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Thrombospondin-4 correlates with MRI measures of structural damage and pain sensitisation: a new biomarker in knee osteoarthritis
No full textBackground
We hypothesised thrombospondin-4 (TSP-4), a molecule mediating pain sensitisation in peripheral nerve injury, is associated with pain sensitisation in OA.
Methods
A cross-sectional study of clinical, imaging and fluid biomarkers from knee OA participants was conducted. TSP-4 was assessed by immunohistochemistry (IHC) for OA tissue samples and by ELISA in serum samples. Type II collagen degradation products (CTX-II), linked to OA structural damage, was determined from urine samples. A general linear model (GLM) was used to: a) investigate how patient-reported WOMAC (Western Ontario and McMaster Universities OsteoArthritis Index) pain/stiffness subscales and pain sensitisation measured by painDETECT, related to the Hospital Anxiety and Depression Scale (HADS), structural damage quantified from MRI and X-rays, CTX-II and TSP-4; b) how TSP-4 related to structural damage. We used linear discriminant analysis (LDA) to determine a classifier for pain-sensitisation from clinical and wet-biomarkers.
Results
TSP-4 was expressed in cartilage, bone marrow lesion (BML) and synovial tissue from OA samples. Upregulated TSP-4 protein was observed in cartilage, synovial tissue and BMLs in a perivascular distribution and in fibrotic tissue. Serum TSP-4 was significantly higher (p = 0.001) in those with pain sensitisation (painDETECT level ≥19) compared with non-sensitised participants. Serum TSP-4 was significantly increased with Hoffa’s synovitis (p < 0.001) and number of BMLs (p < 0.001 to p < 0.05). LDA provided classification accuracy of 80 % for pain sensitisation using TSP-4, CTX-II and HADS, supporting the biopsychosocial model of pain in OA.
Conclusion
Our data suggests TSP-4 is associated with pain sensitisation in OA and is a biomarker stratifying for pain sensitisation
Surgical management of atypical femoral fracture non-unions - strategies and outcomes
No full textOBJECTIVES: Atypical femoral fractures are associated with high rates of non-union and reoperation due to their complex pathogenesis. There is no consensus in literature on the optimal treatment strategy of these difficult cases. This study demonstrates a standardized management protocol for atypical femoral fracture non-unions, with surgical mechanical alignment of the non-union, without bone grafting or use of biological adjuncts, and with immediate unrestricted weight bearing post operatively. The study aimed to examine whether comparable union and complications rates can be achieved to those published in literature. METHODS: A retrospective analysis of a prospectively collected trauma database at a tertiary referral centre for non-union was conducted. Demographic data, serial radiographs, and clinical records were reviewed. The primary outcomes were union rate and time to union. RESULTS: 13 consecutively treated patients with atypical femoral fracture non-union were included with a union rate 92 % (12 out of 13). The single ongoing non-union was in a patient who died shortly post-operatively and once excluded, the union rate was 100 %. 1 of the 12 patients who achieved union required two procedures. The average time to union of the 11 patients who underwent a single procedure for non-union was 8.3 months. The revision fixation methods were reconstruction intramedullary nail (n = 4), a reconstruction type nail with adjuvant plate (n = 5), or a 95-degree blade plate (n = 4). No bone graft or any other biological adjuncts were used in any cases. CONCLUSIONS: This study demonstrated a comparable union rate for atypical femoral fracture non-unions to studies previously reported and achieved this without any form of bone grafting and no complications from immediate weight bearing. To our knowledge, this is the only case series where no bone grafting was used in the management of AFFNU
Defining the analytical characteristics of a novel high-sensitivity point-of-care troponin I assay in its intended clinical environment
No full textObjectives
To assess the imprecision and stability of the point-of-care troponin I assay in the Emergency Department and its correlation and bias to two central laboratory troponin I assays (Siemens Atellica and Abbott Alinity).
Methods
Imprecision and stability testing was performed on opportunistically selected samples using whole blood in the emergency department by non-laboratory trained personnel. Assay comparisons were undertaken on samples taken from participants of the Mersey Acute Coronary syndrome Rule Out Study.
Results
The coefficient of variation (95 % confidence interval), at the 99th percentile for the point-of-care assay, was 8.1 % (6.1–12.1 %) but with a wide confidence interval reflective of considerable scatter at values just below the 99th percentile. The 10 % limit of quantification was 7.5 ng/L (1.7–61.8 ng/L). All samples met the ≤2 ng/L stability criteria for a duration of 4 h and under. The point-of-care assay very strongly correlated and had a negative bias with the Siemens Atellica and Abbott Alinity assays, Pearson’s R=0.99 and 0.95, mean difference −29.7 ng/L and −13.3 ng/L respectively.
