Cardiovascular Magnetic Resonance in the Management of Cardiac Amyloidosis: Current and Future Clinical Applications.

Cardiac magnetic resonance represents the gold standard imaging technique to assess cardiac volumes, wall thickness, mass, and systolic function but also to provide noninvasive myocardial tissue characterization across almost all cardiac diseases. In patients with cardiac amyloidosis, increased wall thickness of all heart chambers, a mildly reduced ejection fraction and occasionally pleural and pericardial effusion are the characteristic morphologic anomalies. The typical pattern after contrast injection is represented by diffuse areas of late gadolinium enhancement, which can be focal and patchy in very early stages, circumferential, and subendocardial in intermediate stages or even diffuse transmural in more advanced stages.

Non-transmural myocardial infarction associated with regional contractile function is an independent predictor of positive outcome: an integrated approach to myocardial viability.

BACKGROUND: Cardiovascular magnetic resonance permits assessment of irreversible myocardial fibrosis and contractile function in patients with previous myocardial infarction. We aimed to assess the prognostic value of myocardial fibrotic tissue with preserved/restored contractile activity. METHODS: In 730 consecutive myocardial infarction patients (64 ± 11 years), we quantified left ventricular (LV) end-diastolic (EDV) and end-systolic (ESV) volumes, ejection fraction (EF), regional wall motion (WM) (1 normal, 2 hypokinetic, 3 akinetic, 4 dyskinetic), and WM score index (WMSI), and measured the transmural (1-50 and 51-100) and global extent of the infarct scar by late gadolinium enhancement (LGE). Contractile fibrotic (CT-F) segments were identified as those showing WM-1 and WM-2 with LGE ≤ or ≥ 50%. RESULTS: During follow-up (median 2.5, range 1-4.7 years), cardiac events (cardiac death or appropriate implantable defibrillator shocks) occurred in 123 patients (17%). At univariate analysis, age, LVEDV, LVESV, LVEF, WMSI, extent of LGE, segments with transmural extent > 50%, and CT-F segments were associated with cardiac events. At multivariate analysis, age > 65 years, LVEF < 30%, WMSI > 1.7, and dilated LVEDV independently predicted cardiac events, while CT-F tissue was the only independent predictor of better outcome. After adjustment for LVEF < 30% and LVEDV dilatation, the presence of CT-F tissue was associated with good prognosis. CONCLUSIONS: In addition to CMR imaging parameters associated with adverse outcome (severe LV dysfunction, poor WM, and dilated EDV), the presence of fibrotic myocardium showing contractile activity in patients with previous myocardial infarction yields a beneficial effect on patient survival.

Diastolic dysfunction evaluated by cardiac magnetic resonance: the value of the combined assessment of atrial and ventricular function.

OBJECTIVES: We sought to evaluate the role of cardiac magnetic resonance imaging (CMR) in the evaluation of diastolic function by a combined assessment of left ventricular (LV) and left atrial (LA) function in a cohort of subjects with various degrees of diastolic dysfunction (DD) detected by echocardiography. METHODS: Forty patients with different stages of DD and 18 healthy controls underwent CMR. Short-axis cine steady-state free precession images covering the entire LA and LV were acquired. Parameters of diastolic function were measured by the analysis of the LV and LA volume/time (V/t) curves and the respective derivative dV/dt curves. RESULTS: At receiver operating characteristic (ROC) curve analysis, the peak of emptying rate A indexed by the LV filling volume with a cut-off of 3.8 was able to detect patients with grade I DD from other groups (area under the curve [AUC] 0.975, 95% confidence interval [CI] 0.86-1). ROC analysis showed that LA ejection fraction with a cut-off of ≤36% was able to distinguish controls and grade I DD patients from those with grade II and grade III DD (AUC 0.996, 95% CI 0.92-1, p < 0.001). The isovolumetric pulmonary vein transit ratio with a cut-off of 2.4 allowed class III DD to be distinguished from other groups (AUC 1.0, 95%CI 0.93-1, p < 0.001). CONCLUSIONS: Analysis of LV and LA V/t curves by CMR may be useful for the evaluation of DD. KEY POINTS: • Combined atrial and ventricular volume/time curves allow evaluation of diastolic function. • Atrial emptying fraction allows distinction between impaired relaxation and restrictive/pseudo-normal filling. • Isovolumetric pulmonary vein transit ratio allows distinction between restrictive and pseudo-normal filling.

