitudinal patient care and to aid the design of clinical trials. Objective To explore changes in health, well-being and cognition over the 2 years following mTBI using latent growth curve (LGC) modelling. Methods Sixty-one adults with mTBI presenting to a UK Major Trauma Centre completed comprehensive longitudinal assessment at up to five time points after injury: 2 weeks, 3 months, 6 months, 1 year and 2 years. Results Persisting problems were seen with neurological symptoms, cognitive issues and poor quality of life measures including 28% reporting incomplete recovery on the Glasgow Outcome Score Extended at 2 years. Harmful drinking, depression, psychological distress, disability, episodic memory and working memory did not improve significantly over the 2 years following injury. For other measures, including the Rivermead Post-Concussion Symptoms and Quality of Life after Brain Injury (QOLIBRI), LGC analysis revealed significant improvement over time with recovery tending to plateau at 3–6 months. Interpretation Significant impairment may persist as late as 2 years after mTBI despite some recovery over time. Longitudinal analyses which make use of all available data indicate that recovery from mTBI occurs over a longer timescale than is commonly believed. These findings point to the need for long-term management of mTBI targeting individuals with persisting impairment.

Background: Preliminary evidence has highlighted a possible association between severe COVID-19 and persistent cognitive deficits. Further research is required to confirm this association, determine whether cognitive deficits relate to clinical features from the acute phase or to mental health status at the point of assessment, and quantify rate of recovery. Methods: 46 individuals who received critical care for COVID-19 at Addenbrooke's hospital between 10th March 2020 and 31st July 2020 (16 mechanically ventilated) underwent detailed computerised cognitive assessment alongside scales measuring anxiety, depression and post-traumatic stress disorder under supervised conditions at a mean follow up of 6.0 (± 2.1) months following acute illness. Patient and matched control (N = 460) performances were transformed into standard deviation from expected scores, accounting for age and demographic factors using N = 66,008 normative datasets. Global accuracy and response time composites were calculated (G_SScore & G_RT). Linear modelling predicted composite score deficits from acute severity, mental-health status at assessment, and time from hospital admission. The pattern of deficits across tasks was qualitatively compared with normal age-related decline, and early-stage dementia. Findings: COVID-19 survivors were less accurate (G_SScore=-0.53SDs) and slower (G_RT=+0.89SDs) in their responses than expected compared to their matched controls. Acute illness, but not chronic mental health, significantly predicted cognitive deviation from expected scores (G_SScore (p=​​0.0037) and G_RT (p = 0.0366)). The most prominent task associations with COVID-19 were for higher cognition and processing speed, which was qualitatively distinct from the profiles of normal ageing and dementia and similar in magnitude to the effects of ageing between 50 and 70 years of age. A trend towards reduced deficits with time from illness (r∼=0.15) did not reach statistical significance. Interpretation: Cognitive deficits after severe COVID-19 relate most strongly to acute illness severity, persist long into the chronic phase, and recover slowly if at all, with a characteristic profile highlighting higher cognitive functions and processing speed. Funding: This work was funded by the National Institute for Health Research (NIHR) Cambridge Biomedical Research Centre (BRC), NIHR Cambridge Clinical Research Facility (BRC-1215-20014), the Addenbrooke's Charities Trust and NIHR COVID-19 BioResource RG9402. AH is funded by the UK Dementia Research Institute Care Research and Technology Centre and Imperial College London Biomedical Research Centre. ETB and DKM are supported by NIHR Senior Investigator awards. JBR is supported by the Wellcome Trust (220258) and Medical Research Council (SUAG/051 G101400). VFJN is funded by an Academy of Medical Sciences/ The Health Foundation Clinician Scientist Fellowship. The views expressed are those of the authors and not necessarily those of the NHS, the NIHR or the Department of Health and Social Care., This work was funded by the NIHR Cambridge Biomedical Research Centre and by the Addenbrooke’s Charities Trust. AH is funded by the UK Dementia Research Institute Care Research and Technology Centre and Imperial College London Biomedical Research Centre. ETB and DKM are supported by NIHR Senior Investigator awards. VFJN is funded by an Academy of Medical Sciences/ The Health Foundation Clinician Scientist Fellowship.

