No description available.

The supine posture has been shown to limit exercise-induced plasma volume expansion. Differences in hydrostatic pressure gradients between the standing and seated position indicate that treadmill exercise might promote a greater plasma volume expansion than cycle ergometer exercise. To test this hypothesis ten subjects performed intermittent high intensity exercise (4 min at 85% VO2max, 5 min at 40% VO2max repeated 8 times) on separate days on the treadmill and cycle ergometer. Changes in plasma volume expansion were calculated from changes in hematocrit and hemoglobin. Stroke volume (SV), trans-thoracic impedance (Z0), HR, and arterial blood pressure (non-invasive arm cuff, SBP & DBP) were assessed in the seated position before and postexercise. Zo increased (p<0.05) as subjects started exercise (both treadmill and cycling), indicating a reduction in central blood volume (CBV), which returned to baseline towards the end of exercise. Postexercise Zo returned to control levels within 30 min regardless of the previous exercise mode. A significant post-exercise hypotension was observed following cycle ergometer exercise (p<0.05) but not following treadmill exercise. Plasma volume increased 6.1±1.0% and 7.0 ± 1.1% (p<0.05) following treadmill and cycle ergometer exercise, respectively. The increase in PV was similar for both exercise modes. Initial differences in central blood volume disappeared over the course of the exercise protocol and during recovery, possibly indicating that there is a postural threshold and moving beyond it yields no further effect. The lack of differences between modes of exercise on plasma albumin content and Z0 indicate that the upright postures were not different from each other. As such, PV expansion following high intensity intermittent exercise appears to be independent of upright exercise mode.

Venous thromboembolism (VTE) is a chronic illness that affects nearly 10 million people every year worldwide. Anticoagulant therapy with direct oral anticoagulants is the mainstay of treatment for patients with VTE, and should be continued for at least 3-6 months. Thereafter, a decision should be made to discontinue anticoagulation or continue it indefinitely. This decision is most challenging for patients with a first unprovoked VTE because of uncertainty in estimates for the long-term benefits (e.g., reduction in recurrent VTE) and harms (e.g., increase in major bleeding) of extended anticoagulation, and the trade-offs between them. The overarching aim of this doctoral thesis was to address these key evidence gaps that are pertinent to making decisions regarding the duration of anticoagulation for patients with a first unprovoked VTE. The first three studies of this thesis synthesized contemporary and reliable estimates for the long-term risks and consequences of recurrent VTE and major bleeding, with and without extended anticoagulation (parameters that can influence the clinical and cost-effectiveness of discontinuing versus continuing anticoagulation indefinitely). Broadly, these systematic reviews and meta-analyses found that: 1) the long-term risks and consequences of major bleeding during extended anticoagulation are considerable, particularly with vitamin K antagonists as well as in older patients, patients using antiplatelet therapy, and in patients with kidney disease, a history of bleeding, or anemia; and 2) the long-term risks of recurrent VTE during extended anticoagulation and major bleeding after discontinuing anticoagulation are reassuringly low but not negligible. The fourth study incorporated the synthesized evidence to compare the lifetime clinical benefits, harms, and costs of discontinuing versus continuing anticoagulation indefinitely. This decision analytic modelling study showed that indefinite anticoagulation is unlikely to either result in a net clinical benefit or be cost-effective in all (i.e., unselected) patients with a first unprovoked VTE. Findings from this thesis can serve to impact clinical practice and health policy by informing patient prognosis to guide shared decision-making regarding the duration of treatment for unprovoked VTE, and informing future research to ultimately identify which patients should receive anticoagulation indefinitely in order to maximize health benefits for the available healthcare resources.

No description available.

No description available.

