Safety of inhaled nitric oxide withdrawal in severe chronic pulmonary hypertension.

Inhaled nitric oxide (iNO) is a potent and selective pulmonary vasodilator with a safety concern due to rebound pulmonary hypertension (PH) associated with its withdrawal. We report short-term pulsed iNO in patients with severe pulmonary arterial hypertension (PAH) and nonoperable chronic thromboembolic PH (nCTEPH). This is a retrospective analysis of 33 patients: 22 with PAH and 11 with nCTEPH. We assessed hemodynamic, echocardiographic, and other noninvasive variables to evaluate safety and efficacy of iNO. We performed an iNO withdrawal test during right heart catheterization and after 3 days of iNO treatment. iNO significantly improved all variables examined in 22 patients with PAH and 11 with nCTEPH. Two patterns of response were observed after sudden iNO withdrawal. Twenty-nine patients (88%) showed minimal hemodynamic, oxygenation and clinical changes. Four patients (12%) had a reduction in cardiac index ≥20% and PaO2 ≥ 5%, three patients did not show clinical deterioration, and one patient developed hemodynamic collapse that needed iNO administration. This retrospective study suggests that short-term iNO improves hemodynamics and clinical conditions in some patients with PAH an nCTPEH. However, pulsed iNO withdrawal PH rebound could be a serious concern in these patients. Given the lack of evidence, we do not recommend the use of pulsed iNO in the treatment of patients with chronic PH.

Prognosis after heart transplant in patients with hypertrophic and restrictive cardiomyopathy. A nationwide registry analysis.

INTRODUCTION AND OBJECTIVES: Posttransplant outcomes among recipients with a diagnosis of hypertrophic cardiomyopathy (HCM) or restrictive cardiomyopathy (RCM) remain controversial. METHODS: Retrospective analysis of a nationwide registry of first-time recipients undergoing isolated heart transplant between 1984 and 2021. One-year and 5-year mortality in recipients with HCM and RCM were compared with those with dilated cardiomyopathy (DCM). RESULTS: We included 3703 patients (3112 DCM; 331 HCM; 260 RCM) with a median follow-up of 5.0 [3.1-5.0] years. Compared with DCM, the adjusted 1-year mortality risk was: HCM: HR, 1.38; 95%CI, 1.07-1.78; P=.01, RCM: HR, 1.48; 95%CI, 1.14-1.93; P=.003. The adjusted 5-year mortality risk was: HCM: HR, 1.17; 95%CI, 0.93-1.47; P=.18; RCM: HR, 1.52; 95%CI, 1.22-1.89; P<.001. Over the last 20 years, the RCM group showed significant improvement in 1-year survival (adjusted R2=0.95) and 5-year survival (R2=0.88); the HCM group showed enhanced the 5-year survival (R2=0.59), but the 1-year survival remained stable (R2=0.16). CONCLUSIONS: Both RCM and HCM were linked to a less favorable early posttransplant prognosis compared with DCM. However, at the 5-year mark, this unfavorable difference was evident only for RCM. Notably, a substantial temporal enhancement in both early and late mortality was observed for RCM, while for HCM, this improvement was mainly evident in late mortality.

Review of the allocation criteria for heart transplant in Spain in 2023. SEC-Heart Failure Association/ONT/SECCE consensus document.

Heart transplant (HT) remains the best therapeutic option for patients with advanced heart failure (HF). The allocation criteria aim to guarantee equitable access to HT and prioritize patients with a worse clinical status. To review the HT allocation criteria, the Heart Failure Association of the Spanish Society of Cardiology (HFA-SEC), the Spanish Society of Cardiovascular and Endovascular Surgery (SECCE) and the National Transplant Organization (ONT), organized a consensus conference involving adult and pediatric cardiologists, adult and pediatric cardiac surgeons, transplant coordinators from all over Spain, and physicians and nurses from the ONT. The aims of the consensus conference were as follows: a) to analyze the organization and management of patients with advanced HF and cardiogenic shock in Spain; b) to critically review heart allocation and priority criteria in other transplant organizations; c) to analyze the outcomes of patients listed and transplanted before and after the modification of the heart allocation criteria in 2017; and d) to propose new heart allocation criteria in Spain after an analysis of the available evidence and multidisciplinary discussion. In this article, by the HFA-SEC, SECCE and the ONT we present the results of the analysis performed in the consensus conference and the rationale for the new heart allocation criteria in Spain.