Advanced Non-invasive Imaging Techniques in Chronic Heart Failure and Cardiomyopathies : Focus on Cardiac Magnetic Resonance Imaging and Computed Tomographic.

Cardiomyopathies (Cs) are a heterogeneous group of myocardial diseases with structural and/or functional abnormalities.The aetiology is due to genetic-family substrate in most cases, however, the correct and detailed analysis of morphofunctional abnormalities (severity and distribution of hypertrophy, ventricular dilatation, ventricular dysfunction) and tissue characteristics (myocardial fibrosis, myocardial infiltration) are a crucial element for a definite diagnosis.Among the different diagnostic imaging modalities applied in clinical practice (echocardiography, nuclear medicine), cardiac magnetic resonance (CMR) has emerged as a non-invasive diagnostic tool having high ability to quantify systolic function and tissue abnormalities that represent the substrates of many Cs.The main added value of CMR is the ability to identify cardiomyopathies with respect to ischemic heart disease and, above all, to discriminate the major types of cardiomyopathies based on morpho-functional presentation patterns and the presence and location of myocardial fibrosis.Many CMR elements allow increasing diagnostic accuracy but CMR data should be integrated with an appropriate clinical and instrumental context.Computed Tomographic (CT) scan technology has showed a complementary role in patients having Cs and HF.In this chapter, the diagnostic, pathophysiologic and prognostic value of CMR and CT in heart failure due to the most common cardiomyopathies will be discussed.

Transient Left Ventricular Dysfunction from Cardiomyopathies to Myocardial Viability: When and Why Cardiac Function Recovers.

Transient left ventricular dysfunction (TLVD), a temporary condition marked by reversible impairment of ventricular function, remains an underdiagnosed yet significant contributor to morbidity and mortality in clinical practice. Unlike the well-explored atherosclerotic disease of the epicardial coronary arteries, the diverse etiologies of TLVD require greater attention for proper diagnosis and management. The spectrum of disorders associated with TLVD includes stress-induced cardiomyopathy, central nervous system injuries, histaminergic syndromes, various inflammatory diseases, pregnancy-related conditions, and genetically determined syndromes. Furthermore, myocardial infarction with non-obstructive coronary arteries (MINOCA) origins such as coronary artery spasm, coronary thromboembolism, and spontaneous coronary artery dissection (SCAD) may also manifest as TLVD, eventually showing recovery. This review highlights the range of ischemic and non-ischemic clinical situations that lead to TLVD, gathering conditions like Tako-Tsubo Syndrome (TTS), Kounis syndrome (KS), Myocarditis, Peripartum Cardiomyopathy (PPCM), and Tachycardia-induced cardiomyopathy (TIC). Differentiation amongst these causes is crucial, as they involve distinct clinical, instrumental, and genetic predictors that bode different outcomes and recovery potential for left ventricular function. The purpose of this review is to improve everyday clinical approaches to treating these diseases by providing an extensive survey of conditions linked with TLVD and the elements impacting prognosis and outcomes.

The enigma of the 'smoker's paradox': Results from a single-center registry of patients with STEMI undergoing primary percutaneous coronary intervention.

BACKGROUND: Smoker's paradox usually refers to the observation of a favorable outcome of smoking patients in acute myocardial infarction. METHODS: From April 2006 to December 2018 a population of 2456 patients with ST segment elevation myocardial infarction (STEMI) treated with primary percutaneous coronary intervention (pPCI) were prospectively enrolled in the MATRIX registry. Ischemic time, clinical, demographics, angiographic data, and 1-year follow-up were collected. RESULTS: Among 2546 patients admitted with STEMI, 1007 (41 %) were current smokers. Smokers were 10 years younger and had lower crude in-hospital and 1-year mortality (1.5 % vs 6 %, p < 0.0001 and 5 % vs 11 %, p < 0.0001), shorter ischemic time (203 [147-299] vs 220 [154-334] minutes, p = 0.002) and shorter decision time (60 [30-135] vs 70 [36-170] minutes, p = 0.0063). Smoking habit [OR:0.37(95 % CI:0.18-0.75)-p < 0.01], younger age [OR 1.06 (95%CI:1.04-1.09)-p < 0.001] and shorter ischemic time [OR:1.01(95%CI:1.01-1.02)-p < 0.05] were associated to lower in-hospital mortality. Only smoking habit [HR:0.65(95 % CI: 0.44-0.9)-p = 0.03] and younger age [HR:1.08 (95%CI:1.06-1.09)-p < 0.001] were also independently associated to lower all-cause death at 1-year follow-up. After propensity matching, age, cardiogenic shock and TIMI flow <3 were associated with in-hospital mortality, while smoking habit was still associated with reduced mortality. Smoking was also associated with reduced mortality at 1-year follow-up (HR 0.54, 95 % CI [0.37-0.78]; p < 0.001). CONCLUSIONS: Smoking patients show better outcome after PCI for STEMI at 1-year follow-up. Although "Smoking paradox" could be explained by younger age of patients, other factors may have a role in the explanation of the phenomenon.