Background Accumulated electronic data from a wide variety of clinical settings has been processed using a range of informatics methods to determine the sequence of care activities experienced by patients. The “as is” or “de facto” care pathways derived can be analysed together with other data to yield clinical and operational information. It seems likely that the needs of both health systems and patients will lead to increasing application of such analyses. A comprehensive review of the literature is presented, with a focus on the study context, types of analysis undertaken, and the utility of the information gained. Methods A systematic review was conducted of literature abstracting sequential patient care activities (“de facto” care pathways) from care records. Broad coverage was achieved by initial screening of a Scopus search term, followed by screening of citations (forward snowball) and references (backwards snowball). Previous reviews of related topics were also considered. Studies were initially classified according to the perspective captured in the derived pathways. Concept matrices were then derived, classifying studies according to additional data used and subsequent analysis undertaken, with regard for the clinical domain examined and the knowledge gleaned. Results 254 publications were identified. The majority (n = 217) of these studies derived care pathways from data of an administrative/clinical type. 80% (n = 173) applied further analytical techniques, while 60% (n = 131) combined care pathways with enhancing data to gain insight into care processes. Discussion Classification of the objectives, analyses and complementary data used in data-driven care pathway mapping illustrates areas of greater and lesser focus in the literature. The increasing tendency for these methods to find practical application in service redesign is explored across the variety of contexts and research questions identified. A limitation of our approach is that the topic is broad, limiting discussion of methodological issues. Conclusion This review indicates that methods utilising data-driven determination of de facto patient care pathways can provide empirical information relevant to healthcare planning, management, and practice. It is clear that despite the number of publications found the topic reviewed is still in its infancy.

Additional file 1.

Additional file 1. Appendix A: Full classification of literature with clinical domain. Table A1: Publications deriving an administrative/clinical process model, classified by supplemental technique and enhancing data. Table A2: Publications deriving a clinical process model, classified by supplemental technique and enhancing data. Appendix B: Further discussion of selected literature.

Human coronavirus disease 2019 (COVID-19) due to severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) has multiple neurological consequences, but its long-term effect on brain health is still uncertain. The cerebrovascular consequences of COVID-19 may also affect brain health. We studied the chronic effect of COVID-19 on cerebrovascular health, in relation to acute severity, adverse clinical outcomes and in contrast to control group data. Here we assess cerebrovascular health in 45 patients six months after hospitalisation for acute COVID-19 using the resting state fluctuation amplitudes (RSFA) from functional magnetic resonance imaging, in relation to disease severity and in contrast with 42 controls. Acute COVID-19 severity was indexed by COVID-19 WHO Progression Scale, inflammatory and coagulatory biomarkers. Chronic widespread changes in frontoparietal RSFA were related to the severity of the acute COVID-19 episode. This relationship was not explained by chronic cardiorespiratory dysfunction, age, or sex. The level of cerebrovascular dysfunction was associated with cognitive, mental, and physical health at follow-up. The principal findings were consistent across univariate and multivariate approaches. The results indicate chronic cerebrovascular impairment following severe acute COVID-19, with the potential for long-term consequences on cognitive function and mental wellbeing.

Introduction Treatment urgency of myocardial infarction (MI) is currently stratified by ST elevation (STEMI) or lack of ST elevation (NSTEMI) on the electrocardiogram. This categorisation arose from the theory that ST elevation indicated total acute coronary artery occlusion (1). However, one-quarter of all NSTEMI have acute occlusion, have a higher mortality and are potentially missed by this strategy (2). Purpose The study purpose is to identify clinical features that could help distinguish an occlusive MI from non-occlusive MI. Methods The prospectively British Cardiovascular Intervention Society (BCIS) data set was collected from patients undergoing primary cutaneous intervention (dataset) was analysed from the years 2015 to 2019. Data collected included presentation characteristics, co-morbidities, treatments and outcomes. We further undertook latent class analysis, to determine whether distinct patterns of presentation and history are associated with acutely occluded NSTEMI. This methodology proceeds through segmentation of a dataset into clusters (“classes”) based on case similarities for the set of variables or “indicators” of interest; the classes are then statistically analysed to evaluate the differences between them. Results A total of 2025 patients underwent percutaneous coronary intervention (PCI) between 2015 and 2019. Of these, 1412 underwent PCI for MI, 510 had a STEMI, and 263 had occlusive MI on angiogram. STEMI patients tended to be younger (66 vs 67; p=0.045), in shock (6.1% vs 1.9%; p Conclusion Features between occlusive MI and STEMI are broadly very similar. However, unlike STEMI/NSTEMI, there was no difference in age and risk of cerebrovascular disease in the occlusive MI/non-occlusive MI group. This could indicate occlusion MI occurs in higher numbers in elderly and frail patients and may be frequently missed, possibly from greater collateralisation. There is no reliable characteristic for identifying occlusive between non-occlusive MI. Improved methods are needed for the identification of occlusive MI patients. Funding Acknowledgement Type of funding sources: Public grant(s) – EU funding. Main funding source(s): A project supported by the European Union's INTERREG VA Programme, managed by the Special EU Programmes Body (SEUPB). The funders of this project had no input in designing, implementation or writing of this review. Step 1 of latent class analysis

