Rapid Assay Diagnostic for Acute Stroke Recognition (RADAR): study protocol for a diagnostic accuracy study

\ua9 Author(s) (or their employer(s)) 2024. Re-use permitted under CC BY. Published by BMJ.INTRODUCTION: Large-vessel occlusion (LVO) stroke is effectively treated by time-critical thrombectomy, a highly specialised procedure only available in a limited number of centres. Many patients with suspected stroke are admitted to their nearest hospital and require transfer to access treatment, with resulting delays. This study is evaluating the accuracy of a new rapid portable test for LVO stroke which could be used in the future to select patients for direct admission to a thrombectomy centre. METHODS AND ANALYSIS: Rapid Assay Diagnostic for Acute Stroke Recognition (RADAR) is a prospective observational cohort study taking place in stroke units in England. Participants are adults with a new suspected stroke with at least one face, arm or speech (FAST) symptom(s) and known onset within 6 hours or last known to be well 6-24 hours ago. The index test (\u27LVOne test\u27 (Upfront Diagnostics)), consists of two portable lateral flow assays which use fingerprick capillary blood to detect d-dimer and glial fibrillary acidic protein concentrations. Reference standards comprise independently adjudicated standard CT/MRI brain\ub1CT/MR angiography with senior clinician opinion to establish: ischaemic stroke\ub1LVO; intracerebral haemorrhage; transient ischaemic attack; stroke mimic. Analyses will report sensitivity, specificity and negative and positive predictive values for identification of LVO stroke. Powered using a primary analysis population (≥2 FAST symptoms and known onset within 6 hours), 276 participants will detect a test specificity of 92%. The broader total study population which allows evaluation of the test for milder symptoms and unknown onset times is estimated to be 552 participants. ETHICS AND DISSEMINATION: Ethical (North East-Newcastle & North Tyneside 2 Research Ethics Committee (reference: 23/NE/0043), Health Research Authority and participating National Health Service Trust approvals are granted. Consent is required for enrolment. Dissemination of results will include presentations at conferences, publication in journals and plain English summaries. TRIAL REGISTRATION NUMBER: ISRCTN12414986

Mapping decision-making pathways: determination of intervention entry points for diagnostic tests in suspected serious infection

Background: PROTECT (Platform Randomised evaluation of clinical Outcomes using novel TEChnologies to optimise antimicrobial Therapy) has brought together a team of researchers to design a platform trial to rapidly evaluate and adopt into care multiple diagnostic technologies, bringing immediate benefit to patients. Rapid diagnostic tests will be used to identify patients at risk of deterioration from severe infection, before they become critically unwell. The platform will assess their comparative clinical and cost-effectiveness relative to current standard of care. Preliminary work, conducted under a Health Technology Assessment Application Acceleration Award, provided key evidence to optimise the design of the PROTECT platform. Methods: Qualitative methods which involved consulting key stakeholders in the field of serious infection addressed the key priorities. A high-level care pathway analysis focusing on serious infection in secondary care, captured the points of contact, actions, decisions, and potential outcomes associated with a patient’s care. Results: Two use cases of rapid diagnostic tests for serious infection were identified; (1) in acute emergency medicine to decide on antimicrobial initiation and/or escalation of care, and (2) in hospitalised patients to monitor treatment response. Within the emergency department, clinicians believed a test would be used as an adjunct to existing standard of care and would be used to either rule-in or rule-out serious infection. The “ideal” test should be rapid, point-of-care, cheap to procure, have capacity for high usability, and ability to be performed and interpreted by all staff. Facilitators to the adoption of infection diagnostic tests is their clinical need, and the main potential barrier is poor change management and behavioural change. Conclusions: Any new test should provide robust evidence of its effectiveness and have the potential to benefit the clinical pathway for patients, clinicians, and hospitals as a whole, to be considered for adoption as a new standard of care

Autonomic symptoms are common and are associated with overall symptom burden and disease activity in primary Sjögren's syndrome