Clinical Features and Patient Outcomes in Infective Endocarditis with Surgical Indication: A Single-Centre Experience.

BACKGROUND: Infective endocarditis (IE) is marked by a heightened risk of embolic events (EEs), uncontrolled infection, or heart failure (HF). METHODS: Patients with IE and surgical indication were enrolled from October 2015 to December 2018. The primary endpoint consisted of a composite of major adverse events (MAEs) including all-cause death, hospitalizations, and IE relapses. The secondary endpoint was all-cause death. RESULTS: A total of 102 patients (66 ± 14 years) were enrolled: 50% with IE on prosthesis, 33% with IE-associated heart failure (IE-aHF), and 38.2% with EEs. IE-aHF and EEs were independently associated with MAEs (HR 1.9, 95% CI 1.1-3.4, p = 0.03 and HR 2.1, 95% CI 1.2-3.6, p = 0.01, respectively) and Kaplan-Meier survival curves confirmed a strong difference in MAE-free survival of patients with EEs and IE-aHF (p < 0.01 for both). IE-aHF (HR 4.3, 95% CI 1.4-13, p < 0.01), CRP at admission (HR 5.6, 95% CI 1.4-22.2, p = 0.01), LVEF (HR 0.9, 95% CI 0.9-1, p < 0.05), abscess (HR 3.5, 95% CI 1.2-10.6, p < 0.05), and prosthetic detachment (HR 4.6, 95% CI 1.5-14.1, p < 0.01) were independently associated with the all-cause death endpoint. CONCLUSIONS: IE-aHF and EEs were independently associated with MAEs. IE-aHF was also independently associated with the secondary endpoint.

Late plasma exosome microRNA-21-5p depicts magnitude of reverse ventricular remodeling after early surgical repair of primary mitral valve regurgitation.

Introduction: Primary mitral valve regurgitation (MR) results from degeneration of mitral valve apparatus. Mechanisms leading to incomplete postoperative left ventricular (LV) reverse remodeling (Rev-Rem) despite timely and successful surgical mitral valve repair (MVR) remain unknown. Plasma exosomes (pEXOs) are smallest nanovesicles exerting early postoperative cardioprotection. We hypothesized that late plasma exosomal microRNAs (miRs) contribute to Rev-Rem during the late postoperative period. Methods: Primary MR patients (n = 19; age, 45-71 years) underwent cardiac magnetic resonance imaging and blood sampling before (T0) and 6 months after (T1) MVR. The postoperative LV Rev-Rem was assessed in terms of a decrease in LV end-diastolic volume and patients were stratified into high (HiR-REM) and low (LoR-REM) LV Rev-Rem subgroups. Isolated pEXOs were quantified by nanoparticle tracking analysis. Exosomal microRNA (miR)-1, -21-5p, -133a, and -208a levels were measured by RT-qPCR. Anti-hypertrophic effects of pEXOs were tested in HL-1 cardiomyocytes cultured with angiotensin II (AngII, 1 µM for 48 h). Results: Surgery zeroed out volume regurgitation in all patients. Although preoperative pEXOs were similar in both groups, pEXO levels increased after MVR in HiR-REM patients (+0.75-fold, p = 0.016), who showed lower cardiac mass index (-11%, p = 0.032). Postoperative exosomal miR-21-5p values of HiR-REM patients were higher than other groups (p < 0.05). In vitro, T1-pEXOs isolated from LoR-REM patients boosted the AngII-induced cardiomyocyte hypertrophy, but not postoperative exosomes of HiR-REM. This adaptive effect was counteracted by miR-21-5p inhibition. Summary/Conclusion: High levels of miR-21-5p-enriched pEXOs during the late postoperative period depict higher LV Rev-Rem after MVR. miR-21-5p-enriched pEXOs may be helpful to predict and to treat incomplete LV Rev-Rem after successful early surgical MVR.

