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Timing of intervention in aortic stenosis: a review of current and future strategies
Russell James Everett1,
Marie-Annick Clavel2,
Philippe Pibarot2,
Marc Richard Dweck1
1 BHF/Centre for Cardiovascular Science, University of Edinburgh, Edinburgh, UK
2 Department of Medicine, Quebec Heart and Lung Institute, Quebec, Canada
Correspondence to Dr Russell James Everett, BHF/Centre for Cardiovascular Science, University of Edinburgh, Edinburgh EH16 4SB, UK; russell.everett{at}ed.ac.uk
cardiac magnetic resonance (cmr) imaging
valve disease surgery
transcatheter valve interventions
To review the pathophysiology of fibrocalcific aortic stenosis, the myocardial response to pressure overload and current clinical guidelines concerning the timing of valve intervention.
To explore and to quantify the risks of earlier intervention in asymptomatic patients compared with the risks of a watchful waiting strategy.
To detail future potential strategies for deciding on timing of aortic valve intervention and current ongoing randomised controlled trials.
Aortic stenosis (AS) is the most common valve disease requiring surgical intervention in high-income countries.1 It is characterised by progressive thickening, fibrosis and calcification of the leaflets leading to restriction and valve obstruction.2 The consequent increase in left ventricular afterload leads to a hypertrophic response of the left ventricle, normalising wall tension and maintaining cardiac output. However, with progressive valvular stenosis, this hypertrophic response eventually decompensates resulting in symptom development, heart failure and death.
With no medications proven to attenuate or reverse stenosis progression, the only available treatment is valve replacement. This should ideally be performed when the risks of the disease process (ie, sudden cardiac death, irreversible functional impairment and heart failure) outweigh those of intervention (ie, procedural risk, long-term complications and potential need for reoperation). However, we frequently lack robust evidence to make accurate assessments of such risk. Deciding on the timing of valvular intervention is therefore difficult in many patients, and contemporary clinical guidelines are often underpinned by historical observational data rather than high-quality randomised controlled trials. This article will review our current understanding of the pathophysiology of AS, describe and examine the evidence behind current guideline recommendations and explore potential future strategies to optimise the timing of valve intervention.
Pathophysiology of valvular stenosis and the hypertrophic response
Since the original description of AS by Mönckeberg in 1904, the decline in rheumatic fever and ageing population have led to a demographic transition towards fibrocalcific disease. For many years, fibrocalcific AS was viewed as a degenerative disease where progressive 'wear and tear' led to structural damage and passive valvular calcification. However, contemporary thinking is that fibrocalcific AS develops as part of a series of intricate and highly regulated inflammatory, fibrotic and osteogenic processes. The pathophysiological processes driving aortic valve stenosis can be divided into two phases.2 The initiation phase is characterised by endothelial injury accompanied by infiltration of lipids, lipid oxidation and proinflammatory response. Despite the clear similarities with atherosclerosis, three large randomised trials have failed to show any effect of statins on disease progression or clinical outcome. The propagation phase is characterised by the appearance of osteoblast-like cells that coordinate progressive valvular calcium and bone matrix deposition. This osteogenic phenotype involves many signalling molecules involved in bone formation and is both self-perpetuating and highly regulated.2 Advances in imaging now allow for non-invasive assessment of both the burden and activity of calcification in the valve3 4; however, the severity of aortic valve obstruction is still best assessed using echocardiography.5
Myocardial response
The traditional focus of AS assessments has been on the valve. However, the left ventricular myocardial response to pressure overload is equally important,6 particularly as the correlation between echocardiographic measures of AS severity and the degree of myocardial hypertrophy is moderate at best.7 While left ventricular hypertrophy maintains wall stress and cardiac output for many years, it eventually decompensates, with cell death and myocardial fibrosis identified as key processes.8 Many imaging and biomarker surrogates of these processes have been investigated providing significant prognostic information that will be discussed later in this article. Gender appears to have an important influence on both the LV remodelling response and patient outcomes,9 but detailed discussion is beyond the scope of this article.
Current guideline-recommended treatment strategies and their limitations
Broadly speaking, contemporary clinical guidelines recommend aortic valve intervention when stenosis severity is deemed severe and there is evidence of left ventricular decompensation, using either direct objective or surrogate symptomatic measures (figure 1 and table 1).10 11 Haemodynamic severity is best assessed using echocardiography but can be challenging when measures of severity are discordant or low-flow states exist. New recommendations for confirming AS severity are given in the 2017 ESC/EACTS guideline update.5 Detailed discussion of low-flow states is beyond the scope of this article but can be found elsewhere.12
ESC/EACTS algorithm for management of severe AS (2017 guidelines). AS, aortic stenosis; LVEF, left ventricular ejection fraction; SAVR, surgical aortic valve replacement; TAVI, transcatheter aortic valve implantation.
Recommendations for Intervention in patients with severe AS (ESC/EACTS guidelines 2017)
Presence of AS-related symptoms
It is universally accepted that the development of patient symptoms (exertional dyspnoea, angina or syncope; table 2) serves as an indicator of left ventricular decompensation and a dismal prognosis without intervention. This was first described in the seminal paper by Braunwald and Ross in 196813 and forms the underlying framework of how we manage patients today. However, this finding was based on retrospective data from just 12 patients with a mixture of bicuspid and rheumatic valve disease and a mean age of death of 63 years. The changing demographics of AS make it difficult to interpret the current relevance of these historical data to the patients seen in current practice who are frequently in their eighth or ninth decades. Symptom assessment can be highly challenging in these patients due to the high prevalence of both comorbidity, which may cause symptoms to be falsely attributed to AS, and physical inactivity, which can conceal exertion-related problems.
Symptomatology of severe aortic stenosis
Exercise testing may help unmask symptoms in many patients and is safe when performed in stable patients.14 ESC guidelines recommend surgery in patients with severe ASand typical symptoms on exercise test (class I, level C) or a fall in systolic blood pressure at peak exercise (class IIa, level C). This recommendation is based largely on observational data demonstrating that a positive exercise test is a strong predictor of sudden death or symptom development.15 However, these data are limited, consisting of a series of relatively small observational studies with inherent risk of bias and heterogeneity as to what constituted an abnormal test. According to a recent meta-analysis, while the negative predictive value of stress testing for subsequent cardiac events is reasonable (79%), the positive predictive value is modest (66%).14 Exercise testing has other major limitations; up to 20% of patients will be unable to perform the test due to poor mobility, while pre-existing ECG abnormalities are present in up to 50% of patients confounding test interpretation.16 It is worth noting that exercise testing may also detect abnormalities caused by coexistent coronary disease, which is an important determinant of both management and prognosis.17
Impaired left ventricular ejection fraction
Development of left ventricular systolic impairment, as identified by a reduced left ventricular ejection fraction, is an inevitable consequence of progressive and untreated valvular stenosis assuming sudden death does not occur. Although the risk of perioperative mortality is elevated in the setting of reduced ejection fraction, these patients have a dismal prognosis without intervention and improved long-term outcomes with valve replacement earning a class I, level C recommendation in clinical guidelines.10 11
In clinical practice, patients with AS can develop a reduction in ejection fraction for a variety of reasons, and it remains important to consider the mechanism of this reduction and whether it is reversible. Reductions in ejection fraction occur as a direct response to increases in afterload and will reverse following valve replacement. By contrast, the ejection fraction does not improve in approximately 25% of patients10 11 18 19 who are more likely to remain symptomatic and who have adverse long-term outcomes (twice as likely to die over 5 years follow-up).20 In these patients, persistent systolic dysfunction appears related to the development of irreversible scar due to either myocardial infarction or decompensation of the hypertrophic response.21 In sick, frail patients, such information may govern whether valve intervention is likely to be of benefit.
Reductions in ejection fraction are therefore a late, non-specific and often irreversible feature in AS, leading to interest in alternative methods for detecting left ventricular decompensation7 22–24 as will be discussed.
Very severe AS
Patients with critical AS appear to have a particularly poor prognosis, similar to that of symptomatic severe AS.25 Indeed patients with peak aortic jet velocities of >5.0 and >5.5 m/s demonstrate a 2-year event-free survival of 43% and 25%, respectively, compared with 70% in those with Vmax 4.0–4.9 m/s.26 The ESC/EACTS guidelines therefore recommend consideration of aortic valve replacement in patients with Vmax >5.5 m/s if the estimated surgical risk is low (class IIa, level C). However, these observational studies mostly examined the composite endpoint of mortality and referral for aortic valve intervention with a strong risk of referral bias and event rates mainly driven by decisions to perform surgery.
Rapid haemodynamic progression
Although the average rate of progression (measured by peak aortic-jet velocity) is 0.24±0.30 m/s/year, this rate is highly variable.27 Moreover, it is subject to scan–rescan variation in peak velocity measurements, which can be high in clinical practice. Patients with rapid progression (>0.3 m/s/year) and significant valve calcification have a rate of symptom development or mortality of 79% at 2 years.28 As a result, referral for surgical intervention in these patients is given a class IIa, level C recommendation in the latest guidelines. However, again, this is based on limited observational data, and this strategy requires standardised high-quality echocardiography over several years to confidently determine rate of progression.
Elevation of B-type natriuretic peptide (BNP) levels
BNP is the first cardiac biomarker to be included in the decision-making algorithm for aortic valve replacement. Early studies investigating natriuretic peptides in AS showed promise but were criticised for their small size, observational nature and use of softer outcome endpoints.29 30 In addition, many patients were symptomatic, and the variation in normal BNP with age and sex were not accounted for. A more recent study of 565 patients with asymptomatic moderate-to-severe AS identified that a BNP ratio (measured BNP value divided by upper limit of normal for patient's age and sex) of >1 was independently predictive of mortality and a ratio of >3 had an HR of 7.3 for survival in patients with asymptomatic severe AS.31 As such, the latest clinical guidelines reflect these data with a level IIa, class C recommendation for aortic valve replacement if the BNP ratio is persistently above 3 and overall surgical risk is low. However, BNP is a non-specific marker of cardiac dysfunction, and its utility, like each of the other parameters, has yet to be tested in a randomised controlled trial.
The recently published ESC clinical guidelines also removed two previous IIb indications for AVR in asymptomatic patients: an increase in mean aortic gradient of >20 mm Hg with exercise, or the finding of excessive LV hypertrophy in the absence of hypertension.
Balancing competing risks
There are clear limitations with many of our guideline-advocated strategies. Most are based on limited observational data and supported by level C recommendations. There is therefore a need for randomised controlled trials assessing the optimal timing of surgery and novel objective methods to guide this major clinical decision. Ideally, intervention would be performed in patients just as the left ventricle is starting to decompensate but before substantial irreversible damage has accrued and at a time when the short-term and long-term risks of the intervention are outweighed by the risks of not intervening (figure 2 and table 3). An understanding of these competing risks is therefore critical.
Optimising the timing of aortic valve intervention in progressive aortic stenosis. TAVI, transcatheter aortic valve insertion.
Estimates of clinical risks associated with watchful waiting or early intervention strategies
Risks of valve intervention
Surgical aortic valve replacement remains the standard of care for valvular intervention, with improvements in surgical and postoperative care driving perioperative mortality down to ~1%–3%. Other important perioperative complications include conduction disease requiring permanent pacemaker insertion (1.5%–8.6%32) and cerebrovascular accidents (2.4%–8.1%33–35). There is also the risk of cognitive decline (due to perioperative cerebral hypoperfusion microemboli or anaesthetic agent neurotoxicity35). An individual's risk of these complications can be estimated using surgical risk calculators such as EUROSCORE II and the Society of Thoracic Surgeons score. An argument in favour of early surgery is that operative risk is lower in younger patients that are asymptomatic, have less comorbidity and have normal left ventricular function.
The emergence of minimally invasive transcatheter aortic valve insertion (TAVI) over the last 10 years has completely changed the landscape for decision making regarding valve intervention in symptomatic patients. Current trials show non-inferiority of this percutaneous technique compared with surgical intervention in both high-risk and intermediate-risk patients,34 36–39 and procedural risk may further reduce with increasing clinical experience and advances in prosthesis design and delivery. Indeed, major vascular complications have decreased substantially (from >10% to <5%40) as have stroke rates, which are between 2% and 3% in contemporary cohorts.40 However, the requirement for permanent cardiac pacing postprocedure remains consistently higher than surgical intervention at >10%40 and while TAVI allows for rapid patient recovery and mobilisation, the long-term durability of these bioprostheses has not been demonstrated.41 This will be key before their widespread use in younger or asymptomatic patient groups can be recommended.
Performing valve intervention introduces small but significant annual risks associated with the presence of a prosthetic valve. These risks are heavily influenced by valve type, with both anticoagulant related major bleeding (1.8%–2.6% per year) and thromboembolism (0.7%–1.0% per year) more frequent with mechanical valves.42 In addition, there is an increased risk of endocarditis (1%–3% during the first year then <0.5% per year43), which has a high associated morbidity and mortality. Whereas structural valve degeneration is exceedingly rare in mechanical valves, bioprosthetic valves have a limited lifespan which can be difficult to predict. In these patients, valve degeneration usually starts to occur 10 years following implantation44 and occurs more rapidly in younger patients.45 This is an extremely important issue if bioprosthetic valves are to be used in younger asymptomatic patients. Ongoing research into decellularisation techniques and tissue engineering may lead to improved bioprosthetic valve longevity, while advances in mechanical valve design might eventually eliminate the need for anticoagulation and associated bleeding risk. In addition, the use of a transcatheter valve inside a surgical bioprosthetic valve (so called valve-in-valve TAVI) may reduce the risk of future procedures should valve degeneration occur.
Risks of not intervening
The risk of sudden cardiac death in patients with asymptomatic severe AS managed conservatively is ~1% per year and occurs without preceding symptoms in 70% of cases.46–48 Once symptoms develop, further clinical deterioration can be rapid with a significant risk of sudden death while awaiting intervention (4% at 1 month, 12% at 6 months).49
