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BackgroundMobility limitation in older age reduces quality of life, generates substantial health- and social-care costs, and increases mortality.ObjectiveThe REtirement in ACTion (REACT) trial aimed to establish whether or not a community-based active ageing intervention could prevent decline in physical functioning in older adults already at increased risk of mobility limitation.DesignA multicentre, pragmatic, two-arm, parallel-group randomised controlled trial with parallel process and health economic evaluations.SettingUrban and semi-rural locations across three sites in England.ParticipantsPhysically frail or pre-frail older adults (aged \u2265\u200965 years; Short Physical Performance Battery score of 4\u20139). Recruitment was primarily via 35 primary care practices.InterventionsParticipants were randomly assigned to receive brief advice (three healthy ageing education sessions) or a 12-month, group-based, multimodal exercise and behavioural maintenance programme delivered in fitness and community centres. Randomisation was stratified by site and used a minimisation algorithm to balance age, sex and Short Physical Performance Battery score. Data collection and analyses were blinded.Main outcome measuresThe primary outcome was change in lower limb physical function (Short Physical Performance Battery score) at 24 months, analysed using an intention-to-treat analysis. The economic evaluation adopted the NHS and Personal Social Services perspective.ResultsBetween June 2016 and October 2017, 777 participants (mean age 77.6 years, standard deviation 6.8 years; 66% female; mean Short Physical Performance Battery score 7.37, standard deviation 1.56) were randomised to the intervention arm (n\u2009=\u2009410) or the control arm (n\u2009=\u2009367). Data collection was completed in October 2019. Primary outcome data at 24 months were provided by 628 (80.8%) participants. At the 24-month follow-up, the Short Physical Performance Battery score was significantly greater in the intervention arm (mean 8.08, standard deviation 2.87) than in the control arm (mean 7.59, standard deviation 2.61), with an adjusted mean difference of 0.49 (95% confidence interval 0.06 to 0.92). The difference in lower limb function between intervention and control participants was clinically meaningful at both 12 and 24 months. Self-reported physical activity significantly increased in the intervention arm compared with the control arm, but this change was not observed in device-based physical activity data collected during the trial. One adverse event was related to the intervention. Attrition rates were low (19% at 24 months) and adherence was high. Engagement with the REACT intervention was associated with positive changes in exercise competence, relatedness and enjoyment and perceived physical, social and mental well-being benefits. The intervention plus usual care was cost-effective compared with care alone over the 2 years of REACT; the price year was 2019. In the base-case scenario, the intervention saved \u00a3103 per participant, with a quality-adjusted life-year gain of 0.04 (95% confidence interval 0.006 to 0.074) within the 2-year trial window. Lifetime horizon modelling estimated that further cost savings and quality-adjusted life-year gains were accrued up to 15 years post randomisation.ConclusionA relatively low-resource, 1-year multimodal exercise and behavioural maintenance intervention can help older adults to retain physical functioning over a 24-month period. The results indicate that the well-established trajectory of declining physical functioning in older age is modifiable.LimitationsParticipants were not blinded to study arm allocation. However, the primary outcome was independently assessed by blinded data collectors. The secondary outcome analyses were exploratory, with no adjustment for multiple testing, and should be interpreted accordingly.Future workFollowing refinements guided by the process evaluation findings, the REACT intervention is suitable for large-scale implementation. Further research will optimise implementation of REACT at scale.Trial registrationThis trial is registered as ISRCTN45627165.FundingThis project was funded by the National Institute for Health and Care Research (NIHR) Public Health Research programme and will be published in full in Public Health Research; Vol. 10, No. 14. See the NIHR Journals Library website for further project information.