CMR predictors of secondary moderate to severe mitral regurgitation and its additive prognostic role in previous myocardial infarction.

BACKGROUND: We aimed to determine predictors and the additive prognostic role of moderate to severe (MS) ischemic mitral regurgitation (MR) in myocardial infarction (MI). METHODS: Four hundred twenty-two patients with previous MI underwent cardiac magnetic resonance (CMR) imaging for the assessment of left ventricular (LV) ejection fraction (EF), end-diastolic (EDV) and end-systolic volume (ESV), sphericity index, wall motion score index (WMSI), and late gadolinium enhancement (LGE). Echocardiography was performed to assess MR. RESULTS: Thirty-eight had from moderate to severe MR (MS-MR group) and 384 did not (No MS-MR group). The S-MR group had higher LV volumes, sphericity index, WMSI, and LGE extent, and lower LVEF. At univariate logistic regression analysis, dilated volumes, SI >0.43, dyskinesia of inferolateral wall, papillary muscle (PM)-LGE, and LGE extent >16% were associated with MS-MR. At multivariate analysis, only SI (OR=5.7) and PM-LGE (OR=3) were independently associated with MS-MR. Considering only patients without LV dilatation, only dyskinesia in the inferolateral wall was a predictor of MS-MR (OR 34.8). Thirty cardiac events (cardiac death, appropriate implantable cardioverter-defibrillator firing, and resuscitated cardiac arrest) occurred during a median follow-up of 1,276 days. After adjusting the prognostic variables at univariate analysis by age (>65 years) and selecting those that were significant (EDV > 95 ml/m2, ESV >53 ml/m2, EF <30%, WMSI >1.65, LGE >12%, S-MR), only WMSI >1.65 and MS-MR remained an independent predictor of cardiac events. CONCLUSIONS: Increased WMSI and PM-LGE in the overall population and inferolateral dyskinesia in patients without ESV dilatation are predictors of MS-MR; MS-MR and elevated WMSI have independent negative prognostic value.

Patent foramen ovale: anatomical complexity and long-tunnel morphology related issues.

Patent foramen ovale (PFO) is present in about one-quarter of the population and should be considered an anatomical variant rather than a malformation. The association of PFO with cryptogenic stroke, migraine, peripheral embolism and other pathologies is still controversial. The evaluation of anatomical complexity, and particularly the long-tunnel morphology, is crucial for the assessment of the risk profile and for a targeted therapeutic management. Long-tunnel PFOs seem to be more prone to clot formation and complications related to percutaneous closure procedures. Echocardiography is the most useful method to investigate anatomical complexity, confirm and reinforce the indication to treatment, select the appropriate device and guide the PFO closure towards a successful procedure.

Management of Pacemaker Implantation during COVID-19 Infection.

The management of device implantation during the COVID-19 infection has not well defined yet. This is the first case of complete atrioventricular block in a symptomatic patient affected by the COVID-19 infection treated with early pacemaker implantation to minimize the risk of virus contagion.

Detection of myocardial iron overload by two-dimensional speckle tracking in patients with beta-thalassaemia major: a combined echocardiographic and T2* segmental CMR study.

We aimed to evaluate the role of two-dimensional speckle tracking imaging (2DSTI) in detecting early changes of myocardial deformation in patients affected by thalassemia major (TM) and its relation with myocardial iron overload (MIO) detected by T2* cardiovascular magnetic resonance (CMR). We studied 28 TM patients (15 males, 37.4 ± 10 years). All patients underwent CMR and echocardiography in the same day. Segmental and global T2* values were measured. Values of global longitudinal strain (GLS) were derived from the three apical views, while radial and circumferential strain were obtained as average strain from the short axis views at basal, mid and apical level. Six patients (21.4%) showed significant MIO (global heart T2* < 20 ms). GLS showed a significant correlation with T2* values (R = -0.49; P = 0.001) and it was significantly lower in patients with a significant MIO than in those with no significant MIO (-18.3 ± 2 vs. -21.3 ± 2.7, P = 0.02). No significant difference was found for radial and circumferential strain in relation to the severity of MIO. Patients with impaired GLS (<-19.5%) had a significant higher risk of showing significant MIO (Odds-ratio-OR = 17; 95%). GLS is related with global T2* in TM patients. Moreover, GLS can identify TM patients with severe MIO detected by CMR.

