A randomised controlled trial of neuromuscular stimulation in non-operative venous disease improves clinical and symptomatic status.

Funder: Actergy HealthBACKGROUND: This randomised controlled trial investigates the dosing effect of neuromuscular electrical stimulation (NMES) in patients with chronic venous disease (CVD). METHODS: Seventy-six patients with CEAP C3-C5 were randomised to Group A (no NMES), B (30 minutes of NMES daily) or C (60 minutes of NMES daily). Primary outcome was percentage change in Femoral Vein Time Averaged Mean Velocity (TAMV) at 6 weeks. Clinical severity scores, disease-specific and generic quality of life (QoL) were assessed. RESULTS: Seventy-six patients were recruited - mean age 60.8 (SD14.4) and 47:29 male. Six patients lost to follow-up. Percentage change in TAMV (p<0.001) was significantly increased in Groups B and C. Aberdeen Varicose Veins Questionnaire Score (-6.9, p=0.029) and Venous Clinical Severity Score (-4, p-0.003) improved in Group C, and worsened in Group A (+1, p=0.025). CONCLUSIONS: Daily NMES usage increases flow parameters, with twice daily usage improving QoL and clinical severity at 6 weeks in CVD patients

Abdominal aortic aneurysm clinical practice guidelines: a methodological assessment using the AGREE II instrument.

OBJECTIVES: Abdominal aortic aneurysm (AAA) clinical practice guidelines (CPGs) provide evidence-based information on patient management; however, methodological differences exist in the development of CPGs. This study examines the methodological quality of AAA CPGs using a validated assessment tool. METHODS: Medline, EMBASE and online CPG databases were searched from 1946 to 31 October 2021. Full-text, English language, evidence-based AAA CPGs were included. Consensus-based CPGs, summaries of CPGs or CPGs which were only available on purchase were excluded. Five reviewers assessed their quality using the Appraisal of Guidelines for Research and Evaluation II instrument. An overall guideline assessment scaled score of ≥80% was considered as the threshold to recommend CPG use in clinical practice. RESULTS: Seven CPGs were identified. Scores showed good inter-reviewer reliability (intraclass correlation coefficient 0.943, 95% CI 0.915 to 0.964). On average, CPGs performed adequately with mean scaled scores of over 50% in all domains. However, between CPGs, significant methodological heterogeneity was observed in all domains. Four CPGs scored ≥80% (European Society of Cardiology, the Society of Vascular Surgery, the European Society of Vascular Surgery and the National Institute of Health and Care Excellence), supporting their use in clinical practice. CONCLUSIONS: Four CPGs were considered of adequate methodological quality to recommend their use in clinical practice; nonetheless, these still showed areas for improvement, potentially through performing economic analysis and trial application of recommendations. A structured approach employing validated CPG creation tools should be used to improve rigour of AAA CPGs. Future work should also evaluate recommendation accuracy using validated appraisal tools

Evaluating pharmacological THRomboprophylaxis in Individuals undergoing superficial endoVEnous treatment across NHS and private clinics in the UK:a multi-centre, assessor-blind, randomised controlled trial-THRIVE trial

INTRODUCTION: Endovenous therapy is the first choice management for symptomatic varicose veins in NICE guidelines, with 56-70 000 procedures performed annually in the UK. Venous thromboembolism (VTE), including deep vein thrombosis (DVT) and pulmonary embolism (PE), is a known complication of endovenous therapy, occurring at a rate of up to 3.4%. Despite 73% of UK practitioners administering pharmacological thromboprophylaxis to reduce VTE, no high-quality evidence supporting this practice exists. Pharmacological thromboprophylaxis may have clinical and cost benefit in preventing VTE; however, further evidence is needed. This study aims to establish whether when endovenous therapy is undertaken: a single dose or course of pharmacological thromboprophylaxis alters the risk of VTE; pharmacological thromboprophylaxis is associated with an increased rate of bleeding events; pharmacological prophylaxis is cost effective.METHODS AND ANALYSIS: A multi-centre, assessor-blind, randomised controlled trial (RCT) will recruit 6660 participants from 40 NHS and private sites across the UK. Participants will be randomised to intervention (single dose or extended course of pharmacological thromboprophylaxis plus compression) or control (compression alone). Participants will undergo a lower limb venous duplex ultrasound scan at 21-28 days post-procedure to identify asymptomatic DVT. The duplex scan will be conducted locally by blinded assessors. Participants will be contacted remotely for follow-up at 7 days and 90 days post-procedure. The primary outcome is imaging-confirmed lower limb DVT with or without symptoms or PE with symptoms within 90 days of treatment. The main analysis will be according to the intention-to-treat principle and will compare the rates of VTE at 90 days, using a repeated measures analysis of variance, adjusting for any pre-specified strongly prognostic baseline covariates using a mixed effects logistic regression.ETHICS AND DISSEMINATION: Ethical approval was granted by Brent Research Ethics Committee (22/LO/0261). Results will be disseminated in a peer-reviewed journal and presented at national and international conferences.TRIAL REGISTRATION NUMBER: ISRCTN18501431.</p