\n \n\n \n \nBetter understanding of breathlessness perception addresses an unmet clinical need for more effective treatments for intractable dyspnoea, a prevalent symptom of multiple medical conditions. The insular-cortex is predominantly activated in brain-imaging studies of dyspnoea, but its precise role remains unclear. We measured experimentally-induced hypercapnic air-hunger in three insular-glioma patients before and after surgical resection. Tests involved one-minute increments in inspired CO2, raising end-tidal PCO2 to 7.5\u2009mmHg above baseline (38.5\u2009\u00b1\u20095.7\u2009mmHg), whilst ventilation was constrained (10.7\u2009\u00b1\u20092.3\u2009L/min). Patients rated air-hunger on a visual analogue scale (VAS). Patients had lower stimulus-response (2.8\u2009\u00b1\u20092 vs. 11\u2009\u00b1\u20094 %VAS/mmHg; p\u2009=\u20090.004), but similar threshold (40.5\u2009\u00b1\u20093.9 vs. 43.2\u2009\u00b1\u20095.1\u2009mmHg), compared to healthy individuals. Volunteered comments implicated diminished affective valence. After surgical resection; sensitivity increased in one patient, decreased in another, and other was unable to tolerate the ventilatory limit before any increase in inspired CO2.We suggest that functional insular-cortex is essential to register breathlessness unpleasantness and could be targeted with neuromodulation in chronically-breathless patients. Neurological patients with insula involvement should be monitored for blunted breathlessness to inform clinical management.
\n \n\n \n \nSymptoms in people with carpal tunnel syndrome (CTS) are traditionally attributed to neural tissue, but recent studies suggest that the subsynovial connective tissue (SSCT) may also play a role in CTS. The SSCT undergoes fibrotic thickening which is generally described as \u201cnon-inflammatory\u201d based on basic histology. This study uses immunohistochemistry to determine the presence of macrophages and T-cells within SSCT and their relationship with symptoms in people with CTS. SSCT was collected from twenty people with CTS and eight controls undergoing wrist fracture surgery. Immunohistochemical quantification of CD3+ T-cells and CD68+ macrophage densities as well as CD4+/CD8+ T-cell subpopulations were compared between groups using independent t-tests. Spearman correlations were used to identify associations between immune cell densities and CTS symptom scores. The density of CD3+ T-cells was significantly higher in SSCT of people with CTS compared to controls (CTS mean 26.7 (SD 13.7); controls 6.78 (6.3), p = 0.0005) while the density of CD68+ macrophages was lower (CTS mean 9.5 (SD 6.0); controls 17.7 (8.2), p = 0.0058). Neither CD68+ nor CD3+ cell densities correlated with symptom scores. In contrast to previous assumptions, our data show that the SSCT in the carpal tunnel in both people with CTS and controls is not devoid of immune cells. Whereas the higher density of CD68+ macrophages in control participants may be associated with their early recruitment after acute fracture, CD3+ cells within the SSCT may play a role in chronic CTS.
\n \n\n \n \nAbstractThere is strong evidence of brain-related abnormalities in COVID-191\u201313. However, it remains unknown whether the impact of SARS-CoV-2 infection can be detected in milder cases, and whether this can reveal possible mechanisms contributing to brain pathology. Here we investigated brain changes in 785 participants of UK Biobank (aged 51\u201381 years) who were imaged twice\u00a0using magnetic resonance imaging, including 401 cases who tested positive for infection with SARS-CoV-2 between their two scans\u2014with 141 days on average separating their diagnosis and the second scan\u2014as well as 384 controls. The availability of pre-infection imaging data reduces the likelihood of pre-existing risk factors being misinterpreted as disease effects. We identified significant longitudinal effects when comparing the two groups, including (1) a greater reduction in grey matter thickness and tissue contrast in the orbitofrontal cortex and parahippocampal gyrus; (2) greater changes in markers of tissue damage in regions that are functionally connected to the primary olfactory cortex; and (3) a greater reduction in global brain size\u00a0in the SARS-CoV-2 cases. The participants who were infected with SARS-CoV-2 also showed on average a greater cognitive decline between the two time points. Importantly, these imaging and cognitive longitudinal effects were still observed after excluding the 15 patients who had been hospitalised. These mainly limbic brain imaging results may be the in vivo hallmarks of a degenerative spread of the disease through olfactory pathways, of neuroinflammatory events, or of the loss of sensory input due to anosmia. Whether this deleterious effect can be partially reversed, or whether these effects will persist in the long term, remains to be investigated with additional follow-up.