Optimization of Patient Pathway in Heart Failure with Reduced Ejection Fraction and Worsening Heart Failure. Role of Vericiguat.

Heart failure (HF) is a progressive condition with periods of apparent stability and repeated worsening HF events. Over time, unless optimization of HF treatment, worsening HF events become more frequent and patients enter into a cycle of recurrent events with high morbidity and mortality. In patients with HF there is an activation of deleterious neurohormonal pathways, such as the renin angiotensin aldosterone system and the sympathetic system, and an inhibition of protective pathways, including natriuretic peptides and guanylate cyclase. Therefore, HF burden can be reduced only through a holistic approach that targets all neurohormonal systems. In this context, vericiguat may play a key role, as it is the only HF drug that activates the nitric oxide-soluble guanylate cyclase-cyclic guanosine monophosphate system. On the other hand, it has been described relevant disparities in the management of HF population. Consequently, it is necessary to homogenize the management of these patients, through an integrated patient-care pathway that should be adapted at the local level. In this context, the development of new technologies (ie, video call, specific platforms, remote control devices, etc.) may be very helpful. In this manuscript, a multidisciplinary group of experts analyzed the current evidence and shared their own experience to provide some recommendations about the therapeutic optimization of patients with recent worsening HF, with a particular focus on vericiguat, and also about how the integrated patient-care pathway should be performed.

Invasive management of significant tricuspid regurgitation in clinical practice.

BACKGROUND: Tricuspid regurgitation (TR) is a prevalent condition inside valvular heart disease (VHD) with relevant prognosis implications. However, concordance between real management in clinical practice and invasive treatment recommendations of European Society of Cardiology (ESC) guidelines is unknown. METHODS: A substudy of ESC VHD II survey was performed to evaluate the real treatment of TR compared to the clinical ESC guidelines recommendations published in 2012, 2017 and 2021 was performed. TR cases with surgical indication were divided in 3 groups: 1: severe isolated TR without previous left VHD; 2: moderate/severe TR and concomitant severe left VHD; 3: severe TR plus previous left VHD surgery. RESULTS: Of 902 patients assessed, 123 had significant TR. Fifty (41%) cases demonstrated ESC guidelines 2012-2017 Class I or IIa recommendations for invasive treatment: 9(18%) of group 1, 37(74%) of group 2 and 4(8%) of group 3. Surgery was performed in 24 patients (48%); 1 in group 1(4%), 22 in group 2(92%) and 1 in group 3(4%). Overall concordance was 48% (group 1: 11%; group 2: 59%; group 3: 25%). Regarding the 2021 ESC guidelines only one patient changed groups with an overall concordance of 47% (group 1: 10%; group 2: 59%; group 3: 25%). CONCLUSION: Concordance between 2012, 2017 and 2021 ESC guidelines recommendations and clinical practice for TR surgical intervention is low, especially in those without concomitant severe left VHD. These results suggest the need to improve further guideline implementation and alternative treatments, such as percutaneous, which could resolve potential discrepancies in those clinical scenarios.

Cardiogenic shock code 2023. Expert document for a multidisciplinary organization that allows quality care.

Despite the efforts made to improve the care of cardiogenic shock (CS) patients, including the development of mechanical circulatory support (MCS), the prognosis of these patients continues to be poor. In this context, CS code initiatives arise, based on providing adequate, rapid, and quality care to these patients. In this multidisciplinary document we try to justify the need to implement the SC code, defining its structure/organization, activation criteria, patient flow according to care level, and quality indicators. Our specific purposes are: a) to present the peculiarities of this condition and the lessons of infarction code and previous experiences in CS; b) to detail the structure of the teams, their logistics and the bases for the management of these patients, the choice of the type of MCS, and the moment of its implantation, and c) to address challenges to SC code implementation, including the uniqueness of the pediatric SC code. There is an urgent need to develop protocolized, multidisciplinary, and centralized care in hospitals with a large volume and experience that will minimize inequity in access to the MCS and improve the survival of these patients. Only institutional and structural support from the different administrations will allow optimizing care for CS.

Practical tips for managing FLT3 mutated acute myeloid leukemia with midostaurin.