High-risk patients with mild-moderate left ventricular dysfunction after a previous myocardial infarction. A long-term prognostic data by cardiac magnetic resonance.

BACKGROUND: Few studies have explored prognosis in patients with previous myocardial infarction (MI) with mild-moderate (MM) left ventricular (LV) dysfunction (D). The aim of our study was to investigate whether combining LV parameters obtained by cardiac magnetic resonance (CMR) improves risk stratification of patients with previous MI and MM-LV-D. METHODS: In 418 consecutive patients (63.3±11.3years old, female 12.9%) with previous MI, we quantified LVEF, volumes and wall motion score index (WMSI) and measured the infarct extent by late gadolinium enhancement (LGE). According to LVEF, patients were considered with normal LVEF (>55%), MM-LV-D (LVEF>30 and ≤55%) and severe (S) LV-D (LVEF ≤30). RESULTS: During follow-up (median, 39.7months) cardiac events (cardiac death or appropriate intra-cardiac defibrillator shocks) occurred in 17/99 of patients with S-LV-D, in 15/201 with MM-LV-D, and in only 1/118 of those with normal LV-EF. After adjustment for age, an extent of LGE >11.3%, a dilated LV (male >112ml/m2; female >92ml/m2) and a WMSI>1.59 were associated with adverse cardiac events in patients with MM-LV-D. In patients with MM-LV-D, when each of these 3 factors was observed, the prognosis was worse respect to those with 1-2 factors and no factor (p=0.035 and p=0.004, respectively). Prognosis was similar (p=0.61) between MM-LV-D patients with all 3 factors and those with S-LV-dysfunction. CONCLUSIONS: A multiparametric CMR approach, which includes LGE, dilated LV and WMSI, permits to identify post MI patients with MM-LV-D with a risk of cardiac events similar to those with S-LV-D. Further multicenter studies are needed to confirm our data.

Isolated double orifice mitral valve in a young asymptomatic woman.

: Double orifice mitral valve (DOMV) is a rare congenital malformation of the mitral apparatus frequently associated with other congenital malformations of the heart, whereas the isolated form is rare. The prevalence is about 1% of congenital heart disease; valve stenosis and regurgitation are common findings. Echocardiography represents the best method to diagnose DOMV, providing both anatomical and functional data. We report a case of a young woman presenting with an isolated DOMV, in the absence of stenosis and significant regurgitation. The dysmorphic valve has been evaluated with both two-dimensional and three-dimensional echocardiography, providing impressive and detailed images of the peculiar anatomical configuration of the valve.

Usefulness of late gadolinium enhancement MRI combined with stress imaging in predictive significant coronary stenosis in new-diagnosed left ventricular dysfunction.

BACKGROUND: To evaluate the accuracy of late gadolinium enhancement (LGE) cardiac magnetic resonance (CMR) and imaging stress test in predicting significant coronary artery disease (CAD) in left ventricular (LV) dysfunction. METHODS: We enrolled 187 consecutive out-patients (61±17years) with new evidence of depressed (<45%) ejection fraction and no history of previous heart diseases and absence of Q-waves. All patients underwent coronary angiography (CA) and to LGE-CMR examination to identify ischemic and non-ischemic LGE. All patients underwent stress imaging to determine the presence of myocardial ischemia. RESULTS: Ischemic-LGE was found in 83 patients and non-ischemic-LGE in 104. Significant CAD on CA was found in 86/187 patients. Ischemic-LGE showed a specificity of 94%, a sensitivity of 89% and an accuracy of 92% in identifying significant CAD. Imaging stress test was negative in 98/105 patients without CAD, and positive in 42/82 with significant CAD, showing a specificity of 93%, a sensitivity of 51% and an accuracy of 75% in identifying CAD. Combining CMR and stress test imaging, 94 patients had ischemic-LGE pattern and/or positive stress test for ischemia; of these 81/94 had significant CAD on CA and 13 had no CAD. Among the 93 patients with both tests negative, significant CAD was found in 5/93 patients. The combination of LGE and stress respect to only LGE did not improve the diagnostic accuracy (90 vs 92% respectively). CONCLUSION: LGE-CMR had high accuracy in predicting significant CAD in ischemic LV dysfunction or as a bystander in non ischemic dysfunction.