\n \n\n \n \nAbstractThere is strong evidence for brain-related abnormalities in COVID-191\u201313. It remains unknown however whether the impact of SARS-CoV-2 infection can be detected in milder cases, and whether this can reveal possible mechanisms contributing to brain pathology. Here, we investigated brain changes in 785 UK Biobank participants (aged 51\u201381) imaged twice, including 401 cases who tested positive for infection with SARS-CoV-2 between their two scans, with 141 days on average separating their diagnosis and second scan, and 384 controls. The availability of pre-infection imaging data reduces the likelihood of pre-existing risk factors being misinterpreted as disease effects. We identified significant longitudinal effects when comparing the two groups, including: (i) greater reduction in grey matter thickness and tissue-contrast in the orbitofrontal cortex and parahippocampal gyrus, (ii) greater changes in markers of tissue damage in regions functionally-connected to the primary olfactory cortex, and (iii) greater reduction in global brain size. The infected participants also showed on average larger cognitive decline between the two timepoints. Importantly, these imaging and cognitive longitudinal effects were still seen after excluding the 15 cases who had been hospitalised. These mainly limbic brain imaging results may be the in vivo hallmarks of a degenerative spread of the disease via olfactory pathways, of neuroinflammatory events, or of the loss of sensory input due to anosmia. Whether this deleterious impact can be partially reversed, or whether these effects will persist in the long term, remains to be investigated with additional follow up.
\n \n\n \n \nAbstractBackgroundThe medium-term effects of Coronavirus disease (COVID-19) on multiple organ health, exercise capacity, cognition, quality of life and mental health are poorly understood.MethodsFifty-eight COVID-19 patients post-hospital discharge and 30 comorbidity-matched controls were prospectively enrolled for multiorgan (brain, lungs, heart, liver and kidneys) magnetic resonance imaging (MRI), spirometry, six-minute walk test, cardiopulmonary exercise test (CPET), quality of life, cognitive and mental health assessments.FindingsAt 2-3 months from disease-onset, 64% of patients experienced persistent breathlessness and 55% complained of significant fatigue. On MRI, tissue signal abnormalities were seen in the lungs (60%), heart (26%), liver (10%) and kidneys (29%) of patients. COVID-19 patients also exhibited tissue changes in the thalamus, posterior thalamic radiations and sagittal stratum on brain MRI and demonstrated impaired cognitive performance, specifically in the executive and visuospatial domain relative to controls. Exercise tolerance (maximal oxygen consumption and ventilatory efficiency on CPET) and six-minute walk distance (405\u00b1118m vs 517\u00b1106m in controls, p<0.0001) were significantly reduced in patients. The extent of extra-pulmonary MRI abnormalities and exercise tolerance correlated with serum markers of ongoing inflammation and severity of acute illness. Patients were more likely to report symptoms of moderate to severe anxiety (35% versus 10%, p=0.012) and depression (39% versus 17%, p=0.036) and a significant impairment in all domains of quality of life compared to controls.InterpretationA significant proportion of COVID-19 patients discharged from hospital experience ongoing symptoms of breathlessness, fatigue, anxiety, depression and exercise limitation at 2-3 months from disease-onset. Persistent lung and extra-pulmonary organ MRI findings are common. In COVID-19 survivors, chronic inflammation may underlie multiorgan abnormalities and contribute to impaired quality of life.FundingNIHR Oxford and Oxford Health Biomedical Research Centres, British Heart Foundation Centre for Research Excellence, UKRI, Wellcome Trust, British Heart Foundation.