Objectives - To determine the prevalence of autonomic dysfunction (dysautonomia) among patients with primary Sjögren's syndrome (PSS) and the relationships between dysautonomia and other clinical features of PSS. Methods - Multicentre, prospective, cross-sectional study of a UK cohort of 317 patients with clinically well-characterised PSS. Symptoms of autonomic dysfunction were assessed using a validated instrument, the Composite Autonomic Symptom Scale (COMPASS). The data were compared with an age- and sex-matched cohort of 317 community controls. The relationships between symptoms of dysautonomia and various clinical features of PSS were analysed using regression analysis. Results - COMPASS scores were significantly higher in patients with PSS than in age- and sex-matched community controls (median (IQR) 35.5 (20.9–46.0) vs 14.8 (4.4–30.2), p32.5, a cut-off value indicative of autonomic dysfunction. Furthermore, the COMPASS total score correlated independently with EULAR Sjögren's Syndrome Patient Reported Index (a composite measure of the overall burden of symptoms experienced by patients with PSS) (β=0.38, p<0.001) and disease activity measured using the EULAR Sjögren's Syndrome Disease Activity Index (β=0.13, p<0.009). Conclusions - Autonomic symptoms are common among patients with PSS and may contribute to the overall burden of symptoms and link with systemic disease activity

Symptom-based stratification of patients with primary Sjögren's syndrome: multi-dimensional characterisation of international observational cohorts and reanalyses of randomised clinical trials

Background: Heterogeneity is a major obstacle to developing effective treatments for patients with primary Sjögren's syndrome. We aimed to develop a robust method for stratification, exploiting heterogeneity in patient-reported symptoms, and to relate these differences to pathobiology and therapeutic response. / Methods: We did hierarchical cluster analysis using five common symptoms associated with primary Sjögren's syndrome (pain, fatigue, dryness, anxiety, and depression), followed by multinomial logistic regression to identify subgroups in the UK Primary Sjögren's Syndrome Registry (UKPSSR). We assessed clinical and biological differences between these subgroups, including transcriptional differences in peripheral blood. Patients from two independent validation cohorts in Norway and France were used to confirm patient stratification. Data from two phase 3 clinical trials were similarly stratified to assess the differences between subgroups in treatment response to hydroxychloroquine and rituximab. / Findings: In the UKPSSR cohort (n=608), we identified four subgroups: Low symptom burden (LSB), high symptom burden (HSB), dryness dominant with fatigue (DDF), and pain dominant with fatigue (PDF). Significant differences in peripheral blood lymphocyte counts, anti-SSA and anti-SSB antibody positivity, as well as serum IgG, κ-free light chain, β2-microglobulin, and CXCL13 concentrations were observed between these subgroups, along with differentially expressed transcriptomic modules in peripheral blood. Similar findings were observed in the independent validation cohorts (n=396). Reanalysis of trial data stratifying patients into these subgroups suggested a treatment effect with hydroxychloroquine in the HSB subgroup and with rituximab in the DDF subgroup compared with placebo. / Interpretation: Stratification on the basis of patient-reported symptoms of patients with primary Sjögren's syndrome revealed distinct pathobiological endotypes with distinct responses to immunomodulatory treatments. Our data have important implications for clinical management, trial design, and therapeutic development. Similar stratification approaches might be useful for patients with other chronic immune-mediated diseases. / Funding: UK Medical Research Council, British Sjogren's Syndrome Association, French Ministry of Health, Arthritis Research UK, Foundation for Research in Rheumatology

Fatigue in primary Sjögren's syndrome (pSS) is associated with lower levels of proinflammatory cytokines: a validation study