Conclusions
The Siemens VTLi point-of-care assay fulfils high-sensitivity criteria when operated by non-laboratory trained staff using whole blood in its intended environment. Lithium heparin samples are likely stable up to 4 h. Significant bias between the point-of-care and two central laboratory assays negates the use of these assays interchangeably
Preventable deaths related to haemorrhage in England and Wales, 2013–2022: A systematic case series of coroners’ reports
Full text linkObjectives
To identify preventable haemorrhage-related deaths, classify coroner concerns and explore organisational responses.
Study design
Retrospective systematic case series of coroners’ Prevention of Future Deaths (PFD) reports from 1st July 2013 to 16 November 2022, in England and Wales.
Methods
Reports were acquired from the Courts and Tribunals Judiciary website and screened for haemorrhage-related deaths using a reproducible automated computer code. Demographic information, coroners’ concerns, and organisational responses to PFDs were extracted and analysed, including risk factors predisposing to haemorrhage.
Results
339 PFDs (8 % of all PFDs) involved a haemorrhage event contributing to death. The average age of death was 78 years, and 57 % were male. The majority of haemorrhages were intracranial (64 %). 31 % of haemorrhage-related PFDs reported the use of anticoagulation, most often warfarin. Coroners reported 942 concerns directly relevant to the haemorrhage event, including failures to follow protocols, guidelines, or risk assessments (17 %), failures in communication or handovers (14 %), and failures in providing appropriate care, including investigations and observations (13 %). Just under half (48 %) of PFDs did not have responses published on the Judiciary website. Of the organisations who responded, 85 % reported plans to initiate new changes to address these concerns. Improvements most frequently focused on improving protocols, pathways and guidance documents, as well as education and training.
Conclusions
Coroner PFDs offer unique insights into haemorrhage-related deaths, highlighting the systems and processes which fail in everyday practice. Improving awareness and dissemination of these reports to clinicians and policymakers nationally may improve patient safety and save lives
Variations and Opportunities in Postnatal Management of Hemolytic Disease of the Fetus and Newborn.
Full text linkIMPORTANCE: Preventive efforts in pregnancy-related alloimmunization have considerably decreased the prevalence of hemolytic disease of the fetus and newborn (HDFN). International studies are therefore essential to obtain a deeper understanding of the postnatal management and outcomes of HDFN. Taken together with numerous treatment options, large practice variations among centers may exist. OBJECTIVES: To assess variations in postnatal management and outcomes of HDFN among international centers and to identify opportunities to improve care. DESIGN, SETTING, AND PARTICIPANTS: In this international, retrospective, cohort study, 31 expert centers from 22 countries retrieved data on neonates with HDFN managed between January 1, 2006, and July 1, 2021. Statistical analysis was performed from July 19, 2023, to October 28, 2024. MAIN OUTCOMES AND MEASURES: Main outcomes included the frequency of exchange transfusions, administration of intravenous immunoglobulin, administration of erythropoiesis-stimulating agents, and red blood cell transfusions, as well as the association of gestational age at birth with exchange transfusion frequency and risk factors for adverse neonatal outcomes. RESULTS: The study included 1855 neonates (median gestational age at birth, 36.4 weeks [IQR, 35.0-37.3 weeks]; 1034 boys [55.7%]), of whom 1017 (54.8%) received any form of antenatal treatment. Most neonates (1447 [78.0%]) had anti-D antibodies. Exchange transfusions were performed in 436 neonates (23.5%), with proportions in exchange transfusion frequency varying from 0% to 78% among centers. Intravenous immunoglobulin was administered to 429 of 1743 neonates (24.6%), with proportions varying from 0% to 100% among centers. A higher gestational age at birth was associated with a reduction in exchange transfusion frequency in neonates with intrauterine transfusion, decreasing from approximately 38.2% (13 of 34) at 34 weeks to 16.8% (18 of 107) after 37 weeks and 0 days. A weekly increase in gestational age at birth was associated with a 43.3% decrease (95% CI, 36.1%-49.7%) in the likelihood of adverse neonatal outcomes, and neonates who received an exchange transfusion were 1.55 (95% CI, 1.10-2.18) times more likely to experience unfavorable outcomes. CONCLUSIONS AND RELEVANCE: In this cohort study of neonates with HDFN managed at 31 centers in 22 countries, significant practice variations in the postnatal management of HDFN were identified, highlighting the lack of, and need for, consensus. The study suggests that there is a potential beneficial clinical association of waiting for delivery until after 37 weeks and 0 days with frequency of exchange transfusions among neonates with HDFN. The framework to implement international guidelines is provided
Naxos Disease and Related Cardio-Cutaneous Syndromes.