Captan (a trichloromethyl sulfenyl fungicide) is commonly used for control of Neonectria ditissima in apple. In New Zealand, picking and leaf scars are the main source of new infections. The captan concentrations required for wound protection of leaf scars, picking and rasp wounds was determined in planta. Fresh wounds, inoculated with N. ditissima, were sprayed with captan using a motorised knapsack (leaf scars) or hand-held spray bottles targeting the wound area (picking and rasp wounds). Captan concentrations ranged from 0 to 400% field rate (100% = 2 kg captan/ha). Wounds were sampled pre- and post-captan application for residue analyses and the remainder assessed regularly in the field for disease expression. Disease development decreased as captan concentrations increased. Approximately 2 μg captan/scar (100% field rate) was required to protect leaf scars. Four times the field rate of captan was needed for a 55 and 70% disease reduction on picking and rasp wounds, respectively. Label-rate applications of captan controlled low incidence of N. ditissima leaf-scar infections in the field in autumn, but disease control of picking scars and other large wounds might be difficult to achieve.

The third Sandia Fracture Challenge highlighted the geometric and material uncertainties introduced by modern additive manufacturing techniques. Tasked with the challenge of predicting failure of a complex additively-manufactured geometry made of 316L stainless steel, we combined a rigorous material calibration scheme with a number of statistical assessments of problem uncertainties. Specifically, we used optimization techniques to calibrate a rate-dependent and anisotropic Hill plasticity model to represent material deformation coupled with a damage model driven by void growth and nucleation. Through targeted simulation studies we assessed the influence of internal voids and surface flaws on the specimens of interest in the challenge which guided our material modeling choices. Employing the Kolmogorov–Smirnov test statistic, we developed a representative suite of simulations to account for the geometric variability of test specimens and the variability introduced by material parameter uncertainty. This approach allowed the team to successfully predict the failure mode of the experimental test population as well as the global response with a high degree of accuracy.

Aims, Objectives and BackgroundPatients who have sustained a traumatic brain injury (TBI) can have disturbances in coagulation that are distinct from other traumatic bleeding states.1 Coagulopathy is a risk factor for exacerbation of the primary injury, and these patients have less favourable outcomes and increased mortality compared to non-coagulopathic patients.1 Little is known about the longitudinal coagulation changes following TBI.The aim of this pilot study was to investigate the coagulation profiles of patients presenting with severe TBI over the first 7 days following injury.Method and DesignDesign: Prospective observational study25 patients presenting to an UK major trauma centre with TBI between August 2021-March 2022 were recruited Coagulation was assessed using thromboelastographs (TEGs) and conventional coagulation tests including Hb, Plt, PT, aPPT and fibrinogen. Pre-hospital, clinical, laboratory and imaging data were collected during the patient admission.Coagulopathy was defined as having an INR >1.2. The longitudinal changes in the coagulation parameters were plotted for the first seven 7 days and graphically represented. This is a pre-liminary analysis.Results and Conclusion25 patients with severe TBI (GCS 1.2 (38% n=7). 7 patients who did not have INR >1.2 on their first admission blood test later developed coagulopathy (with an INR >1.2).Further exploration of the trends seen in conventional coagulation tests and TEG’s over time is required and to understand how these changes correlate to the clinical and imaging findings. The utility of viscoelastic studies such as TEG’s in the assessment of TBI associated coagulopathy remains unclear.

Background The small sample sizes available within many very preterm (VPT) longitudinal birth cohort studies mean that it is often necessary to combine and harmonise data from individual studies to increase statistical power, especially for studying rare outcomes. Curating and mapping data is a vital first step in the process of data harmonisation. To facilitate data mapping and harmonisation across VPT birth cohort studies, we developed a custom classification system as part of the Research on European Children and Adults born Preterm (RECAP Preterm) project in order to increase the scope and generalisability of research and the evaluation of outcomes across the lifespan for individuals born VPT. Methods The multidisciplinary consortium of expert clinicians and researchers who made up the RECAP Preterm project participated in a four-phase consultation process via email questionnaire to develop a topic-specific classification system. Descriptive analyses were calculated after each questionnaire round to provide pre- and post- ratings to assess levels of agreement with the classification system as it developed. Amendments and refinements were made to the classification system after each round. Results Expert input from 23 clinicians and researchers from the RECAP Preterm project aided development of the classification system’s topic content, refining it from 10 modules, 48 themes and 197 domains to 14 modules, 93 themes and 345 domains. Supplementary classifications for target, source, mode and instrument were also developed to capture additional variable-level information. Over 22,000 individual data variables relating to VPT birth outcomes have been mapped to the classification system to date to facilitate data harmonisation. This will continue to increase as retrospective data items are mapped and harmonised variables are created. Conclusions This bespoke preterm birth classification system is a fundamental component of the RECAP Preterm project’s web-based interactive platform. It is freely available for use worldwide by those interested in research into the long term impact of VPT birth. It can also be used to inform the development of future cohort studies.