COVID-19 trajectories among 57 million adults in England: a cohort study using electronic health records

BACKGROUND: Updatable estimates of COVID-19 onset, progression, and trajectories underpin pandemic mitigation efforts. To identify and characterise disease trajectories, we aimed to define and validate ten COVID-19 phenotypes from nationwide linked electronic health records (EHR) using an extensible framework. METHODS: In this cohort study, we used eight linked National Health Service (NHS) datasets for people in England alive on Jan 23, 2020. Data on COVID-19 testing, vaccination, primary and secondary care records, and death registrations were collected until Nov 30, 2021. We defined ten COVID-19 phenotypes reflecting clinically relevant stages of disease severity and encompassing five categories: positive SARS-CoV-2 test, primary care diagnosis, hospital admission, ventilation modality (four phenotypes), and death (three phenotypes). We constructed patient trajectories illustrating transition frequency and duration between phenotypes. Analyses were stratified by pandemic waves and vaccination status. FINDINGS: Among 57 032 174 individuals included in the cohort, 13 990 423 COVID-19 events were identified in 7 244 925 individuals, equating to an infection rate of 12·7% during the study period. Of 7 244 925 individuals, 460 737 (6·4%) were admitted to hospital and 158 020 (2·2%) died. Of 460 737 individuals who were admitted to hospital, 48 847 (10·6%) were admitted to the intensive care unit (ICU), 69 090 (15·0%) received non-invasive ventilation, and 25 928 (5·6%) received invasive ventilation. Among 384 135 patients who were admitted to hospital but did not require ventilation, mortality was higher in wave 1 (23 485 [30·4%] of 77 202 patients) than wave 2 (44 220 [23·1%] of 191 528 patients), but remained unchanged for patients admitted to the ICU. Mortality was highest among patients who received ventilatory support outside of the ICU in wave 1 (2569 [50·7%] of 5063 patients). 15 486 (9·8%) of 158 020 COVID-19-related deaths occurred within 28 days of the first COVID-19 event without a COVID-19 diagnoses on the death certificate. 10 884 (6·9%) of 158 020 deaths were identified exclusively from mortality data with no previous COVID-19 phenotype recorded. We observed longer patient trajectories in wave 2 than wave 1. INTERPRETATION: Our analyses illustrate the wide spectrum of disease trajectories as shown by differences in incidence, survival, and clinical pathways. We have provided a modular analytical framework that can be used to monitor the impact of the pandemic and generate evidence of clinical and policy relevance using multiple EHR sources. FUNDING: British Heart Foundation Data Science Centre, led by Health Data Research UK

Linked electronic health records for research on a nationwide cohort of more than 54 million people in England: data resource