Full text linkNaxos disease is a rare autosomal recessive condition combining arrhythmogenic right ventricular cardiomyopathy, woolly hair, and palmoplantar keratoderma. The first identified causative variant was in the gene encoding the desmosomal protein plakoglobin. Naxos disease exhibits fibro-fatty myocardial replacement with immunohistological abnormalities in cardiac protein and signaling pathways, highlighting the role of inflammation and potential anti-inflammatory treatments. Childhood cutaneous signs precede cardiac features, which are diagnosed by familial and genetic evaluation, electrocardiography and cardiac imaging. Disease progression necessitates holistic care with risk management and lifestyle adjustments, often needing treatment for arrhythmia and heart failure. Similar phenotypes have been linked to desmoplakin and rarely desmocollin2 gene variants, highlighting the importance of familial and genetic evaluation. This document summarizes current knowledge on Naxos disease and related cardiocutaneous syndromes and initiates an international endeavor to collect and study all global cases, aiming to improve understanding, treatment, and patient care through shared data and research
Cost-effectiveness of digoxin versus beta blockers in permanent atrial fibrillation: the Rate Control Therapy Evaluation in Permanent Atrial Fibrillation (RATE-AF) randomised trial.
Full text linkBACKGROUND: Atrial fibrillation (AF) is a major and increasing burden on health services. This study aimed to evaluate the cost-effectiveness of digoxin versus beta-blockers for heart rate control in patients with permanent AF and symptoms of heart failure. METHODS: RAte control Therapy Evaluation in permanent Atrial Fibrillation (RATE-AF) was a randomised, open-label, blinded, endpoint trial embedded in the UK National Health Service (NHS) to directly compare low-dose digoxin with beta-blockers (ClinicalTrials.gov: NCT02391337). A trial-based cost-utility analysis was performed from a healthcare perspective over 12 months. Resource use in primary and secondary healthcare services, medications and patient-reported quality of life were prospectively collected to estimate differences in costs and quality-adjusted life years (QALYs). RESULTS: RATE-AF randomised 160 patients with mean age of 76 (SD 8) years and 46% women, of which 149 patients (n=73 digoxin, n=76 beta blockers) had complete data and survived to 12-month follow-up. Treatment with digoxin was significantly less costly, with a mean saving of £530.41 per patient per year (95% CI -£848.06 to -£249.38, p=0.001). This was principally due to substantially lower rates of adverse events, with less primary and secondary healthcare utilisation compared with beta-blocker therapy. There was no significant difference in QALYs (0.013; 95% CI -0.033 to 0.052, p=0.56). At the £20 000 per-QALY willingness to pay threshold, the probability of digoxin being cost-effective compared with beta-blockers was 94%, with potential annual savings to the NHS of £102 million/year (95% CI £48 million to £164 million saving, p=0.001). CONCLUSIONS: Digoxin is a less costly option when compared with beta-blockers for control of heart rate in suitable patients with permanent AF, with larger cost-effectiveness studies warranted to advise on national and global policy-making. TRIAL REGISTRATION NUMBER: NCT02391337, EudraCT 2015-005043-13
Antifungal stewardship in the UK: where are we now?
Full text linkBACKGROUND: Antifungal stewardship (AFS) is the judicious use of today's antifungal agents with the aim of improving patient outcomes and preserving their future effectiveness. Antifungal resistance (AFR) is increasing globally, with more patients at risk of Invasive Fungal Disease (IFD), highlighting the urgent need to standardize AFS practices in the UK. The aim of this position paper is to understand the current AFS landscape in the UK. METHODS: A virtual panel discussion was held from September to October 2023 on an online platform followed by a virtual meeting with nine healthcare professionals from across the UK selected for their expertise on IFD management and AFS. The discussion was structured across four topics: current AFS landscape, key elements of an AFS programme, diagnostics and diagnostic stewardship, and unmet needs in education and training. A thematic analysis was carried out. The results represent the collated and summarized views from these activities. RESULTS AND DISCUSSION: Participants reported barriers to implementing AFS and its integration within antimicrobial stewardship (AMS) programmes in the UK. The primary challenge identified was a lack of resources, including funding and staff time. Sub-optimal fungal diagnostics and limited mycology expertise was reported as a barrier to AFS, clinical IFD and AFR surveillance. Approaches to combatting these challenges may include investing in formal mycology networks to serve as centres of clinical expertise and diagnostic hubs. CONCLUSION: National standards for AFS services and associated outcome metrics need to be established to set a benchmark for centres to improve AFS
Longitudinal Twin Growth Discordance Patterns and Adverse Perinatal Outcomes.