PFO: Button me up, but wait Comprehensive evaluation of the patient.

Patent foramen ovale (PFO) is a slit or tunnel-like communication in the atrial septum occurring in approximately 25% of the population. A wide number of pathological conditions have been linked to its presence, most notably, cryptogenic stroke (CS) and migraine. However, in the setting of a neurological event, it is not often clear whether the PFO is pathogenically related to the index event or an incidental finding. Therefore, a detailed analysis of several clues is needed for understanding PFO's clinical significance, with a frequent case-by-case decision about destination therapy. Indeed, the controversy about PFO's pathogenicity prompted a paradigm shift of research interest from medical therapy with antiplatelets or anticoagulants to percutaneous transcatheter closure, in secondary prevention. Observational data and meta-analysis of observational studies had previously suggested that PFO closure with a device was a safe procedure with a low recurrence rate of stroke. To date, however, recent randomized controlled trials have not shown the superiority of PFO closure over medical therapy. Thus, the optimal strategy for secondary prevention of paradoxical embolism in patients with a PFO remains unclear. Moreover, the latest guidelines for the prevention on stroke restricted indications for PFO closure to patients with deep vein thrombosis and high-risk of its recurrence. Given these recent data, in the present review, we critically discuss current treatment options, pointing out the role of a comprehensive patient evaluation in overcoming PFO closure restrictions and planning the best management for each patient.

Cardiovascular imaging in the diagnosis and monitoring of cardiotoxicity: cardiovascular magnetic resonance and nuclear cardiology.

Chemotherapy-induced cardiotoxicity (CTX) is a determining factor for the quality of life and mortality of patients administered potentially cardiotoxic drugs and in long-term cancer survivors. Therefore, prevention and early detection of CTX are highly desirable, as is the exploration of alternative therapeutic strategies and/or the proposal of potentially cardioprotective treatments. In recent years, cardiovascular imaging has acquired a pivotal role in this setting. Although echocardiography remains the diagnostic method most used to monitor cancer patients, the need for more reliable, reproducible and accurate detection of early chemotherapy-induced CTX has encouraged the introduction of second-line advanced imaging modalities, such as cardiac magnetic resonance (CMR) and nuclear techniques, into the clinical setting. This review of the Working Group on Drug Cardiotoxicity and Cardioprotection of the Italian Society of Cardiology aims to afford an overview of the most important findings from the literature about the role of CMR and nuclear techniques in the management of chemotherapy-treated patients, describe conventional and new parameters for detecting CTX from both diagnostic and prognostic perspectives and provide integrated insight into the role of CMR and nuclear techniques compared with other imaging tools and versus the positions of the most important international societies.

Cardiovascular imaging in the diagnosis and monitoring of cardiotoxicity: cardiovascular magnetic resonance and nuclear cardiology.

Chemotherapy-induced cardiotoxicity (CTX) is a determining factor for the quality of life and mortality of patients administered potentially cardiotoxic drugs and in long-term cancer survivors. Therefore, prevention and early detection of CTX are highly desirable, as is the exploration of alternative therapeutic strategies and/or the proposal of potentially cardioprotective treatments. In recent years, cardiovascular imaging has acquired a pivotal role in this setting. Although echocardiography remains the diagnostic method most used to monitor cancer patients, the need for more reliable, reproducible and accurate detection of early chemotherapy-induced CTX has encouraged the introduction of second-line advanced imaging modalities, such as cardiac magnetic resonance (CMR) and nuclear techniques, into the clinical setting. This review of the Working Group on Drug Cardiotoxicity and Cardioprotection of the Italian Society of Cardiology aims to afford an overview of the most important findings from the literature about the role of CMR and nuclear techniques in the management of chemotherapy-treated patients, describe conventional and new parameters for detecting CTX from both diagnostic and prognostic perspectives and provide integrated insight into the role of CMR and nuclear techniques compared with other imaging tools and versus the positions of the most important international societies.