Delaying aortic valve intervention until there is evidence of advanced left ventricular decompensation results in greater perioperative risks.48 Observational studies have quoted increased perioperative mortality (9%–19%10 20 50) in patients who have developed left ventricular systolic impairment and advanced myocardial fibrosis.51 Further risk stratification can be performed using stress echocardiography to assess myocardial contractile reserve, with lower perioperative risks if contractile reserve is present (5% vs 22%–32%11 52). However, given the dismal prognosis of untreated AS, even patients without contractile reserve have improved long-term survival if they survive the perioperative period.10 11
The highest burden in mortality and morbidity related to delaying valve intervention appears to occur in the months and years following AVR, particularly in those patients that have evidence of left ventricular decompensation. As discussed, patients with an impaired ejection fraction prior to AVR have a poor long-term prognosis,20 while in a recent study of AS patients with a high probability of LV decompensation, more than half were either dead or admitted to hospital with heart failure within 2 years.53 Both these observations may reflect the development of irreversible scarring in the myocardium while patients are waiting for surgery.
Possible future strategies
Several different strategies for optimising the timing of valve replacement in AS have been proposed, many of which are currently being evaluated within the context of randomised controlled trials (figure 3 and table 4). Many of these target asymptomatic patients, and it should be recognised that many patients that feel otherwise fit and healthy might not want to undergo major heart surgery.
Comparison of EARLY-TAVR and EVoLVeD randomised controlled trial designs. Currently, recruiting randomised controlled trials generally fall into two groups: those investigating valve intervention in all asymptomatic patients with severe AS (eg, EARLY-TAVR) and those looking to target intervention based on measures of left ventricular decompensation (eg, EVoLVeD). AS, aortic stenosis; CMR, cardiac magnetic resonance; EARLY-TAVR, Evaluation of Transcatheter Aortic Valve Replacement Compared to SurveilLance for Patients with AsYmptomatic Severe Aortic Stenosis; EVoLVeD, Early Valve Replacement Guided by Biomarkers of Left Ventricular Decompensation in Asymptomatic Patients with Severe AS; hs, high-sensitivity; LV, left ventricular; TAVI, transcatheter aortic valve insertion.
Current and planned randomised controlled trials investigating timing of aortic valve intervention
All-comers with severe AS
Historical teaching has been that 'aortic valve replacement is the most common cause of death in patients with asymptomatic severe aortic stenosis'. However, improving outcomes following surgical and transcatheter valve replacement are challenging this doctrine. Performing valve intervention on all asymptomatic patients with severe AS is a simple and pragmatic solution that does not seek to identify the point at which left ventricular decompensation occurs. Although some patients will undergo intervention earlier than they may have required (and therefore be exposed unnecessarily to the problems associated with prosthetic valves), the risks associated with contemporary intervention techniques are low, and no patient should be left with irreversible left ventricular decompensation. This strategy is supported by evidence from the Japanese Contemporary outcomes after sURgery and medical tREatmeNT in patients with severe Aortic Stenosis (CURRENT AS) registry. Propensity-score matching was used to compare 291 asymptomatic patients who underwent early surgery with 291 patients who were managed conservatively. Those who received early AVR had a reduced all-cause mortality at 5 years (15%) compared with those who were initially managed conservatively (26%). Heart failure hospitalisation was also reduced in the early intervention group (4% vs 20%). However, propensity matching may not have accounted for all potential influences on outcomes and a significant proportion of the conservatively managed patients who developed symptoms were not referred for intervention, undoubtedly contributing to the worse observed survival in this group: confounding by indication. Three randomised controlled trials (AVATAR, ESTIMATE and EARLY-TAVR; table 4) are currently recruiting, which will examine whether valve intervention in unselected asymptomatic patients with severe AS can improve clinical outcomes.
Refined assessment of valve structure and function
An alternative strategy is to operate only in asymptomatic patients with very high peak aortic-jet velocities. Peak velocities >4.5 m/s are associated with increased referral for surgical intervention26 but also increased rates of perioperative death and cardiac death in a prospective cohort study with propensity matching.47 The RECOVERY randomised controlled trial will examine whether early aortic valve replacement in asymptomatic patients with velocities >4.5 m/s and a negative exercise test leads to improved patient outcomes compared with watchful waiting (table 4).
The total haemodynamic load seen by the left ventricle can also be quantified by calculating the valvuloarterial impedence (ZVa=(systolic blood pressure+mean AV gradient)/indexed LV stroke volume). This measure has consistently been shown to be an independent marker of adverse outcome in asymptomatic patients54 and warrants further study for its use in determining the timing of intervention.
Another approach is to quantify valvular calcium burden using CT calcium scoring. Validated, sex-specific thresholds for severe AS have been proposed (2000 Agatston units (AU) for men, 1200 AU for women),5 which provide powerful prediction of clinical events of incremental value to echocardiographic assessments.3 Performing valve intervention on the basis of severe valvular calcification on CT might therefore represent an attractive alternative strategy.
Imaging and biomarkers of left ventricular decompensation
Simple cardiac biomarkers beyond BNP are being investigated in AS as markers of LV decompensation. Cardiac troponin is a structural protein present in cardiomyocytes, which is released into the bloodstream during myocardial injury and can now be detected at very low plasma concentrations using high-sensitivity assays. In AS, troponin I concentrations are associated with a more advanced left ventricular hypertrophic response, replacement myocardial fibrosis and worse long-term patient outcomes in patients with AS.55 They are thought to reflect the cardiomyocyte death that drives progressive left ventricular decompensation alongside myocardial fibrosis.8 Elevation in cardiac troponin is not however specific to AS. By contrast, the presence of LVH and the strain pattern on the 12-lead ECG demonstrate high specificity (but low sensitivity) for left ventricular hypertrophy and myocardial fibrosis, respectively, and also provides prognostic information.56 As will be discussed, there is interest in using these simple and cheap biomarkers as screening tools to aid the detection of LV decompensation (figure 4).
Imaging and biomarker assessments of stage of valvular stenosis and myocardial response to increased afterload. Progressive haemodynamic obstruction as a result of aortic leaflet restriction is assessed using echocardiography. However, specific valvular pathologies such as fibrosis and calcification can be assessed using CT methods. Ejection fraction is a poorly sensitive marker of myocardial decompensation with abnormalities in Doppler measures, longitudinal strain and systolic function, which are all detectable prior to this. However, these measures, along with biomarkers such as troponin and B-type natriuretic peptide (BNP) are non-specific and may be abnormal as a result of coexistent myocardial pathology such as coronary heart disease. T1 mapping methods and late gadolinium enhancement are more specific for decompensation as a result of pressure overload.
What about imaging assessment to detect left ventricular decompensation? Despite its limitations, ejection fraction remains the current gold standard; however, several imaging techniques are under early investigation that can detect earlier abnormalities in left ventricular function. Echocardiography can detect alteration in various measures of diastolic and longitudinal systolic function in patients with AS, which appear related to the presence of myocardial fibrosis.7 Reduced left ventricular global longitudinal strain can be observed in asymptomatic patients with AS, acting as an independent predictor of mortality.23 However, several of these measures still require standardisation across vendor platforms and all suffer from significant overlap between results in healthy individuals and those with AS. Moreover, these imaging markers are not specific to valve heart disease and like symptoms might equally reflect comorbidity such as ischaemic heart disease.
Perhaps the most promising technique is cardiac MRI, which offers myocardial tissue characterisation and can detect the myocardial fibrosis that drives the development of left ventricular decompensation. Indeed, the late gadolinium enhancement technique allows direct visualisation of this fibrosis in a midwall pattern that can easily be differentiated from prior myocardial infarction. Midwall fibrosis is a direct and specific marker of left ventricular decompensation with close association with measures of left ventricular function, myocardial injury and functional capacity.7 Furthermore, multiple studies have confirmed that midwall fibrosis is a strong independent predictor of all-cause mortality and cardiovascular death.21 51 57 Increasing burden of midwall fibrosis correlates with a worse outcome,21 51 and this fibrosis appears irreversible following valve intervention.58 Midwall fibrosis therefore appears as a useful tool to identify the early stages of irreversible left ventricular decompensation. T1 mapping is an alternative technique that might allow detection of the preceding stage of reversible diffuse interstitial fibrosis.59 At present, there are issues with variations in T1 values at different magnetic field strengths and on different scanners and problems caused by the overlap of T1 values between different disease states. Further work is required, although recent studies have shown promising early results for T1 parameters that seek to measure the overall myocardial fibrosis volume.7
It is possible that using a multibiomarker strategy to identify LV decompensation may prove superior to any single biomarker in isolation. For example, in the EVoLVeD randomised controlled trial (table 4), patients are initially screened with high sensitivity troponin I and an ECG. Patients with a normal troponin (<6 ng/L) are deemed to have a normal heart with no further imaging required. Patients with an elevated troponin or the ECG-strain pattern proceed to cardiac magnetic resonance (CMR) and those found to have midwall fibrosis then randomised to either early valve intervention or routine clinical care. It is hoped that this strategy will target valve intervention to those patients who will derive greatest benefit.
Practical recommendations and processes of care
Care of the asymptomatic patient with AS can be complex and challenging. While additional evidence is awaited, we advise detailed clinical and echocardiographic assessment with exercise testing and advanced imaging (eg, stress echocardiography, TOE, CT and CMR) performed as indicated to clarify symptoms, severity of AS and myocardial health. This should be performed by heart valve specialists working as part of a heart team.5 Patient involvement in decision making is key where indications for intervention are borderline. Given delays between referral and procedure that are common in most healthcare systems, this could also be discussed with the patient and may inform decision making for earlier intervention. The recent ESC/EACTS guideline update also recommends the establishment of heart valve centres with access to advanced imaging modalities and contemporary interventional techniques supported by robust internal audit processes.5 Finally, patients managed conservatively should be educated as to the typical symptoms of AS (table 2) and the importance of prompt symptom reporting. Regular clinic surveillance is essential, and current guidelines recommend clinical assessment with echocardiography at least every 6 months.5
AS is a common condition; the only treatment for which is replacement of the aortic valve. The optimal timing of this valve intervention remains unclear with current guidelines based on observational data and expert opinion. However, multiple randomised controlled trials are currently underway investigating whether novel strategies might improve patient outcomes compared with current watchful waiting, heralding a new era of evidence-based medicine for patients with heart valve disease.
Aortic stenosis is a disease of both the valve and the myocardium, characterised by fibrosis and calcification of valve leaflets, progressive left ventricular hypertrophy and myocardial fibrosis.
Although no randomised controlled trial data exist, current clinical guidelines recommend valve intervention when severe aortic stenosis is accompanied by evidence of left ventricular decompensation.
Timing of valve intervention is crucial. Too early and the patient will be unnecessarily exposed to risks of intervention and prosthetic valve complications; too late and irreversible myocardial damage can lead to persistent symptoms and risk of adverse events. Ideally valve replacement would be performed just as left ventricular decompensation is starting to develop.
Improved surgical methods and perioperative care, as well as transcatheter aortic valve implantation techniques have resulted in major reductions in procedural risk. As such, earlier valve intervention in asymptomatic patients could be contemplated, and randomised controlled trials are underway that will help inform our future management.
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. 5-year outcomes of transcatheter aortic valve replacement or surgical aortic valve replacement for high surgical risk patients with aortic stenosis (PARTNER 1): a randomised controlled trial. Lancet 2015;385:2477–84. doi:10.1016/S0140-6736(15)60308-7
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. Thromboembolic and bleeding complications in patients with mechanical heart valve prostheses. Circulation 1994;89:635–41. doi:10.1161/01.CIR.89.2.635
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. Low-gradient aortic stenosis: operative risk stratification and predictors for long-term outcome: a multicenter study using dobutamine stress hemodynamics. Circulation 2003;108:319–24. doi:10.1161/01.CIR.0000079171.43055.46
Chin CW,
Messika-Zeitoun D,
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. A clinical risk score of myocardial fibrosis predicts adverse outcomes in aortic stenosis. Eur Heart J 2016;37:713–23. doi:10.1093/eurheartj/ehv525
Hachicha Z,
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. Usefulness of the valvuloarterial impedance to predict adverse outcome in asymptomatic aortic stenosis. J Am Coll Cardiol 2009;54:1003–11. doi:10.1016/j.jacc.2009.04.079
Shah AS,
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. High-sensitivity troponin I concentrations are a marker of an advanced hypertrophic response and adverse outcomes in patients with aortic stenosis. Eur Heart J 2014;35:2312–21. doi:10.1093/eurheartj/ehu189
Vassiliou V, et al
. Left ventricular hypertrophy with strain and aortic stenosis. Circulation 2014;130:1607–16. doi:10.1161/CIRCULATIONAHA.114.011085
Barone-Rochette G,
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. Prognostic significance of LGE by CMR in aortic stenosis patients undergoing valve replacement. J Am Coll Cardiol 2014;64:144–54. doi:10.1016/j.jacc.2014.02.612
Weidemann F,
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. Impact of myocardial fibrosis in patients with symptomatic severe aortic stenosis. Circulation 2009;120:577–84. doi:10.1161/CIRCULATIONAHA.108.847772
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. Left ventricular myocardial structure in aortic valve disease before, intermediate, and late after aortic valve replacement. Circulation 1989;79:744–55. doi:10.1161/01.CIR.79.4.744
Contributors RJE performed the literature search and drafted the article. Critical revisions were performed by M-AC, PP and MRD. All authors approved the final manuscript and MRD is the guarantor for the overall content.
Funding The work was supported by the British Heart Foundation (FS/14/78/31020 to MRD), the Sir Jules Thorn Charitable Trust (15/JTA to MRD), the Québec Heart and Lung Institute Foundation and Canadian Institutes of Health Research (FDN-143225 and MOP-114997 to PP and M-AC).
Patient consent Not required.
Provenance and peer review Commissioned; internally peer reviewed.
Data sharing statement Not applicable.
Author note References which include a * have been selected as key references for this paper.
© Article author(s) (or their employer(s) unless otherwise stated in the text of the article) 2018. All rights reserved. No commercial use is permitted unless otherwise expressly granted. This is an open access article distributed in accordance with the Creative Commons Attribution Non Commercial (CC BY-NC 4.0) license, which permits others to distribute, remix, adapt, build upon this work non-commercially, and license their derivative works on different terms, provided the original work is properly cited and the use is non-commercial. See: http://creativecommons.org/licenses/by-nc/4.0/