As part of its Assessment Reports (ARs), the Intergovernmental Panel on Climate Change (IPCC) publishes Summaries for Policymakers (SPMs) that review key findings on climate science and climate change’s potential impacts. We argue that the IPCC could create more engaging SPMs by incorporating narrative features. This project evaluates AR5’s SPM for narrative opportunities, which are elements that could be narratively restructured or strengthened. Storytelling does not compromise the goals of the IPCC but rather helps public audiences understand and relate to the information. We encourage the adoption of storytelling elements to increase public understanding of and engagement with climate science.

The functional interactions between regions of the human brain can be viewed as a network, empowering neuroscientists to leverage tools such as graph theory to obtain insight about brain function. However, obtaining a brain network from functional neuroimaging data inevitably involves multiple steps of data manipulation, which can affect the organisation (topology) of the resulting network and its properties. Test-retest reliability is a gold standard for both basic research and clinical use: a suitable data-processing pipeline for brain networks should recover the same network topology across repeated scan sessions of the same individual. Analyzing resting-state functional Magnetic Resonance Imaging (rs-fMRI) recordings from two test-retest studies across short (45 minutes), medium (2-4 weeks) and long term delays (5-16 months), we investigated the reliability of network topologies constructed by applying 576 unique pipelines to the same fMRI data, obtained from considering combinations of atlas type and size, edge definition and thresholding, and use of global signal regression. We adopted the portrait divergence, an information-theoretic criterion to measure differences in network topology across all scales, enabling us to quantify the influence of different pipelines on the overall organisation of the resulting network. Remarkably, our findings reveal that the choice of pipeline plays a fundamental role in determining how reproducible an individual’s brain network topology will be across different scans: there is large and systematic variability across pipelines, such that an inappropriate choice of pipeline can distort the resulting network more than an interval of several months between scans. Across datasets and time-spans, we also identify specific combinations of data-processing steps that consistently yield networks with reproducible topology, enabling us to make recommendations about best practices to ensure high-quality brain networks.

Significance Understanding the neural bases of consciousness is of basic scientific and clinical importance. Human neuroimaging has established that a network of interconnected brain regions known as the default mode network disintegrates in anesthesia and after brain damage that causes disorders of consciousness. However, the neurochemical underpinnings of this network change remain largely unknown. Motivated by preclinical animal work and clinical observations, we found that across pharmacological (sedation) and pathological (disorders of consciousness) consciousness perturbation, the dopaminergic source nucleus, the ventral tegmental area, disconnects from the main nodes of the default mode network. As the severity of this dopaminergic disconnection was associated with default mode network disintegration, we propose that dopaminergic modulation may be a central mechanism for consciousness maintenance., Clinical research into consciousness has long focused on cortical macroscopic networks and their disruption in pathological or pharmacological consciousness perturbation. Despite demonstrating diagnostic utility in disorders of consciousness (DoC) and monitoring anesthetic depth, these cortico-centric approaches have been unable to characterize which neurochemical systems may underpin consciousness alterations. Instead, preclinical experiments have long implicated the dopaminergic ventral tegmental area (VTA) in the brainstem. Despite dopaminergic agonist efficacy in DoC patients equally pointing to dopamine, the VTA has not been studied in human perturbed consciousness. To bridge this translational gap between preclinical subcortical and clinical cortico-centric perspectives, we assessed functional connectivity changes of a histologically characterized VTA using functional MRI recordings of pharmacologically (propofol sedation) and pathologically perturbed consciousness (DoC patients). Both cohorts demonstrated VTA disconnection from the precuneus and posterior cingulate (PCu/PCC), a main default mode network node widely implicated in consciousness. Strikingly, the stronger VTA–PCu/PCC connectivity was, the more the PCu/PCC functional connectome resembled its awake configuration, suggesting a possible neuromodulatory relationship. VTA-PCu/PCC connectivity increased toward healthy control levels only in DoC patients who behaviorally improved at follow-up assessment. To test whether VTA–PCu/PCC connectivity can be affected by a dopaminergic agonist, we demonstrated in a separate set of traumatic brain injury patients without DoC that methylphenidate significantly increased this connectivity. Together, our results characterize an in vivo dopaminergic connectivity deficit common to reversible and chronic consciousness perturbation. This noninvasive assessment of the dopaminergic system bridges preclinical and clinical work, associating dopaminergic VTA function with macroscopic network alterations, thereby elucidating a critical aspect of brainstem–cortical interplay for consciousness.