38,470 research outputs found

    Development of an international standard set of outcome measures for patients with atrial fibrillation: a report of the International Consortium for Health Outcomes Measurement (ICHOM) atrial fibrillation working group.

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    AIMS: As health systems around the world increasingly look to measure and improve the value of care that they provide to patients, being able to measure the outcomes that matter most to patients is vital. To support the shift towards value-based health care in atrial fibrillation (AF), the International Consortium for Health Outcomes Measurement (ICHOM) assembled an international Working Group (WG) of 30 volunteers, including health professionals and patient representatives to develop a standardized minimum set of outcomes for benchmarking care delivery in clinical settings. METHODS AND RESULTS: Using an online-modified Delphi process, outcomes important to patients and health professionals were selected and categorized into (i) long-term consequences of disease outcomes, (ii) complications of treatment outcomes, and (iii) patient-reported outcomes. The WG identified demographic and clinical variables for use as case-mix risk adjusters. These included baseline demographics, comorbidities, cognitive function, date of diagnosis, disease duration, medications prescribed and AF procedures, as well as smoking, body mass index (BMI), alcohol intake, and physical activity. Where appropriate, and for ease of implementation, standardization of outcomes and case-mix variables was achieved using ICD codes. The standard set underwent an open review process in which over 80% of patients surveyed agreed with the outcomes captured by the standard set. CONCLUSION: Implementation of these consensus recommendations could help institutions to monitor, compare and improve the quality and delivery of chronic AF care. Their consistent definition and collection, using ICD codes where applicable, could also broaden the implementation of more patient-centric clinical outcomes research in AF