Distributor Anime Limited have revealed plans for the home video release of Rokka -Braves of the Six Flowers- including some surprising news of an English dub!
Getting to the point like we always do, here's all the information we know so far.
Anime Limited will be offering some English dub previews later down the line so stay tuned for those!
Extras (CE): Rigid box with digipack packaging, 48-page Artbook features art of the characters, the fiends, props, storyboards from the opening and ending sequences, and a gallery section.
For more information on the Rokka home video sets, you can view the show page over on Shop AllTheAnime.
The Seven Braves realize there must be one enemy among them, and feelings of suspicion spread through the group – with Adlet being suspected first and foremost.
Thus begins an overwhelming fantasy adventure that brings mystery upon mystery in Rokka -Braves of the Six Flowers-!
And that is all of the information revealed so far. This is pretty exciting news as the series did receive a release in North America by Ponycan US but theirs went through a model similar to Aniplex of America – with 4 episodes per set and was also only subtitled only. This UK release marks the first Ponycan US title to be released on Blu-ray outside of North America.
For more information on the Rokka announcement, you can view the post over on Blog AllTheAnime.
You can check out the entire anime series over on Crunchyroll.
The 50 episode series from Studio Pierrot is coming to UK home video.


The sequel to 2005?s ?Chronicles of Narnia: The Lion, The Witch and The Wardrobe? leaves the audience wanting. Plain and simple. The first film was great. Visually spellbinding, compelling story, Christian parallels present but not too strong. A good movie. This one ? not so much. In this installment, the second film is actually the fourth book of the seven-book series by C. S. Lewis, it is 1300 years after the Pevensie children?s first trip to Narnia. Aslan the Lion has been gone for that time and when the children return, they find all the magical creatures in Narnia have been oppressed and driven into hiding by the invading humans, the Telmarines.