Abstract: Objective: To describe a novel England-wide electronic health record (EHR) resource enabling whole population research on covid-19 and cardiovascular disease while ensuring data security and privacy and maintaining public trust. Design: Data resource comprising linked person level records from national healthcare settings for the English population, accessible within NHS Digital’s new trusted research environment. Setting: EHRs from primary care, hospital episodes, death registry, covid-19 laboratory test results, and community dispensing data, with further enrichment planned from specialist intensive care, cardiovascular, and covid-19 vaccination data. Participants: 54.4 million people alive on 1 January 2020 and registered with an NHS general practitioner in England. Main measures of interest: Confirmed and suspected covid-19 diagnoses, exemplar cardiovascular conditions (incident stroke or transient ischaemic attack and incident myocardial infarction) and all cause mortality between 1 January and 31 October 2020. Results: The linked cohort includes more than 96% of the English population. By combining person level data across national healthcare settings, data on age, sex, and ethnicity are complete for around 95% of the population. Among 53.3 million people with no previous diagnosis of stroke or transient ischaemic attack, 98 721 had a first ever incident stroke or transient ischaemic attack between 1 January and 31 October 2020, of which 30% were recorded only in primary care and 4% only in death registry records. Among 53.2 million people with no previous diagnosis of myocardial infarction, 62 966 had an incident myocardial infarction during follow-up, of which 8% were recorded only in primary care and 12% only in death registry records. A total of 959 470 people had a confirmed or suspected covid-19 diagnosis (714 162 in primary care data, 126 349 in hospital admission records, 776 503 in covid-19 laboratory test data, and 50 504 in death registry records). Although 58% of these were recorded in both primary care and covid-19 laboratory test data, 15% and 18%, respectively, were recorded in only one. Conclusions: This population-wide resource shows the importance of linking person level data across health settings to maximise completeness of key characteristics and to ascertain cardiovascular events and covid-19 diagnoses. Although this resource was initially established to support research on covid-19 and cardiovascular disease to benefit clinical care and public health and to inform healthcare policy, it can broaden further to enable a wide range of research

Linked electronic health records for research on a nationwide cohort of more than 54 million people in England: data resource

Abstract: Objective: To describe a novel England-wide electronic health record (EHR) resource enabling whole population research on covid-19 and cardiovascular disease while ensuring data security and privacy and maintaining public trust. Design: Data resource comprising linked person level records from national healthcare settings for the English population, accessible within NHS Digital’s new trusted research environment. Setting: EHRs from primary care, hospital episodes, death registry, covid-19 laboratory test results, and community dispensing data, with further enrichment planned from specialist intensive care, cardiovascular, and covid-19 vaccination data. Participants: 54.4 million people alive on 1 January 2020 and registered with an NHS general practitioner in England. Main measures of interest: Confirmed and suspected covid-19 diagnoses, exemplar cardiovascular conditions (incident stroke or transient ischaemic attack and incident myocardial infarction) and all cause mortality between 1 January and 31 October 2020. Results: The linked cohort includes more than 96% of the English population. By combining person level data across national healthcare settings, data on age, sex, and ethnicity are complete for around 95% of the population. Among 53.3 million people with no previous diagnosis of stroke or transient ischaemic attack, 98 721 had a first ever incident stroke or transient ischaemic attack between 1 January and 31 October 2020, of which 30% were recorded only in primary care and 4% only in death registry records. Among 53.2 million people with no previous diagnosis of myocardial infarction, 62 966 had an incident myocardial infarction during follow-up, of which 8% were recorded only in primary care and 12% only in death registry records. A total of 959 470 people had a confirmed or suspected covid-19 diagnosis (714 162 in primary care data, 126 349 in hospital admission records, 776 503 in covid-19 laboratory test data, and 50 504 in death registry records). Although 58% of these were recorded in both primary care and covid-19 laboratory test data, 15% and 18%, respectively, were recorded in only one. Conclusions: This population-wide resource shows the importance of linking person level data across health settings to maximise completeness of key characteristics and to ascertain cardiovascular events and covid-19 diagnoses. Although this resource was initially established to support research on covid-19 and cardiovascular disease to benefit clinical care and public health and to inform healthcare policy, it can broaden further to enable a wide range of research