    Endothelin system in human cardiovascular physiology and pathophysiology

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    The experiments presented here arose from an interest in endothelial function and, particularly, a wish to better understand the pharmacology and physiology of the endothelin (ET) system in human blood vessels in health, and the influence of cardiovascular disease on the ET system. This work followed from the discovery of ET-1 as a peptide endothelial mediator of vascular tone in 1988. Publications are grouped into sections representing different aspects of the work.Section 1 is concerned with exploring pharmacological responses to the ET family of peptides, the sarafotoxin analogue peptides, and ET antagonists, in human blood vessels in vivo. This was amongst the first work with ET-1 in humans, and certainly the first to use the sarafotoxins, ET receptor antagonists and ET converting enzyme (ECE) inhibitors. After characterisation of the pharmacological tools, it was possible to show clearly that endogenous ET-1 plays a physiological role in the control of peripheral resistance and blood pressure in healthy humans, suggesting important clinical applications for these agents. It was also shown that the ETA receptor is the major vasocontrictor receptor and that the major role in health of the ETB receptor is endothelium-dependent vasodilatation, enhancement of which may contribute to the beneficial clinical attributes of ETA receptor antagonism. In addition, local ET-1 infusion in the forearm circulation was shown to be a system whereby the clinical efficacy of systemically administered ET receptor antagonists could be modelled pharmacodynamicallySections 2-4 cover work confirming the substantial clinical utility of ET receptor antagonists and ECE inhibitors as vasodilators, particularly in essential hypertension, heart failure and renal failure. Other work, following congenital heart surgery, suggests that a cautious approach may be needed in some cases of pulmonary hypertension. Studies with neutral endopeptidase (NEP) inhibitors show unequivocally, but unexpectedly, that these agents are peripheral vasoconstrictors, and the evidence presented is consistent with this effect occurring because endogenously generated vascular ET-1 is an important substrate for NEP.Section 5 contains some miscellaneous but related studies, together with a series of review articles written from 1991-98 synthesising the literature at each stage and drawing conclusions about potential areas of major clinical interest in cardiovascular diseasePUBLICATIONS: • SECTION 1: CARDIOVASCULAR PHYSIOLOGY, Papers 1-19 • 1. Clarke JG, Benjamin N, Larkin SW, Webb DJ, Davies GJ, Maseri A. Endothelin is a potent long-lasting vasoconstrictor in men. Am J Physiol 1989;257:H2033-5. • 2. Cockcroft JR, Clarke JG, Webb DJ. The effect of intra-arterial endothelin on resting blood flow and sympathetically mediated vasoconstriction in the forearm of man. Br J Clin Pharmacol 1991;31:521-4. • 3. Waugh CJ, Dockrell MEC, Haynes WG, Olverman HJ, Williams BC, Webb DJ. The potassium channel opener BRL 38227 inhibits binding of [l25I]-labelled endothelin-1 to rat cardiac membranes. Biochem Biophys Res Commun 1992;185:630-5. • 4. Haynes WG, Webb DJ. Endothelium dependent modulation of responses to endothelin-1 in human veins. Clin Sci 1993;84:427-33. • 5. Dockrell MEC, Haynes WG, Williams BC, Webb DJ. Endothelin-1 and aggregation of human platelets in vitro. J Cardiovasc Pharmacol 1993;22(suppl 8), S204-6. • 6. Haynes WG, Webb DJ. Venoconstriction to endothelin-1 in humans: role of calcium and potassium channels. Am J Physiol 1993;265:H1676-81. • 7. Haynes WG, Webb DJ. Contribution of endogenous generation of endothelin-1 to basal vascular tone. Lancet 1994;344:852-4. • 8. Haynes WG, Strachan FE, Webb DJ. Endothelin ETA and ETb receptors cause vasoconstriction of human resistance and capacitance vessels in vivo. Circulation 1995;92:357-63. • 9. Strachan FE, Haynes WG, Webb DJ. Endothelium-dependent modulation of venoconstriction to sarafotoxin S6c in human veins in vivo. J Cardiovasc Pharmacol 1995;26(suppl. 3):S 180-2. • 10. Smith PJW, McQueen DS, Webb DJ. The effect of cooling on the contractile response to endothelin-1 in small arteries from humans. J Cardiovasc Pharmacol 1995;26(suppl3):S230-2. • 11. Plumpton C, Haynes WG, Webb DJ, Davenport AP. Phosphoramidon inhibition of the in vivo conversion of big endothelin-1 to endothelin-1 in the human forearm. Br J Pharmacol 1995; 116:1821-8. • 12. Haynes WG, Moffat S, Webb DJ. An investigation into the direct and indirect venoconstrictor effects of endothelin-1 and big endothelin-1 in man. Br J Clin Pharmacol 1995;40:307-11. • 13. Haynes WG, Ferro CJ, O'Kane KPJ, Somerville D, Lomax CC, Webb DJ. Systemic endothelin receptor blockade decreases peripheral vascular resistance and blood pressure in humans. Circulation 1996;93:1860-70. • 14. Dockrell MEC, Webb DJ, Williams BC. Activation of the endothelin B receptor causes a dose-dependent accumulation of cyclic GMP in human platelets. Blood Coag Fibrinolysis 1996;7:178-80. • 15. Plumpton C, Ferro CJ, Haynes WG, Webb DJ, Davenport AP. The increase in human plasma immunoreactive endothelin but not big endothelin-1 or its C-terminal fragment induced by systemic administration of the endothelin antagonist TAK-044. Br J Pharmacol 1996;119:311-4. • 16. Haynes WG, Hand MH, Dockrell MEC, Eadington DW, Lee MR, Benjamin N, Webb DJ. Physiological role of nitric oxide in regulation of renal function in