Calling all entrepreneurs and business professionals!
Do you feel crazy trying to figure out how to use the internet to market your business?
Do you feel frustrated when people talk about online marketing and you're not even sure what that means?
Do you feel like a deer in the headlights trying to figure out what type of online products you should buy to help promote your business?
Do you wonder how you're suppose to juggle your online marketing while running your actual business?
All businesses, no matter the size need to embrace online marketing to stay relevant and be successful.
If you feel you are walking through a murky fog with no end in sight, never fear. After completing this course, the fog will lift … leading to more customers, more sales, and more time.
Online Marketing is incredibly necessary to the success of your business. It can be overwhelming no matter what anyone tells you. With some simple strategies, taught in baby steps, you will have a better understanding of what's needed to promote your business online. All this, on a shoe string budget.
Understanding the power of social media is critical and how to select the right platform for both you and your customers.
Identifying and learning the right tools to stay top of mind with your customers.
Using your personal email for business is a big no-no and how to utilize a commercial email package effectively.
The "secret sauce" to attract new and repeat customers who want to hear more about you and your business.
After completing this course, you will know how to take advantage of the best online marketing tools without breaking the bank.
The Launch4Life team helps business professionals use online marketing tools and social media platforms. Whether you're a solo-preneur with a single product, or a small business team with a wide range of services, we can help launch your business to the next level.
Our mission is to help you understand everything you need to know to market your business online. We provide courses, coaching, consulting, and custom-built marketing packages to meet your needs.
With over 20 years in the Communications and Training industry, Gillian has the skills and experience needed to teach, coach, and mentor clients. As an Instructional Designer, Gillian has developed a wide variety of e-learning courses for students of all ages.
Janet has over 30 years in the Financial Services Industry in marketing and management, coupled with 5 years of intensive dedication to online marketing and social media applications. Janet has coached and trained small business owners on how to adapt to the social media world.


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David Dong Ming Yan (* 18. Juli 1993) ist ein professioneller neuseeländischer Pokerspieler. Er gewann 2016 das High Roller der European Poker Tour und 2022 ein Bracelet bei der World Series of Poker Online.

Pokerkarriere
Yan stammt aus Auckland. Er spielt auf der Onlinepoker-Plattform PokerStars unter dem Nickname MissOracle und nutzt bei GGPoker seinen echten Namen.