1. Abstract 1.1. Background It is uncertain whether 1) patient’s characteristics (e.g., age, weight, height, and sex) influence anti-Xa heparin levels (hereafter referred to as "heparin levels"), or 2) if heparin levels influence recurrent venous thromboembolism (VTE) or bleeding events, in patients with acute VTE treated with weight-adjusted therapeutic-dose subcutaneous (SC) unfractionated heparin (UFH) or SC low-molecular weight heparin (LMWH). To determine if either association exist, we analyzed data from the Fixed-Dose Heparin (FIDO) study, in which patients were randomized to either SC UFH or SC LMWH, each given in fixed weight-adjusted doses and overlapped with 3 month of warfarin therapy for treatment of acute VTE. 1.2. Methods During the original study, 708 patients were asked to participate in a sub-study that would measure peak heparin levels while they were treated with heparin. 408 patients provided blood samples and met the eligibility criteria for the analyses in this thesis. Linear regression was used to examine the influence of patients’ baseline characteristics (e.g., age, weight, height, body mass index [BMI], sex) on heparin levels. The influence of other factors (e.g., type of heparin [UFH or LMWH]) on heparin levels was also assessed. Logistic regression was used to examine the association of heparin levels with the outcomes of 1) recurrent VTE during 3 months of follow up, and 2) bleeding events in the first 10 days of follow up. 1.3. Results: Mean heparin levels were 0.695 in patients treated with UFH, 0.698 in those treated with dalteparin and 1.034 in those treated with enoxaparin (p<0.001; R2=0.08 for variability accounted for by type of heparin). In a univariable analysis, heparin levels increase by 0.04 IU/ml (95% CI 0.02-0.07; p=0.001; R2=0.03) for every 10-kg increment in weight, by 0.02 IU/ml (95% CI 0.01-0.03; p<0.001; R2=0.04) for each unit of BMI, and by 0.03 IU/ml (95% CI 0.01-0.05; p=0.001; R2=0.03) for every 10 mol/l increment in creatinine. In a multivariable analysis, weight, BMI, and creatinine still influenced heparin levels, after adjusting for type of heparin and timing of blood sample withdrawal. Although heparin levels increased with weight, the magnitude was not large enough to suggest altering the current weight-based dosing method for LMWH. Other baseline factors such as age, height, type of VTE, creatinine clearance and hospitalization status did not influence heparin levels in patients treated with UFH or LMWH. In a univariable analysis, when heparin levels were treated as a continuous variable, higher heparin levels were associated with a lower risk of recurrent VTE at 90-days in patients treated with LMWH (OR 0.04, 95% CI 0.003-0.550, for each 1.0 IU/ml increase in heparin levels), but not in patients treated with UFH (OR 1.46, 95% CI 0.37-5.58, for each 1.0 IU/ml increase in heparin levels). In addition, higher heparin levels were associated with a higher risk of bleeding at 10-days in patients treated with UFH (OR 3.32, 95% CI 1.30-8.46 for each 1 IU/ml increase in heparin levels) but not in patients treated with LMWH (OR 3.77, 95% CI 0.42-33.92, for each 1.0 IU/ml increase in heparin levels). In a multivariable analysis, the association of heparin levels with VTE at 90-days in patients receiving LMWH (lower VTE events) and with bleeding events at 10-days in patients receiving UFH (higher bleeding events) persisted after adjusting for antiplatelet use at baseline and diagnosis of cancer at baseline. When heparin levels were treated as a dichotomous variable (subtherapeutic vs. non-subtherapeutic levels and supratherapeutic vs. non-supratherapeutic levels), the proportion of patient with recurrent VTE was significantly higher in patients with subtherapeutic levels compared with non-subtherapeutic levels in patients receiving LMWH (8.6% vs. 1.3%, p = 0.01). No significant difference was found in the proportion of patients with subtherapeutic levels and non-subtherapeutic levels in patients receiving UFH (0% vs. 3.4%, χ2=0.15, p= 0.70). The test of interaction supported the decision to analyze LMWH and UFH groups separately (p=0.02). Finally, the proportion of patient with bleeding was higher in patients with supratherapeutic compared with non-supratherapeutic heparin levels (6.5% vs. 1.5%, χ2=7.65, p=0.01). The test of interaction did not support the decision to analyze LMWH and UFH groups separately (p=0.13). 1.4. Conclusions Although it was possible to identify factors that were associated with heparin levels in patients who had been treated with weight-adjusted UFH or LMWH, none of these associations were strong enough to suggest that variables other than weight should influence SC heparin dosing. Subtherapeutic heparin levels were associated with a higher risk of recurrent VTE in patients treated with LWMH but not UFH, and supratherapeutic heparin levels were associated with a higher risk of bleeding in patients treated with UFH but not LMWH. Indirectly, these findings suggest that adjusting UFH or LMWH dose in response to heparin levels might improve clinical outcomes. / Thesis / Master of Science (MSc)