Metabolic Profiling of Chronic Venous Disease

Introduction Chronic venous disease is a common condition with a diverse range of clinical presentations, including spider veins, varicose veins and venous ulceration. Despite its high prevalence, and varicose vein surgery being one of the most commonly performed procedures on the U.K. National Health Service, much is still unknown about this disease. The prevalence of disease, although described by a number of epidemiological studies, is poorly characterized, particularly due to diverse methodology employed in the published literature. Reporting of primary, secondary care and questionnaire data yields diverse prevalence rates by the very nature of the data used for analysis, resulting in a varicose vein prevalence of 2 – 56% in men and < 1 – 60% in women. Poor characterization of disease epidemiology has important repercussions on both local and national disease management strategies. It further impacts on correct estimation of the future burden of the disease. The pathophysiology of chronic venous disease is also poorly characterized. Increasingly, primary varicose vein weakness and dilatation are being recognized as important players in the development of venous reflux and hypertension, leading to the signs and symptoms observed in the different stages of chronic venous disease. Better characterization of the biological pathways involved in disease development and progression is key in improving the management of a disease that, in the new millennium, still employs the same principles used in Ancient Egypt to treat the condition, i.e. destruction of the refluxing vein, whether by removing, them, burning them or sclerosing them by injecting chemicals. Aims The aims of this PhD are as follows: ¥ To identify a differential metabolic signature according to CEAP classification in individuals with CVD in both serum and urine. ¥ To validate the results of previously performed departmental studies. ¥ To compare the metabolic signature of systemic serum versus serum from a refluxing lower limb vein. ¥ To identify systemic biomarkers for diagnostic, prognostic and therapeutic applications. Methods Following amendment of existing ethical approval for the study, both CVD patients and individuals with no symptoms of CVD and no history of the disease were invited to participate in the study. All participants underwent a comprehensive history and examination, duplex ultrasound assessment, quality of life measures and biofluid sampling in the form of blood and urine testing. Whole blood was centrifuged to obtain serum. All samples were collected following established departmental standard operating procedures (SOPs) (Appendix 9.2) and stored at -80°C. Nuclear Magnetic Resonance Spectroscopy experiments were performed on both serum and urine samples. Spectral data was extracted and processed in MATLAB® software. Multivariate statistical analysis employing principal component analysis (PCA) and orthogonal partial least squares discriminant analysis (OPLS-DA) was performed in SIMCA software and enabled identification of discriminant spectral regions between the variables tested. Metabolite identification was performed with reference to the existing literature, using online databases and Statistical Total Correlation Spectroscopy (STOCSY). Results 517 individuals with CVD and 105 healthy volunteers with no clinical symptoms of CVD were prospectively recruited to the study. In total, 622 individuals were recruited from a single centre from October 2014 to June 2016. Demographic, clinical and quality of life data were collected. The main differentiating criterion between CVD and control groups was symptomatology. The serum experiments were performed on two separate machines, which resulted in a batch effect. After multiple attempts at analyzing the two batches together, it was decided to perform the analysis on the larger batch only to avoid confounding effects from having used a different machine. The urine experiments were all performed on the same machine. Following well-established pre-processing steps, the data was analysed via multivariate statistical tools. Age and CEAP classification were the most statistically significant models upon multivariate analysis (p < 0.0001). A regression analysis was performed for the most significant metabolites across the CEAP spectrum. Serum metabolites positively correlating with increasing CEAP score (and reaching statistical significance) included: 1-methylhistidine, phenylalanine, tyrosine, glycerol, lysine and succinate. Low-density lipoprotein was negatively correlated with increasing CEAP class. The discriminant metabolites for age included formate, phenylalanine, tyrosine, urea, glucose, creatinine, lysine, citrate and succinate, which were found in increased levels in the ≥ 60 group. Arm vs leg serum analysis revealed glycerol as the sole discriminant metabolite, with higher levels present in local serum compared to systemic serum. Urinary metabolites generally correlated negatively with increasing CEAP class. Statistically significant trends included formate, creatinine, glycine, citrate, succinate, pyruvate and α-hydroxyisobutyrate. Age < 60 was associated with increased levels of creatinine, glycine, pyruvate and α –hydroxyisobutyrate. The metabolites identified are involved in three main pathways: the tricarboxylic acid (TCA) cycle for energy metabolism, the hypoxia inducible factor (HIF) pathway activated in hypoxia and the one-carbon metabolism involved in amino acid synthesis and linked to the TCA cycle. These results suggest increased energy metabolism in higher CEAP classes, particularly in the C4 -6 group. This may be due to increased CVD severity, but the possibility that this is secondary to an underlying skin disorder (e.g. skin staining and venous ulceration), as opposed to a vein problem cannot be ruled out. Age was an expected confounding factor; the existing surrounding literature on metabolic profiling and ageing presents varied metabolites. This may be due to the cross- sectional nature of many of these studies, which provide a ‘snapshot assessment’ of the metabolic environment. Conclusions Increasing CEAP class demonstrates correlation with specific metabolites, some of which have been previously reported in superficial venous disease. Possible pathways include energy metabolism, HIF pathway and the one-carbon metabolism. However, it was not possible to discern whether this metabolic change was due to the underlying venous disease or to skin damage caused by sustained venous hypertension. Local blood contains higher levels of glycerol compared to systemic blood. The urine profile revealed a negative correlation of the aforementioned metabolites with increasing CEAP class, which may be related to the fact that the metabolites are being consumed in upregulated intracellular pathways to generate energy.Open Acces