Seine erste Geldplatzierung bei einem Live-Pokerturnier erzielte Yan im Januar 2012 bei der Aussie Millions Poker Championship in Melbourne. Dort erreichte er ein Jahr später im Main Event den Finaltisch und belegte den mit 220.000 Australischen Dollar dotierten sechsten Platz. An gleicher Stelle wurde der Neuseeländer im September 2013 Dritter beim Main Event der Asia Pacific Poker Tour und sicherte sich aufgrund eines Deals mit zwei anderen Spielern eine Auszahlung von 133.000 Australischen Dollar. Bei der World Series of Poker Asia Pacific beendete er das High Roller Mitte Oktober 2014 ebenfalls im Crown Melbourne als Zweiter und erhielt rund 360.000 Australische Dollar. Ende Juni 2015 war Yan erstmals bei der Hauptturnierserie der World Series of Poker im Rio All-Suite Hotel and Casino in Paradise am Las Vegas Strip erfolgreich und kam bei einem Turnier der Variante No Limit Hold'em in die Geldränge. Bei der European Poker Tour (EPT) in Prag wurde er Mitte Dezember 2015 Fünfter beim High Roller und sicherte sich mehr als 150.000 Euro. Im August 2016 belegte der Neuseeländer bei einem eintägigen High-Roller-Event der EPT in Barcelona den zweiten Platz und erhielt aufgrund eines Deals die höchste Auszahlung von über 700.000 Euro. In der Spielbank Berlin gewann er im Oktober 2016 das Main Event des WSOP-Circuits mit einem Hauptpreis von rund 125.000 Euro. Bei der EPT auf Malta setzte sich Yan rund zwei Wochen später beim High Roller durch und sicherte sich rund 465.000 Euro. Mitte Dezember 2016 belegte er bei einem Side-Event der EPT Prag den mit knapp 160.000 Euro dotierten fünften Rang. Bei der EPT Barcelona erreichte der Neuseeländer Mitte August 2022 bei zwei eintägigen High-Roller-Events den Finaltisch und sicherte sich Preisgelder von knapp einer Million Euro. Ende desselben Monats gewann er auf GGPoker das Super Million$ High Roller der World Series of Poker Online und wurde mit einem Bracelet sowie dem Hauptpreis von knapp einer Million US-Dollar prämiert. Ende Januar 2023 entschied er beim PokerStars Caribbean Adventure auf den Bahamas ein 50.000 US-Dollar teures Turnier für sich und erhielt aufgrund eines Deals mit Örpen Kısacıkoğlu eine Auszahlung von knapp 500.000 US-Dollar. Auch beim PSPC Super High Roller der Turnierserie saß Yan wenige Tage später am Finaltisch und belegte den mit knapp 1,5 Millionen US-Dollar dotierten dritten Platz.

Insgesamt hat sich Yan mit Poker bei Live-Turnieren mindestens 7 Millionen US-Dollar erspielt und ist damit der erfolgreichste neuseeländische Pokerspieler.

Weblinks
 David Yan in der Datenbank der World Series of Poker: 2013–2020, 2021–2022 (englisch)

Einzelnachweise

Pokerspieler (Neuseeland)
Braceletgewinner
Gewinner des High Roller der European Poker Tour
Neuseeländer
Geboren 1993
Mann

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text: Q: В xUbuntu 11.10 Voyager нет звука Здравствуйте. ОС: Windows 7 & xUbuntu 11.10 VoyagerЗвуковая карта: Asus Xonar DS AudioВ xUbuntu не работает звук. В параметрах звука отображается звуковая карта Xonar DS (Alsa mixer) каналы выбраны все, что можно, везде звук включен, но его нету. В Windows все работает отлично. Есть идеи с чем может быть проблема?head -n 1 /proc/asound/card*/codec#*==> /proc/asound/card0/codec#0 <==Codec: Realtek ALC888==> /proc/asound/card0/codec#3 <==Codec: Nvidia MCP77/78 HDMIuname -aLinux four 3.0.0-14-generic #23-Ubuntu SMP Mon Nov 21 20:28:43 UTC 2011 x86_64 x86_64 x86_64 GNU/Linuxcat /proc/asound/versionAdvanced Linux Sound Architecture Driver Version 1.0.24.aplay -lСписок PLAYBACK устройствкарта 0: NVidia [HDA NVidia], устройство 0: ALC888 Analog [ALC888 Analog]  Подустройства: 0/1  Подустройство №0: subdevice #0карта 0: NVidia [HDA NVidia], устройство 1: ALC888 Digital [ALC888 Digital]  Подустройства: 1/1  Подустройство №0: subdevice #0карта 0: NVidia [HDA NVidia], устройство 3: HDMI 0 [HDMI 0]  Подустройства: 1/1  Подустройство №0: subdevice #0карта 1: DS [Xonar DS], устройство 0: Multichannel [Multichannel]  Подустройства: 1/1  Подустройство №0: subdevice #0карта 1: DS [Xonar DS], устройство 1: Digital [Digital]  Подустройства: 1/1  Подустройство №0: subdevice #0Заранее благодарю за помощь.

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Earlier this month, the NFL (National Football League) held its annual draft of new talent, drawing a plethora of attention, discussion, and celebration. Next up, the MLB (Major League Baseball) gets it's turn during the first week of June to announce the future of dozens of hopeful young players vying for a shot to play professional baseball. After years of preparation and scouting, it's a big moment for the top prospects in the sport from across the United States to hear if their names are called and to see if they can become the future of the league. One such prospect is Cathedral Catholic High School's very own Brady Aiken, a left-handed pitcher for the school's baseball team who (as of press time) is projected to be the number one pick by a consensus of draft experts.
By all accounts, Aiken's future looks bright to say the least. Being the number one prospect has dozens of world-renowned teams considering Aiken for a spot that could turn the current high school senior into a nationally-known sports star.
Holding onto the number one draft spot is the latest in a long line of accomplishments Aiken has achieved. Most recently, he won USA Baseball's prestigious International Performance of the Year Award for his play on the field, which helped the United States team clinch the gold medal in last September's Baseball World Cup in Taiwan. During his most notable game there, he struck out 10 opposing players and allowed just one run in seven innings.
On draft day this year, the Houston Astros, Miami Marlins, and Chicago White Sox have the top three picks when it comes to choosing players, so Aiken has a solid chance to play for any of those teams.
"It all depends on how well I do before the draft, and what teams would be interested in me in the first place. Any team that would draft me, I'd be honored to get to play for them," Aiken said. However, if something unforeseen happens, Aiken said he received a scholarship to play for UCLA come the fall. "Until the day comes and a team actually drafts me and offers me money, I'm going to UCLA," he said.
For now, Aiken is still just another senior at Cathedral Catholic waiting for graduation and thinking about his future — except the MLB, ESPN and other national media outlets are thinking about it too.
Cutting through all of the hype, getting drafted in June would only be the start of another set of tests for Aiken, which would begin in the minor leagues where good players typically last for around five years before making the majors. Though for one of the most exciting prospects in recent memory, Aiken is currently taking it one day at a time.


text:
Click on the Practice Question to view the synthesis of the literature and the practice guidance or recommendation.
Q: Should dietary and herbal supplements be taken prior to surgery?
The following Practice Questions are part of another Knowledge Pathway. These questions have been included in the Related Questions section of this Knowledge Pathway due to their relevancy to this topic area. Click on the practice question to view the synthesis of the literature and the practice guidance or recommendations.
Related Practice Questions
Q: What herbal beverages/supplements are safe to take during pregnancy and lactation?
Q: Are there any foods or dietary supplements capable of preventing or treating a hangover?
Q: What is the evidence to support the use of cleanses (e.g. herbal products, detoxification diets, colon irrigation) to maintain bowel health, promote general health (including weight loss), and prevent colon cancer and other diseases?
Q: Is there a role for nutrition in preventing glaucoma?
Q: Is there a role for natural health products or nutrients, other than antioxidants, in the prevention or progression of age-related macular degeneration (AMD)?
Q: How beneficial are dietary supplements (e.g. niacin, garlic, policosanol, red yeast rice, red clover, rice bran oil, lecithin, coenzyme Q10, guggul) in the prevention or the treatment of cardiovascular disease?
Q: Should individuals receiving statin medication take coenzyme Q10 supplements to reduce the risk of myotoxicity?
Q: Are there any dietary supplements or nutrients that can help prevent or treat cold sores (herpes labialis caused by herpes simplex virus 1, HSV-1) in adults prone to frequently recurring HSV infections?
Q: Are there any dietary supplements (natural health products) that can help manage the symptoms and co-morbidities of polycystic ovary syndrome (PCOS)?
Q: Are there any foods or natural health products that can help treat erectile dysfunction?
Q: Is there a role for vitamins, minerals, and antioxidants or carnitine in the treatment of male infertility?
Q: Can saw palmetto (Serenoa repens) help alleviate the symptoms of benign prostatic hyperplasia (BPH)?
Q: What nutrients or dietary supplements decrease the frequency (prophylaxis) or acutely treat migraines in children and adults?
Q: What is the efficacy and safety of herbal products (e.g. cannabis, echinacea, Ginkgo biloba, ginseng, St. John's wort, valerian) in individuals with multiple sclerosis (MS)?
Q: Are nutrition supplements (e.g. vitamin E, coenzyme Q10, creatine, herbal supplements) effective in treating or slowing the progression of Parkinson's disease?
Q: Is there any evidence to support the use of milk thistle (silymarin) in chronic liver disease?
Q: Do herbal therapies reduce the symptoms of rheumatoid arthritis?
Q: Are herbal therapies effective and safe to treat osteoarthritis?
Q: Is chondroitin effective and safe in the treatment of osteoarthritis?
Q: Is glucosamine effective and safe in the treatment of osteoarthritis?
Q: Is glucosamine plus chondroitin effective and safe in the treatment of osteoarthritis?
Q: Is methylsulfonylmethane (MSM) effective and safe to treat osteoarthritis?
Q: Is cetyl myristoleate (CMO) effective and safe to treat osteoarthritis?
Q: Are avocado-soybean unsaponifiables (ASU) effective and safe to treat osteoarthritis?
Q: Is S-Adenosyl-L-Methionine (SAMe) effective and safe in the treatment of osteoarthritis?
Q: Are dehydroepiandrosterone (DHEA) supplements safe and effective in reducing disease activity, improving abnormal blood values and improving quality of life in individuals with systemic lupus erythematous (SLE)?
What's New in this Pathway
Alerts and Recalls