Background Oedema, commonly known as tissue swelling, occurs mainly on the leg and the arm. The condition may be associated with a range of causes such as venous diseases, trauma, infection, joint disease and orthopaedic surgery. Oedema is caused by both lymphatic and chronic venous insufficiency, which leads to pooling of blood and fluid in the extremities. This results in swelling, mild redness and scaling of the skin, all of which can culminate in ulceration. Methods We present a method to model a wide variety of geometries of limbs affected by oedema and venous ulcers. The shape modelling is based on the PDE method where a set of boundary curves are extracted from 3D scan data and are utilised as boundary conditions to solve a PDE, which provides the geometry of an affected limb. For this work we utilise a mixture of fourth order and sixth order PDEs, the solutions of which enable us to obtain a good representative shape of the limb and associated ulcers in question. Results A series of examples are discussed demonstrating the capability of the method to produce good representative shapes of limbs by utilising a series of curves extracted from the scan data. In particular we show how the method could be used to model the shape of an arm and a leg with an associated ulcer. Conclusion We show how PDE based shape modelling techniques can be utilised to generate a variety of limb shapes and associated ulcers by means of a series of curves extracted from scan data. We also discuss how the method could be used to manipulate a generic shape of a limb and an associated wound so that the model could be fine-tuned for a particular patient.

Yes / BACKGROUND: Venous leg ulcers (VLUs) are the commonest cause of leg ulceration, affecting 1 in 100 adults. There is a significant health burden associated with VLUs - it is estimated that the cost of treatment for 1 ulcer is up to pound1300 per year in the NHS. The mainstay of treatment is with graduated compression bandaging; however, treatment is often prolonged and up to one quarter of venous leg ulcers do not heal despite standard care. Two previous trials have suggested that low-dose aspirin, as an adjunct to standard care, may hasten healing, but these trials were small and of poor quality. Aspirin is an inexpensive, widely used medication but its safety and efficacy in the treatment of VLUs remains to be established. METHODS/DESIGN: AVURT is a phase II randomised double blind, parallel-group, placebo-controlled efficacy trial. The primary objective is to examine whether aspirin, in addition to standard care, is effective in patients with chronic VLUs (i.e. over 6 weeks in duration or a history of VLU). Secondary objectives include feasibility and safety of aspirin in this population. A target of 100 participants, identified from community leg ulcer clinics and hospital clinics, will be randomised to receive either 300 mg of aspirin once daily or placebo. All participants will receive standard care with compression therapy. The primary outcome will be time to healing of the reference ulcer. Follow-up will occur for a maximum of 27 weeks. The primary analysis will use a Cox proportional hazards model to compare time to healing using the principles of intention-to-treat. Secondary outcomes will include ulcer size, pain evaluation, compliance and adverse events. DISCUSSION: The AVURT trial will investigate the efficacy and safety of aspirin as a treatment for VLU and will inform on the feasibility of proceeding to a larger phase III study. This study will address the paucity of information currently available regarding aspirin therapy to treat VLU. TRIAL REGISTRATION: The study is registered on a public database with clinicaltrials.gov ( NCT02333123 ; registered on 5 November 2014).