Primary Sjögren’s syndrome (pSS) is a chronic autoimmune rheumatic disease with symptoms including dryness, fatigue, and pain. The previous work by our group has suggested that certain proinflammatory cytokines are inversely related to patient-reported levels of fatigue. To date, these findings have not been validated. This study aims to validate this observation. Blood levels of seven cytokines were measured in 120 patients with pSS from the United Kingdom Primary Sjögren’s Syndrome Registry and 30 age-matched healthy non-fatigued controls. Patient-reported scores for fatigue were classified according to severity and compared to cytokine levels using analysis of variance. The differences between cytokines in cases and controls were evaluated using Wilcoxon test. A logistic regression model was used to determine the most important identifiers of fatigue. Five cytokines, interferon-γ-induced protein-10 (IP-10), tumour necrosis factor-α (TNFα), interferon-α (IFNα), interferon-γ (IFN-γ), and lymphotoxin-α (LT-α) were significantly higher in patients with pSS (n = 120) compared to non-fatigued controls (n = 30). Levels of two proinflammatory cytokines, TNF-α (p = 0.021) and LT-α (p = 0.043), were inversely related to patient-reported levels of fatigue. Cytokine levels, disease-specific and clinical parameters as well as pain, anxiety, and depression were used as predictors in our validation model. The model correctly identifies fatigue levels with 85% accuracy. Consistent with the original study, pain, depression, and proinflammatory cytokines appear to be the most powerful predictors of fatigue in pSS. TNF-α and LT-α have an inverse relationship with fatigue severity in pSS challenging the notion that proinflammatory cytokines directly mediate fatigue in chronic immunological conditions

Physical activity but not sedentary activity is reduced in primary Sjögren’s syndrome

The aim of the study was to evaluate the levels of physical activity in individuals with primary Sjögren’s syndrome (PSS) and its relationship to the clinical features of PSS. To this cross-sectional study, self-reported levels of physical activity from 273 PSS patients were measured using the International Physical Activity Questionnaire-short form (IPAQ-SF) and were compared with healthy controls matched for age, sex and body mass index. Fatigue and other clinical aspects of PSS including disease status, dryness, daytime sleepiness, dysautonomia, anxiety and depression were assessed using validated tools. Individuals with PSS had significantly reduced levels of physical activity [median (interquartile range, IQR) 1572 (594–3158) versus 3708 (1732–8255) metabolic equivalent of task (MET) × min/week, p < 0.001], but similar levels of sedentary activity [median (IQR) min 300 (135–375) versus 343 (223–433) (MET) × min/week, p = 0.532] compared to healthy individuals. Differences in physical activity between PSS and controls increased at moderate [median (IQR) 0 (0–480) versus 1560 (570–3900) MET × min/week, p < 0.001] and vigorous intensities [median (IQR) 0 (0–480) versus 480 (0–1920) MET × min/week, p < 0.001]. Correlation analysis revealed a significant association between physical activity and fatigue, orthostatic intolerance, depressive symptoms and quality of life. Sedentary activity did not correlate with fatigue. Stepwise linear regression analysis identified symptoms of depression and daytime sleepiness as independent predictors of levels of physical activity. Physical activity is reduced in people with PSS and is associated with symptoms of depression and daytime sleepiness. Sedentary activity is not increased in PSS. Clinical care teams should explore the clinical utility of targeting low levels of physical activity in PSS

Genome-wide association study identifies susceptibility loci for acute myeloid leukemia

Acute myeloid leukemia (AML) is a hematological malignancy with an undefined heritable risk. Here we perform a meta-analysis of three genome-wide association studies, with replication in a fourth study, incorporating a total of 4018 AML cases and 10488 controls. We identify a genome-wide significant risk locus for AML at 11q13.2 (rs4930561; P = 2.15 × 10^{-8}; KMT5B). We also identify a genome-wide significant risk locus for the cytogenetically normal AML sub-group (N = 1287) at 6p21.32 (rs3916765; P = 1.51 × 10^{−10}; HLA). Our results inform on AML etiology and identify putative functional genes operating in histone methylation (KMT5B) and immune function (HLA)