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The Horror Honeys: #52FilmsByWomen with The Horror Honeys - Week 18!
#52FilmsByWomen with The Horror Honeys - Week 18!
When The Matrix came out in 1999, it would not have been eligible for inclusion in this project, but time has a way of changing things. Over the last several years, both of the Wachowski siblings have come out as trans, and now identify as Lily and Lana respectively. Not only has their admission changed the future of their cinema, but it has equally changed the lens through which scholars view their earlier films, especially The Matrix. Many now see the film as an allegory for a transgender awakening, and when watched through that lens, it isn't hard to understand why. So join us this week as we watch The Matrix with the benefit of knowledge and time!


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Copyright © 2019 Penn Hall School, Wolverhampton.


text:
Breanna McGowan
Daily Point of Light # 4210 Mar 24, 2010 By jaytennier
Breanna McGowan has the heart of a missionary. While volunteering at Outreach orphanage in Ghana for Projects Aboard, she genuinely cared for the children. She wondered how much more improved their futures would be if they only had the resources, and even spent her souvenir money on food for the orphanage. Therefore, when she returned to the United States, she had a goal: to make a tangible difference.
Breanna's work in Ghana inspired her to start a foundation called All's God Children Got Shoes, which sends school supplies and shoes to the children in Ghana. Her community supports Breanna's foundation, organizing a shoe drive and car wash to help out All God's Children Got Shoes. Having purchased 29 pairs of shoes, backpacks and school supplies for the 57 orphans, she intends to make a return trip to Ghana in the summer of 2010.
With her efforts, Breanna has collected food cans for needy families, and she donned facemasks, rubber boots and overalls to rebuild homes. She addresses the needs of ordinary people by doing extraordinary things. Through her actions, Breanna has not only had an impact on the children in Ghana, but she has also encouraged other teenagers in her community to give to those in need.
All God's Children Got Shoes has raised $600 in candy sales for Outreach orphanage in Ghana. Additionally, Breanna will continue helping the children in Ghana by assisting them with college applications and information on universitites in the United States. Breanna's willingness to go out of her way to help others speaks volumes to how much she wishes to change these children's lives for the better.


text:
JAMP Alumni
OutreachAlumniMedical School StudentsJAMP Undergraduate Students
Dr. Diego De la Mora
Undergraduate University:
The U.T. Southwestern Medical Center
Knowing that the journey was long but it was worth it, and that there were so many helpers in the way. JAMP was a great helper. It was a program that received me with open arms and encouraged me to grow to become who I am now. It helped me reach my dream, plain and simple.
How has JAMP helped you as you strive to achieve your goal of becoming a doctor?
JAMP was the best way for me to get exposure to medical school and to the medical school admissions team. I spent a summer in what was to be my medical school which was very helpful in my decision to go there. I also met some of the best Cardiologist in Texas and the United States. This strengthened my decision to continue to pursue a medical career. I met good friends and I had a taste of what was to come in medical school. The economic support through a scholarship is a major plus, but the richness of the program lies in the human interactions that are so essential in the growth of any doctor. JAMP helped me tremendously in so many ways. I will always be indebted to everybody who made this program possible.
What advice would you like to offer current or future JAMP students?
To future JAMP students:
Do not let this opportunity go. The JAMP program is truly life-changing. It is the best way to prepare you for what is ahead in medical school and your best friend in the rough journey towards medical school. The summer programs give you tons of exposure to medical school and the medical field, is the closest you can be to be a medical student and still be in college. You will also get to meet a lot of great people that will follow you throughout your career.
To current JAMP students:
Take advantage of this opportunity to the fullest. The JAMP program is not just a means to an end, the experiences and the learning that you get through the program will enrich your medical career. Make friends out of your peers, get to know your mentors and learn something every day. Also remember that Texas needs more doctors that come from the diverse backgrounds like you, so that our communities are well served. It is this social conscience that makes us a unique group in the medical profession.
What aspect of JAMP has been most beneficial to you?
The most beneficial aspect of JAMP has to be the assured acceptance into a medical school in Texas. I do not know of any other program that was similar in Texas when I joined JAMP. It was unique also in the sense that we would spend summer in different medical schools, getting to know the admissions team, the medical students, other JAMP students, the campus and the faculty. I met my future medical school in a summer JAMP program and I loved it. I felt so at home with the staff and the faculty were impressive to say the least. Not only did the summer programs made it even clearer that I wanted to become a doctor; JAMP also placed me in the right medical school, gave me the interview and finally the letter of admission. What else could a pre-med student ask for?
About Dr. De la Mora
I am currently an Assistant Professor at Texas Tech University HSC – El Paso Paul L Foster Medical School and I wake up every day happy to be here. I came back home, but with all the experiences gained from the great UT Southwestern Medical School and Internal Medicine Residency. Knowing that the journey was long but it was worth it, and that there were so many helpers in the way. JAMP was a great helper. It was a program that received me with open arms and encouraged me to grow to become who I am now. It helped me reach my dream, plain and simple. But it also served as a reminder of the great responsibility that physicians have towards their own communities, that our profession is key in the development and well being of our society and that there is only one thing better than being a physician: To be a physician and serve your own community.