\n \n\n \n \nABSTRACTSARS-CoV-2 infection has been shown to damage multiple organs, including the brain. Multiorgan MRI can provide further insight on the repercussions of COVID-19 on organ health but requires a balance between richness and quality of data acquisition and total scan duration. We adapted the UK Biobank brain MRI protocol to produce high-quality images while being suitable as part of a post-COVID-19 multiorgan MRI exam. The analysis pipeline, also adapted from UK Biobank, includes new imaging-derived phenotypes (IDPs) designed to assess the effects of COVID-19. A first application of the protocol and pipeline was performed in 51 COVID-19 patients post-hospital discharge and 25 controls participating in the Oxford C-MORE study.The protocol acquires high resolution T1, T2-FLAIR, diffusion weighted images, susceptibility weighted images, and arterial spin labelling data in 17 minutes. The automated imaging pipeline derives 1575 IDPs, assessing brain anatomy (including olfactory bulb volume and intensity) and tissue perfusion, hyperintensities, diffusivity, and susceptibility. In the C-MORE data, these quantitative measures were consistent with clinical radiology reports. Our exploratory analysis tentatively revealed that recovered COVID-19 patients had a decrease in frontal grey matter volumes, an increased burden of white matter hyperintensities, and reduced mean diffusivity in the total and normal appearing white matter in the posterior thalamic radiation and sagittal stratum, relative to controls. These differences were generally more prominent in patients who received organ support. Increased T2* in the thalamus was also observed in recovered COVID-19 patients, with a more prominent increase for non-critical patients.This initial evidence of brain changes in COVID-19 survivors prompts the need for further investigations. Follow-up imaging in the C-MORE study is currently ongoing, and this protocol is now being used in large-scale studies. The pipeline is widely applicable and will contribute to new analyses to hopefully clarify the medium to long-term effects of COVID-19.HighlightsUK Biobank brain MRI protocol and pipeline was adapted for multiorgan MRI of COVID-19High-quality brain MRI data from 5 modalities are acquired in 17 minutesAnalysis pipeline derives 1575 IDPs of brain anatomy, perfusion, and microstructureEvidence of brain changes in COVID-19 survivors was found in the C-MORE studyThis MRI protocol is now being used in multiple large-scale studies on COVID-19
\n \n\n \n \nExtracellular vesicles (EVs), through their complex cargo, can reflect the state of their cell of origin and change the functions and phenotypes of other cells. These features indicate strong biomarker and therapeutic potential and have generated broad interest, as evidenced by the steady year-on-year increase in the numbers of scientific publications about EVs. Important advances have been made in EV metrology and in understanding and applying EV biology. However, hurdles remain to realising the potential of EVs in domains ranging from basic biology to clinical applications due to challenges in EV nomenclature, separation from non-vesicular extracellular particles, characterisation and functional studies. To address the challenges and opportunities in this rapidly evolving field, the International Society for Extracellular Vesicles (ISEV) updates its 'Minimal Information for Studies of Extracellular Vesicles', which was first published in 2014 and then in 2018 as MISEV2014 and MISEV2018, respectively. The goal of the current document, MISEV2023, is to provide researchers with an updated snapshot of available approaches and their advantages and limitations for production, separation and characterisation of EVs from multiple sources, including cell culture, body fluids and solid tissues. In addition to presenting the latest state of the art in basic principles of EV research, this document also covers advanced techniques and approaches that are currently expanding the boundaries of the field. MISEV2023 also includes new sections on EV release and uptake and a brief discussion of in vivo approaches to study EVs. Compiling feedback from ISEV expert task forces and more than 1000 researchers, this document conveys the current state of EV research to facilitate robust scientific discoveries and move the field forward even more rapidly.
\n \n\n \n \nObjective: To generate a Korean version of the Oxford Cognitive Screen (K-OCS) and obtain cutoff scores that determine the impairment of each subdomain. Post-stroke cognitive impairment (PSCI) negatively impacts the rehabilitation process and independence in daily life. Its obscure manifestations require effective screening for appropriate rehabilitation. However, in most rehabilitation clinics, psychological evaluation tools for Alzheimer\u2019s dementia have been used without such considerations. The OCS is a screening assessment tool for PSCI and vascular dementia that can evaluate the cognitive domains most often affected by stroke, including language, attention, memory, praxis, and numerical cognition. It comprises 10 subtasks and enables quick and effective cognitive evaluation. Methods: The K-OCS, which considers Korea\u2019s unique cultural and linguistic characteristics, was developed with the approval and cooperation of the original author. Enrollment of participants without disabilities was announced at Duksung Women\u2019s University, Yongin Sevrance Hospital, CHA Bundang Medical Center. The study was conducted between September 2020 and March 2022 on 97 male and female participants aged \u226530 years.Results: All the 97 participants completed the task. In this study, the 5th percentile score was presumed to be the cutoff value for each score, and the values are provided here. The cutoff score for each OCS subtask was similar to that of the original British version.Conclusion: We suggest the usability of the K-OCS as a screening tool for PSCI by providing the cutoff value of each subtask.