humans. Am J Physiol 1997;272:F364-71. • 17. Ferro CJ, Haynes WG, Johnston NR, Lomax CC, Newby DE, Webb DJ. The peptide endothelin receptor antagonist, TAK-044, produces sustained inhibition of endothelin1 mediated arteriolar vasoconstriction. Br J Clin Pharmacol 1997;44:377-383. • 18. Verhaar MC, Strachan FE, Newby DE, Cruden NL, Koomans HA, Rabelink TJ, Webb DJ. Endothelin-A receptor antagonist-mediated vasodilatation is attenuated by inhibition of nitric oxide synthesis and by endothelin-B receptor blockade. Circulation 1998;97:752-6. • 19. Strachan FE, Spratt JC, Wilkinson IB, Gray GA, Johnston NR, Webb DJ. Systemic blockade of the endothelin-B receptor increases peripheral vascular resistance in healthy men. Hypertension 1999;33:581-5. • SECTION 2: HYPERTENSION AND RENAL DYSFUNCTION Papers 20-24 | 20. Haynes WG, Hand MF, Johnstone HA, Padfield PL, Webb DJ. Direct and sympathetically mediated venoconstriction in essential hypertension: enhanced responses to endothelin-1. J Clin Invest 1994;94:1359-64. • 2 1. Sturrock NDC, Lang CC, MacFarlane LJ, Dockrell MEC, Ryan M, Webb DJ, Struthers AD. Serial changes in blood pressure, renal function, endothelin and lipoprotein (a) during the first 9 days of cyclosporin therapy in males. J Hypertens 1995;13:667-73. • 22. Hand MF, Haynes WG, Johnstone HA, Anderton JL, Webb DJ. Erythropoietin enhances vascular responsiveness to norepinephrine in renal failure. Kidney Int 1995;48:806-13. • 23. Ferro CJ, Spratt JCS, Haynes WG, Webb DJ. Inhibition of neutral endopeptidase causes vasoconstriction of human resistance vessels in vivo. Circulation 1998;97:2323-30. • 24. Hand MH, Haynes WG, Webb DJ. Reduced endogenous endothelin-1-mediated vascular tone in chronic renal failure. Kidney Int 1999;55:613-20. • SECTION 3 | ISCHAEMIC HEART DISEASE Papers 25-27 | 25. Wieczorek I, Haynes WG, Webb DJ, Ludlam CA, Fox KAA. Raised plasma endothelin in unstable angina and non-Q wave myocardial infarction: relation to cardiovascular outcome. Br Heart J 1994;72:436-41. • 26. Flaynes WG, Hamer DW, Robertson CE, Webb DJ. Plasma endothelin following cardiac arrest: differences between survivors and non-survivors. Resuscitation 1994;27:117-22. • 27. Newby DE, Flint LL, Fox KAA, Boon NA, Webb DJ. Reduced responsiveness to endothelin-1 in peripheral resistance vessels of patients with syndrome X. J Am Coll Cardiol 1998;31:1585-90. • SECTION 4 | HEART FAILURE AND PULMONARY HYPERTENSION Papers 28-30 | 28. Davidson NC, Coutie WJ, Webb DJ, Struthers AD. Hormonal and renal differences between low dose and high dose angiotensin converting enzyme inhibitor treatment in patients with chronic heart failure. Heart 1996;75:576-81. • 29. Love MP, Haynes WG, Gray GA, Webb DJ, McMurray JJV. Vasodilator effects of endothelin-converting enzyme inhibition and endothelin ETA receptor blockade in chronic heart failure patients treated with ACE inhibitors. Circulation 1996;94:2131-7. • 30. Prendergast B, Newby DE, Wilson LE, Webb DJ, Mankad PS. Early therapeutic experience with the endothelin antagonist, BQ-123, in pulmonary hypertension after congenital heart surgery. Heart 1999;82:505-8 • SECTION 5 | MISCELLANEOUS TOPICS AND REVIEWS Papers 31-34 and 35-46 | 31. Sanai L, Haynes WG, McKenzie A, Grant IS, Webb DJ. Endothelin production in sepsis and the adult respiratory distress syndrome. Intens Care Med 1996;22:52-6. • 32. Mickley EJ, Gray GA, Webb DJ. Activation of endothelin ETa receptors masks the constrictor role of endothelin ETg receptors in rat isolated small esenteric arteries. Br J Pharmacol 1997;120:1376-82. • 33. McEwan PE, Valdenaire O, Sutherland L, Webb DJ, Gray GA. A non-radioactive method for localization of endothelin receptor mRNA in situ. J Cardiovasc Pharmacol 1998;31(suppl l):S443-6. • 34. Smith PJW, Ferro CJ, McQueen DS, Webb DJ. Functional studies in small arteries do not support a primary role for endothelin in the pathogenesis of Raynaud's disease. J Cardiovasc Pharmacol 1998;31(suppl l):S473-6. • 35. Webb DJ. Endothelin receptors cloned, endothelin converting enzyme characterised and pathophysiology explored. TiPS 1991;12:43-6. • 36. Haynes WG, Webb DJ. The endothelin family of peptides: local hormones with diverse roles in health and disease. Clin Sci 1993;84:485-500. • 37. Haynes WG, Davenport AP, Webb DJ. Endothelin: progress in pharmacology and physiology. TiPS 1993;14:225-8. • 38. Kennedy RL, Haynes WG, Webb DJ. Endothelins as regulators of growth and function in endocrine tissues. Clin Endocrinol 1993;39:259-65. • 39. Webb DJ, Haynes WG. Endothelins come of age. Lancet 1993;342:1439-40. • 40. Webb DJ. Evidence for endothelin-1-mediated vasoconstriction in severe chronic heart failure: endothelin antagonism in heart failure. Circulation 1995;92:3372. • 41. Ferro CJ, Webb DJ. The clinical potential of endothelin receptor antagonists in cardiovascular medicine. Drugs 1996;51:12-27. • 42. Gray GA, Webb DJ. The endothelin system and its potential as a therapeutic target in cardiovascular disease. Pharmacol Ther 1996;72:109-48. • 43. Newby DN, Webb DJ. The endothelin system in cardiovascular disease: discovery to drug development in under a decade. BMJ 1997;314:531-2. • 44. Webb DJ. Endothelin: from molecule to man [BPS Research Prize Lecture]. Br J Clin Pharmacol 1997;44:9-20. • Webb DJ, Monge JC, Rabelink A, Yanagisawa M. Endothelin: new discoveries and rapid progress in the clinic. Trends Pharmacol Sci 1998;19:5-8. • 46. Haynes WG, Webb DJ. Endothelin as a regulator of cardiovascular function in health and disease. J Hypertens 1998;16:1081-98