text:
by Dr Benedict Docherty
Archives for posts with tag: great powers
BREXIT Britain's new Foreign Secretary
Literally the most astonishing day in British politics since yesterday.
— Jamie Dalton (@JamieDalton82) June 30, 2016
So have said many a twitter wag since the British electorate's decision to leave the European Union was announced on the morning of June 24th – but for the record I give credit to @JamieDalton82. Fast forward to today (has it only been twenty odd days?) and as many a twitter wag surmised – "Friend woken from a year coma? Ease them in with the relatively plausible Leicester romping the league by 10 points, then work up from there"
So we live in interesting times, that much is clear. So interesting in fact that according to Matthew Goodwin:
FT journalist: "It's a rather strange day. The Prime Minister resigning is only our third most important story".
— Matthew Goodwin (@GoodwinMJ) June 24, 2016
But as interesting as Stock Market volatility, Article 50, a possible second Scottish independence referendum, mooted attempts to annul the June 23rd referendum, the leadership contests for the Conservative, Labour and UKIP and the publication of the Chilcot Report (!?) have been, it's fair to say people have been somewhat astonished by the new Prime Minister's appointment this evening of the Member for Uxbridge & South Ruislip as Her Majesty's Secretary of State for Foreign & Commonwealth Affairs.
New Foreign Secretary Boris Johnson welcomed to the Foreign Office by @SMcDonaldFCO (official photo) – Not pictured @DiploMog
At this point I am tempted to say that there has been a firestorm on twitter, or that it is having a field day, but when is it not? Clearly though in amongst the myriad references to Foreign Secretary Johnson's legion gaffes and activities, some comic, others as dark as they are revealing, the prevailing view was that such an appointment was ridiculous and as such must have been forced on Theresa May.
Now full credit here to the more learned people that I follow on twitter as from them a contrary view soon emerged which I summarise below. *Remember it wasn't me that spotted this* but rather I'm channeling @Peston and @FraserNelson – click their handles for their own analysis.
So Theresa May is keenest to immediately balance out the Brexit/Remain camps since she a Remainer (albeit quiet) is now leading Brexit Britain and there's a clamour to ensure "Brexit means Brexit" and maybe even trigger Article 50 ASAP.
To wit of the Great Offices of state she's got in place; Philip Hammond (Chancellor), Amber Rudd (Home) and herself (PM) i.e. three remainers. So she needs to keep Brexiters happy which she has done by giving top jobs to Liam Fox (International Post EU trade deals), David Davis (Secretary of State for Exiting the EU) and Boris Johnson (FCO is the last of the four Great Offices).
Away from this balancing act there is the "house of cards" politics of it all. Except here the view is not that Johnson has somehow dictated the terms of a deal with May. Recall that the evening of her appointment, Theresa May is at the height of her powers – just look what happened to George Osborne.
Instead there, consider May's position. Appointing Johnson as Foreign Secretary will keep him out the country and overseas i.e. away from the grass roots (where he is famously/allegedly feted) as well as any plots. Then there's the fact he'll be jet lagged when he's actually here. Although I suppose Whatsapp could be a way around this…
Some (Peston) have noted the similarities to Barack Obama making Hillary Clinton his Secretary of State in 2009 – this was a convenient/respectful way to deal with a vanquished rival. For all Johnson's political capital seemingly collapsed with Michael Gove's betrayal, as others have noted, his supposed idol, Winston Churchill also bounced back after a prolonged spell in the political wilderness albeit thanks to a particularly ugly gathering storm.
Lastly and most importantly there is the role of Foreign Secretary itself. The actual Brexit negotiations will be led by the new Government Dept. headed by David Davis (who was Europe Minister for three years under John Major) whilst the key EU summits (remember the UK is still a member) will be at a Prime Ministerial level where May herself represents the UK.
More broadly in terms of UK foreign policy it's Downing Street and the PM who lead in a crisis. Otherwise, and although it's not my own area of expertise (see my friends and colleagues Victoria Honeyman, Stuart McAnulla, James Strong, Tim Oliver for more) it's a fair observation that strong Prime Ministers run their own foreign policy rather than leaving it to their Secretary of State.
So this leaves the Foreign Secretary as a sort of showman to talk up Brexit Britain and show Brexit was a positive choice where we turn away from the EU institutions rather than the continent and instead towards the wider world. The point here being (made most eloquently by Nelson) that this ideally needs someone who supported Brexit to sell it to the world. Even if the rumours abound as to whether Johnson actually truly supported Brexit.
So yes, being Foreign Secretary is an important job, but perhaps it's more prominent than it is powerful in its own right. And of course with every gaffe Mr Johnson makes he becomes less of a threat to her leadership, and if he really screws up, well she could always sack him?
Now all of this (which recall I got from elsewhere) comes with a huge caveat. A caveat in fact perhaps worthy of Vote Leave or British Intelligence circa 2002-3. Namely that this is a blog about international society and all that I've written above pertains to how Johnson's appointment fits with UK domestic politics and the machinery of the British government.
Simply put, yes some of us in Britain may express a weary sigh if not wry smile at Johnson's Have I Got News For You persona. But how will the rest of international society react to Britain's new chief diplomat? I'm thinking here (purely off the top of my head) of his remarks about US President Obama's "part Kenyan heritage" and the poem he authored abour Turkish President Erdogan. For the avoidance of doubt, the UK's relationship with these two countries is what we academics refer too as of strategic significance.
Again, this is perhaps more an issue of foreign policy analysis (not my expertise) or indeed one for colleagues who assess how personal relationships between leaders – the presence or absence of trust – affect their dealings.
Alternatively the rejoinder could be made that even phenomenally popular state leaders cannot translate international goodwill into their favoured outcomes (see President Obama at the failed 2009 Copenhagen Climate Summit to pick but one example). At the very least therefore another blog post beckons if not quite a PostDoc (without the EU funding of course).
But what I will say in closing for now is that the UK's image on the world stage, its place in international society is being very closely watched, and the perceptions of our international peers (not least the rest of the P5) are of great import.
As I wrote on the morning of Brexit, in my view, Britain's post war history has been the story of collectively assuming rather than critically interrogating, the fact we're still the Great Power we were before the war.
Like Dean Acheson said back in '62 we lost an empire but were yet to find a role. We've leveraged some crucial but essentially limited capabilities to maintain an enlarged role for these islands in international society.
Our influence is not just a product of material might (such as we have it) but also the regard (rightly or wrongly) we are held in. We've talked the talk but otherwise it's been the emperor's new clothes.
As such, to my mind, we've not had a conversation about what our role should be in the world as it is now, and not as it once was. Something tells me we're about to confront the reality we've been dodging all this time, and is reasonable to ask what sort of role Foreign Secretary Johnson, can, will or should play in this most complex, overdue and important of conversations.
Tags Brexit, diplomacy, diplomats, EU, EUref, FCO, Foreign Secretary, great powers, international society, P5, reshuffle
"The Anarchical Society: A Study of Order in World Politics" Considered
Hedley Bull's "The Anarchical Society" is a landmark text and one of my favourites. I recall buying it when I was a sabbatical officer with the intention of making up for only skimming it as an undergrad. I remember taking it to Japan to read on holiday, and again to Carlisle some years later having never quite gotten into it. Needless to say I did and I'm now doing post graduate research in the same field.
"A society of states (or international society) exists when a group of states, conscious of certain common interests and common values, form a society in the sense that they conceive themselves to be bound by a common set of rules in their relations with one another, and share in the working of common institutions" Bull, H. The Anarchical Society : A Study of Order in World Politics (London: Macmillan:1977) pg.13
Bull's thesis is that a society of sovereign states exists in our world today and that this "international society" is anarchical in form given the absence of a central orderer. However as the subtitle to the work indicates, there is most definitely a form of "order" in world politics to which international society contributes. Like many of the best authors Bull sets out not just the topics he will cover, but those that are related but not his focus, most notably justice (xiii). At various points he outlines the notion that order is a pre requisite for justice (86), however he acknowledges that unjust orders exist, and that in his belief justice should not be sacrificed in the cause of order as a "commanding value" (98) – "If international order does have value, this can only be because it is instrumental to the goal of order in human society as a whole" (22). Yet he recognises that the prospect for substantive change here is limited given "to pursue the idea of world justice in the context of the system and society of states is to enter into conflict with the devices through which order is at present maintained" (88).
The sweep of Bull's writing encompasses philosophy, history and then contemporary Cold War international relations. Philosophically, he critiques the common reading of a Hobbesian state of nature, and the simplistic contrast between domestic hierarchy within states and international anarchy (46). What of Lockean cooperation in the absence of a leviathan he asks (48) or primitive stateless societies (62)? Bull argues that conforming to notions of acceptable behaviour is more important than the mere existence of rules and speculates on the reasons states conform. As one would expect from a founder of The English School he makes use of detailed historical comparisons, tracing the evolution of International Society from Christendom to modern Europe before engaging the 1970s Cold War context (113).
The Anarchical Society follows a clear structure over three sections and 320 pages, with Bull outlining the aims and conclusions of each of the 14 chapters. Part One discusses the nature of order in world politics, with Bull focusing on its purpose as the realisation of shared primary goals (53). Here the case is made for international, (second order) society in an abstract sense, as Bull outlines how such a "precarious achievement" is maintained in an anarchical setting in the face of seemingly overwhelming odds. Part Two addresses order in the contemporary international system. In this, the section I most enjoyed, The English School is applied to the traditional notions of; the balance of power; international law; diplomacy; war; and the Great Powers. Although eventually concluding that the study of world politics is purely an intellectual pursuit (319), in Part Three Bull treats the reader to a consideration of alternative paths to world order. At first glance one may consider this a treatise or personal manifesto on Bull's part, a political agenda not in keeping with his otherwise academic detachment. However he remains true to his aims by coolly assessing each in turn, offering criticisms of the unworkable and unlikely where they are due and refraining from any utopian impulses. Indeed as an advocate of The English School, he is naturally inclined to the reform of the states' system rather than its decline or obsolescence.
Does Bull fulfil the task he sets himself? Does he prove the existence and utility of the anarchical society? His reasoning deconstructs the oft levelled comparison between international relations and domestic political arrangements. As the title of the work indicates, Bull agrees that anarchy is a defining feature of international relations, but he rejects hierarchy as the only path to order. Moreover he clearly articulates the contrast between the mechanical series of interactions that characterise an international system, from the mutually held value laden perceptions and interactions that are the hallmark of his international society. Indeed he addresses sceptics head on asserting "my contention is that the element of a society has always been present, and remains present, in the modern international system, although only as one of the elements in it, whose survival is sometimes precarious" (41). This is an important caveat within The English School. Theirs' is a tripartite outlook of an international system, international society and world society simultaneously coexisting. Thus The English School accepts the role that Great Powers play in determining the values and processes of international society and settling questions of stability and change. Bull sees international society jostling alongside war, transnational loyalty and division as elements of international relations (51) (73). Where critics see war (especially by Great Powers) as contrary to international law and thus proving realism's assertion that the national interest and self-help always predominates, Bull points to the significance of states at least alleging they have just cause for war, keen as they are to appear reasonable members of international society (45). He underlines this point in his consideration of the efficacy of international law as "a social reality to the extent that there is a very substantial degree of conformity to its rules; but it does not follow from this that international law is a powerful agent or motive force in world politics" (139).
In his preface, Bull declares that The Anarchical Society is an opportunity to systematically bring together his thinking on international society and international order, where elsewhere he has only done so in "a piecemeal fashion"(ix). To do so he meditates on Hobbes, Grotius and Kant, whose worldviews are associated with the tripartite perspective which is the hallmark of The English School. Variously, Bull cites other notables in relation to their respective fields; Kelsen & Hart on international law; Gilpin & Hunt on the role of transnational corporations; Ali Mazrui and Rajni Kothari on the Developing World's justice agenda; and Richard Falk on the prospect of a New Medievalism. Ultimately this is Bull's own work and the argument and analysis, both historical and political is his own. The Anarchical Society is written for an audience of academics and policy makers. For the latter are special lessons on the responsibilities of Great Powers; the risks posed by nuclear weaponry and the potential of institutions. For the academic or student are definitions of concepts such as order; society; system; justice; war; balance of power and Great Power. Bull methodically contrasts related concepts with one another or details their components such as with the criteria for "socially effective rules" (56). Then there are his multiple levels of analysis, ranging from the international to both regional and global, and which through discussion of New Medievalism, countenance the role of non-state actors. Several times Bull directly addresses himself to his readers on some of the book's most contentious topics and overarching questions. He highlights his refusal to justify order at the expense of justice, recognising this is the de facto position of The West (94). He criticises advocates of the nuclear peace, whilst directing readers to his writings elsewhere on the subject (126). He baldly rejects utopian cosmopolitan schemes as dreamt up by privileged Western elites and as such as patronising and ineffectual as they are impossible (85) (286) (304). In concluding, he chastens readers to accept that we remain in the dark about most things in spite of detailed research and it is foolish to pretend otherwise (320).
Written 40 years ago there are several interesting and insightful facts and observations one can gleam from a read of The Anarchical Society. It is readily apparent that talk of the rise of non-state actors and the phenomenon of globalization are not recent developments, with Bull tracing the globalization of European international society and the role of non-state terrorist actors. He speaks frankly of the post 1945 international society maintaining an order at the expense of equitable and proportionate notions of justice, telling the story of Walter Lippmann's proposed post war regional Great Power management system as one mooted alternative (222). The greatest strength of the work is Bull's careful treatment of concepts with which most international relations scholars are familiar and interested. He explores the paradox of how war is both a cause of disorder and thus a threat to international order/society and yet also an accepted instrument of state policy used to enforce international law or as a driver of change (91) (188). He separates discussion of the viability of international law from a focus on centralised coercion, arguing instead that self-help measures can ensure its application. Indeed he firmly identifies himself as a believer in law as "a social process", rejecting "the idea of law as a 'body of rules' because they hold that this process of authoritative and effective decision-making does not consist simply of the application of a previously existing body of rules, but is shaped by social, moral and political considerations as well." (128). Of particular relevance to my research would be Bull's thoughts on how an unjust order could be sustained (93); his analysis of how Great Powers legitimise themselves (229); and the strength of the cosmopolitan culture upon which international society rests (316).
What then is missing, what issues or questions are avoided by The Anarchical Society? Stanley Hoffmann, Adam Watson, Alan James, Kalevi Holsti, Kai Alderson, Andrew Hurrell, Yale Ferguson, Richard Little, John Williams, Edward Keene, Nicholas Wheeler, Tim Dunne and Barry Buzan are just some of those who have pieced over Bull's legacy and reconsidered The Anarchical Society, now on its Third Edition. The have critiqued his separation of system and society, his moral vision, hesitant pluralism, methodological inexactitude and dismissal of economic integration or sub global developments. For my money, perhaps it is not the place, or it is best that he simply alludes to it, but a deeper (perhaps Gramscian) treatment of the values and institutions that define international society would be welcome. Although this work is picked up elsewhere in The English School. From a contemporary perspective the absence of religion/Islam as a theme is telling of its 1977 provenance. In terms of the existence of bias, as has been mentioned Bull's voice is evident throughout The Anarchical Society, and he does address the reader deliberately whenever he picks sides in a debate, be it on nuclear weapons; cosmopolitanism; structural functionalism or natural law. As he sums up in a witty anecdote about being lost in Scotland, the present international society perhaps isn't the best place to start from in search of world order, but it is here that we are, so it is here we must begin (295).
Tags anarchy, english school, great powers, hedley bull, international society