\n \n\n \n \nOBJECTIVE: The purpose of this study was to develop and evaluate the performance of RPC-Net (Recursive Prosthetic Control Network), a novel method using simple neural network architectures to translate electromyographic activity into hand position with high accuracy and computational efficiency. METHODS: RPC-Net uses a regression-based approach to convert forearm electromyographic signals into hand kinematics. We tested the adaptability of the algorithm to different conditions and compared its performance with that of solutions from the academic literature. RESULTS: RPC-Net demonstrated a high degree of accuracy in predicting hand position from electromyographic activity, outperforming other solutions with the same computational cost. Including previous position data consistently improved results across subjects and conditions. RPC-Net showed robustness against a reduction in the number of electromyography electrodes used and shorter input signals, indicating potential for further reduction in computational cost. CONCLUSION: The results demonstrate that RPC-Net is capable of accurately translating forearm electromyographic activity into hand position, offering a practical and adaptable tool that may be accessible in clinical settings. SIGNIFICANCE: The development of RPC-Net represents a significant advancement. In clinical settings, its application could enable prosthetic devices to be controlled in a way that feels more natural, improving the quality of life for individuals with limb loss.
\n \n\n \n \nThe inspired sinewave technique (IST) is a non-invasive method to measure lung heterogeneity indices (including both uneven ventilation and perfusion or heterogeneity), which reveal multiple conditions of the lung and lung injury. To evaluate the reproducibility and predicted clinical outcomes of IST heterogeneity values, a comparison with a quantitative lung computed tomography (CT) scan is performed. Six anaesthetised pigs were studied after surfactant depletion by saline-lavage. Paired measurements of lung heterogeneity were then taken with both the IST and CT. Lung heterogeneity measured by the IST was calculated by (a) the ratio of tracer gas outputs measured at oscillation periods of 180\u00a0s and 60\u00a0s, and (b) by the standard deviation of the modelled log-normal distribution of ventilations and perfusions in the simulation lung. In the CT images, lungs were manually segmented and divided into different regions according to voxel density. A quantitative CT method to calculate the heterogeneity (the Cressoni method) was applied. The IST and CT show good Pearson correlation coefficients in lung heterogeneity measurements (ventilation: 0.71, and perfusion, 0.60, p\u2009
\n \n\n \n \nBACKGROUND AND AIM: Rapid outpatient evaluation and treatment of TIA in structured clinics have been shown to reduce stroke recurrence. It is unclear whether short-term downtrends in TIA incidence and admissions have had enduring impact on TIA clinic activity. This study aims to measure the impact of the pandemic on hospitals with rapid TIA clinics. METHODS: Relevant services were identified by literature search and contacted. Three years of monthly data were requested - a baseline pre-COVID period (April 2018 to March 2020) and an intra-COVID period (April 2020 to March 2021). TIA presentations, ischemic stroke presentations, and reperfusion trends inclusive of IV thrombolysis (IVT) and endovascular thrombectomy (EVT) were recorded. Pandemic impact was measured with interrupted time series analysis, a segmented regression approach to test an effect of an intervention on a time-dependent outcome using a defined impact model. RESULTS: Six centers provided data for a total of 6,231 TIA and 13,191 ischemic stroke presentations from Australia (52.1%), Canada (35.0%), Italy (7.6%), and England (5.4%). TIA clinic volumes remained constant during the pandemic (2.9, 95% CI -1.8 to 7.6, p =\u20090.24), as did ischemic stroke (2.9, 95% CI -7.8 to 1.9, p =\u20090.25), IVT (-14.3, 95% CI -36.7, 6.1, p
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