Yes / Health Services Research and Pharmacy Practice Conference Abstracts: Partnerships in Healthcare: Advancing Sustainable Medicines Optimisation 17–18 April 2023 University of Bradford.

Venous disease is a common vascular condition affecting the lower limbs and causes considerable morbidity in affected patients. National Health Service (NHS) treatment costs are substantial and there is a large demand for treatment much of which cannot be met. Roughly half a million people in the United Kingdom contact their general practitioner each year about varicose veins and associated clinical symptoms. In order to assign priorities and target interventions properly, authorities need to know which patients with venous disease will progress. Although many epidemiological studies have investigated the prevalence of venous disease, information on deterioration is scarce. The overall aim of this study is to determine the natural history of venous disease in the population and to identify lifestyle and clinical factors related to deterioration which might aid clinical decision making and health services policy. The specific objectives were to determine which risk factors were associated with deterioration of venous disease and venous reflux, and to ascertain the natural history of asymptomatic venous incompetence in terms of deteriorating to overt trunk varicose veins and chronic venous insufficiency. The study design was a population based cohort in the Edinburgh Vein Study which the survivors of the 1566 individuals aged 18 to 64 randomly sampled years from the general population at baseline underwent a 13-year follow-up examination. Details of the 1566 participants in the baseline study were sent to the Practitioner Services Division (PSD) of the NHS in Scotland who provided updated addresses and general practitioner registration details. Information collected on each subject at a follow-up clinic included lifestyle factors and medical history, height and weight measurement (by means of a questionnaire), clinical examination for classification of venous disease according to the Basle and CEAP systems, and duplex scanning to assess incompetence of venous valves in the deep and superficial systems of ten vein segments in each leg. Of the subjects from the baseline, 880 participated in the follow-up study, and 576 did not participate, providing a response rate of 60.4% of which 490 were female (55.7%) and 390 were male (44.3%). The study subjects were generally older and slightly more affluent than residents of the City of Edinburgh. For trunk varicose veins, the baseline prevalence was higher in males compared to females (p<0.01), but there was no difference in prevalence among subjects at the follow-up stage of the study (p=0.56). The overall rate of deterioration in trunk varicose veins was 3.55% per annum. More females than males deteriorated (p=0.04). Among subjects who showed deterioration in their trunk varicose veins, the commonest deterioration was from Basle Grade I (mild) at baseline to Grade II (moderate) at follow-up in both the right and left leg (28.1% and 32.9% respectively). Subjects older than 55 years of age (OR=1.59, 95% CI 1.01-2.51), who had a positive family history of varicose veins or venous ulcer (OR=1.92, 95% CI 1.20-3.07), and sat down at work for more than half the working day (OR=1.69, 95% CI 1.04-2.73) had increased risk of deteriorating trunk varicose veins. There was no significant difference between males and females in the prevalence of chronic venous insufficiency (CVI) among subjects at both the baseline and follow-up stage of the study (p=0.15 and 0.16 respectively). The rate of deterioration in CVI was 1.76% per annum. Similarly, among subjects who deteriorated, the commonest deterioration was from Grade I (mild) to Grade II (moderate) CEAP classification in both the right and left leg (42.4% and 45.5% respectively). The risk of worsening of CVI among those older than 55 was nearly three times more than those aged less than 55 (OR=2.85, 95% CI 1.18-6.87), and was still significant when adjusted for gender. The prevalence of telangiectasia was higher in females than in males in both the baseline and follow-up stages of the study (both p<0.01). The rate of deterioration in telangiectasia was 1.6% per annum. The commonest deterioration was from grade I (mild) at baseline to grade II (moderate) follow-up in the left and right leg (using the Basle Classification). Females subjects (OR=1.87, 95% CI 1.35-2.64), those older