Top foreign policy chief Sartaj Aziz, in a press briefing on Jadhav, also asked how "an innocent man" could have two passports.
At the time of his arrest in March 2016, Jadhav had two passports on him, one in his name, and a second in the name of Hussain Mubarak Patel.
"Why was Jadhav using a fake name in his identity documents?' he asked.
Aziz also slammed the "inflammatory statements and rhetoric of premeditated murder" issued by the Indian government, which he said "will only result in escalation, serving no useful purpose".
Aziz said the April 10 sentence on Jadhav was "as per the law of the land.. He (Jadhav) was involved in subversive activities in Pakistan."
He said that India has not responded to a "Letter of Assistance requesting specific information and access to certain key witnesses" that was shared with them on January 23 this year. "There has been no response from the Indian side so far."
Stating that "fully transparent process" had been followed in the sentencing, the top diplomat said Jadhav had the right to appeal within 40 days to a higher court.
Jadhav, who was tried by a military court, could also file a mercy petition with the Army Chief within 60 days of the decision by the appellate court. His last option was to file a mercy petition with the President of Pakistan within 90 days after the decision of the army chief.
He said Jadhav's sentence was based on "credible, specific evidence" proving his involvement in espionage and terrorist activities in Pakistan.
Rejecting Indian contention that Jadhav was a retired naval commander, he said that India had failed to provide any "credible explanation of why their naval commander was in Balochistan".
Aziz said India's lack of cooperation and refusal to provide Pakistan legal assistance in the case were the reasons why consular access had not been provided to Jadhav. India has said it had sought consular access to him 13 times, and was refused each time. On Friday, its 14th request was turned down.


Allali, Abdelhakim; Holy, Erik W; Sulimov, Dmitry S; Toelg, Ralph; Richardt, Gert; Abdel-Wahab, Mohamed (2018). Long-Term Clinical Outcome of Early Generation Versus New-Generation Drug-Eluting Stents in 481 Patients Undergoing Rotational Atherectomy: A Retrospective Analysis. Cardiology and Therapy, 7(1):89-99.
Latib, Azeem; Naganuma, Toru; Abdel-Wahab, Mohamed; Danenberg, Haim; Cota, Linda; Barbanti, Marco; Baumgartner, Helmut; Finkelstein, Ariel; Legrand, Victor; de Lezo, José Suárez; Kefer, Joelle; Messika-Zeitoun, David; Richardt, Gert; Stabile, Eugenio; Kaleschke, Gerrit; Vahanian, Alec; Laborde, Jean-Claude; Leon, Martin B; Webb, John G; Panoulas, Vasileios F; Maisano, Francesco; Alfieri, Ottavio; Colombo, Antonio (2015). Treatment and clinical outcomes of transcatheter heart valve thrombosis. Circulation. Cardiovascular Interventions, 8(4):e001779.
Maisano, Francesco; Franzen, Olaf; Baldus, Stephan; Schäfer, Ulrich; Hausleiter, Jörg; Butter, Christian; Ussia, Gian Paolo; Sievert, Horst; Richardt, Gert; Widder, Julian D; Moccetti, Tiziano; Schillinger, Wolfgang (2013). Percutaneous mitral valve interventions in the real world: early and 1-year results from the ACCESS-EU, a prospective, multicenter, nonrandomized post-approval study of the MitraClip therapy in Europe. Journal of the American College of Cardiology, 62(12):1052-1061.
This list was generated on Thu Apr 25 08:58:00 2019 CEST.


Yoga has a reputation as a good weight loss programme as well as a women's fitness routine. It steadily shapes your body into new curves and smooths out lumps and bumps but it does it in a way that is long lasting and becomes part of your life style rather than a crash and burn approach which some of the gym based programmes tend to do. Many women find that as they enjoy the other benefit of yoga (calmness) they don't go for food as a prop nearly as much so their weight drops as well as their dress size through the body reshaping.