Full text linkOBJECTIVE: The objective of this study was to conduct a longitudinal assessment of inter-twin growth and Doppler discordance, to identify possible distinct patterns, and to investigate the predictive value of longitudinal discordance patterns for adverse perinatal outcomes in twin pregnancies. METHODS: This retrospective cohort study included twin pregnancies followed and delivered at a tertiary University Hospital in London (UK), between 2010 and 2023. We included pregnancies with at least three ultrasound assessments after 18 weeks and delivery after 34 weeks' gestation. Monoamniotic twin pregnancies, pregnancies with twin-to-twin transfusion syndrome, genetic or structural abnormalities, or incomplete data were excluded. Data on chorionicity, biometry, Doppler indices, maternal characteristics, and obstetric as well as neonatal outcomes were extracted from electronic records. Doppler assessment included velocimetry of the umbilical artery, middle cerebral artery and cerebroplacental ratio. Inter-twin growth discordance was calculated for each scan. The primary outcome was a composite of perinatal mortality and neonatal morbidity. Statistical analysis involved multilevel mixed-effects regression models and unsupervised machine learning algorithms, specifically k-means clustering, to identify distinct patterns of inter-twin discordance and their predictive value. Predictive models were compared using the area under the receiver operating characteristics curve, calibration intercept, and slope, validated with repeated cross-validation. Analyses were performed using R, with significance set at p<0.05. RESULTS: Data from a total of 823 twin pregnancies (647 dichorionic, 176 monochorionic) were analyzed. Five distinct patterns of inter-twin growth discordance-low-stable (n=204, 24.8%), mild-decreasing (n=171, 20.8%), low-increasing (n=173, 21.0%), mild-increasing (n=189, 23.0%), and high-stable (n=86, 10.4%)-were derived using an unsupervised learning algorithm that clustered twin pairs based on the progression and patterns of discordance over gestation. In the high-stable cluster, the rates of perinatal morbidity (46.5%, 40/86) and mortality (9.3%, 8/86) were significantly higher, compared to the low-stable (reference) cluster (p<0.001). High-stable growth pattern was also associated with a significantly higher risk of composite adverse perinatal outcomes (Odds ratio 70.19, 95% confidence interval 24.18-299.03, p<0.001; adjusted Odds ratio 76.44, 95% confidence interval 25.39-333.02, p<0.001). The model integrating discordance pattern with CPR discordance at the last ultrasound before delivery demonstrated superior predictive accuracy, evidenced by the highest area under the receiver operating characteristics curve of 0.802 (95% confidence interval 0.712 - 0.892 0.046, p<0.001), compared to only discordance patterns (area under the receiver operating characteristics curve 0.785, 95% confidence interval 0.697 -0.873), intertwin weight discordance at the last ultrasound prior to delivery (area under the receiver operating characteristics curve 0.677, 95% confidence interval 0.545 - 0.809), combination of single measurements of estimated fetal weight and CPR discordance at the last ultrasound prior to delivery (area under the receiver operating characteristics curve 0.702, 95% confidence interval 0.586 -0.818) and single measurement of CPR discordance only at the last ultrasound (area under the receiver operating characteristics curve 0.633, 95% confidence interval 0.515 - 0.751). CONCLUSION: We identified five distinct trajectories of inter-twin fetal growth discordance using an unsupervised machine learning algorithm. Consistent high discordance is associated with increased rates of adverse perinatal outcomes, with a dose-response relationship. Additionally, a predictive model integrating discordance trajectory and CPR discordance at the last visit demonstrated superior predictive accuracy for the prediction of composite adverse perinatal outcomes, compared to either of these measurements alone or a single value of estimated fetal weight discordance at the last ultrasound prior to delivery
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