    Clinical review: Can we predict which patients are at risk of complications following surgery?

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    There are a vast number of operations carried out every year, with a small proportion of patients being at highest risk of mortality and morbidity. There has been considerable work to try and identify these high-risk patients. In this paper, we look in detail at the commonly used perioperative risk prediction models. Finally, we will be looking at the evolution and evidence for functional assessment and the National Surgical Quality Improvement Program (in the USA), both topical and exciting areas of perioperative prediction

    High intensity interval training for people with Multiple Sclerosis: a systematic review

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    Background: Aerobic High Intensity Interval Training (HIIT) is safe in the general population and more efficient in improving fitness than continuous moderate intensity training. The body of literature examining HIIT in Multiple Sclerosis (MS) is expanding but to date a systematic review has not been conducted. The aim of this review was to investigate the efficacy and safety of HIIT in people with MS. Methods: A systematic search was carried out in September 2017 in EMBASE, MEDline, PEDro, CENTRAL and Web of Science Core collections using appropriate keywords and MeSH descriptors. Reference lists of relevant articles were also searched. Articles were eligible for inclusion if they were published in English, used HIIT, and included participants with MS. Quality was assessed using the PEDro scale. The following data were extracted using a standardised form: study design and characteristics, outcome measures, significant results, drop-outs, and adverse events. Results: Seven studies (described by 11 articles) were identified: four randomised controlled trials, one randomised cross-over trial and two cohort studies. PEDro scores ranged from 3-8. Included participants (n=249) were predominantly mildly disabled; one study included only people with progressive MS. Six studies used cycle ergometry and one used arm ergometry to deliver HIIT. One study reported six adverse events, four which could be attributed to the intervention. The other six reported that there were no adverse events. Six studies reported improvements in at least one outcome measure, however there were 60 different outcome measures in the seven studies. The most commonly measured domain was fitness, which improved in five of the six studies measuring aspects of fitness. The only trial not to report positive results included people with progressive and a more severe level of disability (Extended Disability Status Scale 6.0-8.0). Conclusion: HIIT appears to be safe and effective in increasing fitness in people with MS and low levels of disability. Further research is required to explore the effectiveness of HIIT in people with progressive MS and in those with higher levels of disability

    The dual endothelin converting enzyme/neutral endopeptidase inhibitor SLV-306 (daglutril), inhibits systemic conversion of big endothelin-1 in humans