than 55 (OR=1.68, 95% CI 1.19-2.36), with a positive family history of venous disease (OR=1.60 95% CI 1.14-2.24) were associated with an increased risk of deterioration from telangiectasia compared to male subjects under 55 years of age and with no family history of the disease. The risk of telangiectasia deterioration was more than twice as high in subjects with venous reflux in the greater saphenous vein (origin) (OR=2.34, 95% CI 1.53-3.57), the greater saphenous vein (lower third of the thigh) (OR=2.28, 95% CI 1.59-3.27) and in the small saphenous vein (1.89, 95% CI 1.06-3.36) compared to those with no segments affected. The age and gender adjusted risk was also more than twice as high in subjects with venous reflux in two segments of the superficial system compared to subjects with no venous reflux in any segment (OR=2.06, 95% CI 1.23-3.44), and almost four times as high in subjects with reflux in more than three segments of the superficial system (OR=3.97, 95% CI 2.16-7.31) compared to subjects with no segments affected. On duplex scanning, the prevalence of reflux was higher in females than in males in the superficial system at baseline and follow-up stages of the study (p<0.01 respectively). In the deep system, the prevalence was higher in males than females at the baseline stage (p<0.01) with no significant difference at the follow-up stage (p=0.85). The rate of deterioration in venous reflux was 1.28% per annum. Most subjects deteriorated from one to two vein segments affected in the leg, the majority of which had reflux in the greater saphenous vein (thigh) at baseline and developed reflux in the greater saphenous vein (origin) at follow-up. Subjects more than 55 years of age had significantly more deterioration than those aged less than 55 (p<0.01). Obese or overweight subjects (OR=1.59, 95% CI 1.32-3.67), those aged more than 55 (OR=2.20, 95% CI 1.32-3.67), with a family history of varicose veins (among female subjects only, OR=2.55, 95% CI 1.16-5.56), and who sat down at work more than half the working time (among male subjects only) (OR=2.26, 95%CI 0.97-5.23) had increased risk of showing deterioration in reflux in any leg and in any vein segment from baseline to follow-up. Subjects with venous reflux at baseline were over two and half times more likely to show deterioration in trunk varicose veins compared to those with no reflux (OR=2.69, 95%CI 1.44-5.01), and four times more likely to deteriorate in either trunk varicose veins or chronic venous insufficiency (OR=4.20, 95% CI 2.42-7.29). Subjects with venous reflux at baseline were twice as likely to develop new trunk varicose veins (OR=2.08, 95%CI 1.25-3.46), and 1.78 times more likely to develop either trunk varicose veins or chronic venous insufficiency (OR=1.78, 95%CI 1.12-2.80). Age and gender adjusted risk of trunk varicose veins increased more than fourfold among subjects with venous reflux in the greater saphenous veins (OR=4.04, 95% CI 2.36-6.92), and more than threefold in the greater saphenous vein (lower third of the thigh) (OR=3.13, 95% CI 1.85-5.27) and the small saphenous vein (OR=3.17, 95% CI 1.55-6.48). Subjects with venous reflux in two or more than three vein segments in the superficial system were more than five times more likely to deteriorate from trunk varicose veins (OR=5.39, 95% CI 2.64-10.99 and OR=5.96, 95% CI 2.71-13.10 respectively). The Edinburgh Vein Study follow-up identified factors linked to deterioration of trunk varicose veins and CVI. The findings of this follow-up study have important implications in decision making in NHS and a prognostic tool could be produced to assist clinicians in deciding who should receive treatment or maintained under surveillance. Increasing age, and family history will likely lead to worsening of trunk varicose veins and CVI. The findings also confirm the association between asymptomatic and symptomatic venous valvular incompetence with worsening and developing new cases of venous disease. Such information will be essential for policy makers facing difficult decisions over prioritisation of services in the future. Further research might include trials of surgical and non-surgical interventions designed to limit deterioration in high risk individuals and enable surgeons to target interventions appropriately. Larger prognostic studies of many factors, including genotype, might be conducted to link progression of venous disease, and to provide further information on high risk individuals who might benefit from treatment.