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    Aims - Inhibition of neutral endopeptidases (NEP) results in a beneficial increase in plasma concentrations of natriuretic peptides such as ANP. However NEP inhibitors were ineffective anti-hypertensives, probably because NEP also degrades vasoconstrictor peptides, including endothelin-1 (ET-1). Dual NEP and endothelin converting enzyme (ECE) inhibition may be more useful. The aim of the study was to determine whether SLV-306 (daglutril), a combined ECE/NEP inhibitor, reduced the systemic conversion of big ET-1 to the mature peptide. Secondly, to determine whether plasma ANP levels were increased. Main methods - Following oral administration of three increasing doses of SLV-306 (to reach an average target concentration of 75, 300, 1200 ng ml− 1 of the active metabolite KC-12615), in a randomised, double blinded regime, big ET-1 was infused into thirteen healthy male volunteers. Big ET-1 was administered at a rate of 8 and 12 pmol kg− 1 min− 1 (20 min each). Plasma samples were collected pre, during and post big ET-1 infusion. ET-1, C-terminal fragment (CTF), big ET-1, and atrial natriuretic peptide (ANP) were measured. Key findings - At the two highest concentrations tested, SLV-306 dose dependently attenuated the rise in blood pressure after big ET-1 infusion. There was a significant increase in circulating big ET-1 levels, compared with placebo, indicating that SLV-306 was inhibiting an increasing proportion of endogenous ECE activity. Plasma ANP concentrations also significantly increased, consistent with systemic NEP inhibition. Significance - SLV-306 leads to inhibition of both NEP and ECE in humans. Simultaneous augmentation of ANP and inhibition of ET-1 production is of potential therapeutic benefit in cardiovascular disease

    Short-term heat acclimation is effective and may be enhanced rather than impaired by dehydration

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    Most heat acclimation data are from regimes longer than 1 week, and acclimation advice is to prevent dehydration. Objectives: We hypothesized that (i) short-term (5-day) heat acclimation would substantially improve physiological strain and exercise tolerance under heat stress, and (ii) dehydration would provide a thermally independent stimulus for adaptation. Methods: Nine aerobically fit males heat acclimated using controlled-hyperthermia (rectal temperature 38.5°C) for 90 min on 5 days; once euhydrated (EUH) and once dehydrated (DEH) during acclimation bouts. Exercising heat stress tests (HSTs) were completed before and after acclimations (90-min cycling in T a 35°C, 60% RH). Results: During acclimation bouts, [aldosterone] plasma rose more across DEH than EUH (95%CI for difference between regimes: 40-411 pg ml -1 ; P=0.03; n=5) and was positively related to plasma volume expansion (r=0.65; P=0.05), which tended to be larger in DEH (CI: -1 to 10%; P=0.06; n=9). In HSTs, resting forearm perfusion increased more in DEH (by 5.9 ml 100 tissue ml -1 min -1 : -11.5 to -1.0; P=0.04) and end-exercise cardiac frequency fell to a greater extent (by 11 b min -1 : -1 to 22; P=0.05). Hydration-related effects on other endocrine, cardiovascular, and psychophysical responses to HSTs were unclear. Rectal temperature was unchanged at rest but was 0.3°C lower at end exercise (P < 0.01; interaction: P=0.52). Conclusions: Short-term (5-day) heat acclimation induced effective adaptations, some of which were more pronounced after fluid-regulatory strain from permissive dehydration, and not attributable to dehydration effects on body temperature. Am. J. Hum. Biol. 26:311-320, 2014. © 2014 Wiley Periodicals, Inc

    Imaging in population science: cardiovascular magnetic resonance in 100,000 participants of UK Biobank - rationale, challenges and approaches

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    PMCID: PMC3668194SEP was directly funded by the National Institute for Health Research Cardiovascular Biomedical Research Unit at Barts. SN acknowledges support from the Oxford NIHR Biomedical Research Centre and from the Oxford British Heart Foundation Centre of Research Excellence. SP and PL are funded by a BHF Senior Clinical Research fellowship. RC is supported by a BHF Research Chair and acknowledges the support of the Oxford BHF Centre for Research Excellence and the MRC and Wellcome Trust. PMM gratefully acknowledges training fellowships supporting his laboratory from the Wellcome Trust, GlaxoSmithKline and the Medical Research Council
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