INTRODUCTION: FLT3 inhibitors have been recently introduced as novel treatment targets in patients with FLT3-mutated acute myeloid leukemia (AML). Midostaurin is an oral multikinase inhibitor that targets multiple receptor tyrosine kinases including FLT3 and has been approved for the treatment of AML with FLT3 mutations in patients candidates for intensive chemotherapy. This article presents an updated overall overview of the use of midostaurin in clinical practice. AREAS COVERED: Tests and examinations to be performed before the use of midostaurin, antifungal and antimicrobial treatment, as well as antifungal and antimicrobial prophylaxis are discussed. Practical tips for the treatment of QTc interval prolongation and heart failure are also presented. EXPERT OPINION: Midostaurin is the first agent showing significant survival benefit when combined with chemotherapy in FLT3-mutated AML patients. Optimal use of midostaurin should be a priority, being essential to know the interactions with other drugs like strong CYP3A4 inhibitors or inducers, which are particularly used in the concomitant treatment of AML patients and may increase toxicity or decrease therapeutic benefit. The active role of hematologists and nursing teams is crucial to ensure patient adherence to midostaurin treatment and to minimize adverse effects by administrating the optimal dose for each situation.

Consenso de expertos en la asistencia multidisciplinaria y el abordaje integral de la insuficiencia cardiaca. Desde el alta hospitalaria hasta la continuidad asistencial con primaria / Expert consensus on multidisciplinary management and integrated approaches in heart failure. Continuity of care from hospital discharge to primary care

La insuficiencia cardiaca es una enfermedad que precisa un tratamiento multidisciplinario, dadas la diversidad de causas y entornos clínicos implicados que las tratan y las diferentes estrategias terapéuticas que precisan la participación indispensable de diversas disciplinas. La presencia en los servicios de cardiología de unidades de insuficiencia cardiaca centradas en el tratamiento de los pacientes con esta afección y unidades de rehabilitación cardiaca que, entre sus indicaciones para la reducción de la morbimortalidad, también están implicadas en la atención de esos mismos pacientes puede causar dificultades de coordinación y pérdida de una atención integral centrada en el paciente. Por estos motivos, en el presente documento se plantea una estrategia de coordinación entre las diferentes unidades implicadas en el tratamiento de los pacientes dentro de los servicios de cardiología y la continuidad asistencial con atención primaria, tanto tras haber conseguido la estabilidad como la interrelación para una coordinación posterior más efectiva

Heart failure is a condition that requires a multidisciplinary approach to treatment because of the wide range of causes and clinical contexts that may be involved and because the diverse treatment strategies used necessitate the participation of multiple disciplines. In cardiology departments, the presence of both heart failure units that focus on the treatment of affected patients and cardiac rehabilitation units that, as well as targeting reductions in morbidity and mortality, are also involved in caring for the same patients can create difficulties for coordination and can result in the loss of comprehensive patient-centered care. For these reasons, this paper presents a strategy for coordinating the different units involved in patient management in cardiology departments and for ensuring continuity of care in primary care, both immediately after achieving stabilization and subsequently, when these interactions are important for effective coordination

Use of edoxaban in clinical practice: Comparison of data from the Spanish population in the ETNA-AF-Europe registry.

Aim: To ascertain the clinical profile and management of edoxaban in clinical practice. Materials & methods: Prospective, noninterventional postauthorization study of nonselected patients with atrial fibrillation treated with edoxaban from 12 European countries. Patients' baseline characteristics are presented. Results: A total of 13,638 patients (73.6 ± 9.5 years; 76.6/23.4% edoxaban 60/30 mg; CHA2DS2-VASc 3.1; 838 [6.1%] from Spain) were included. In Spain, the percentage of very elderly and fragile patients was greater and the risk of thromboembolism (CHA2DS2-VASc ≥2, 98.0 vs 87.3%; p < 0.001) and bleeding (HAS-BLED, 3.2 vs 2.7; p < 0.001) was greater in patients treated with edoxaban 30 mg. The proportion of patients taking edoxaban 30 mg was similar than in ENGAGE AF-TIMI 48. Conclusion: In Spain, patients treated with edoxaban were older and fragile.

Tratamiento de la insuficiencia cardiaca: la cuenta atrás empieza en el momento del diagnóstico / Heart failure treatment: the countdown begins at diagnosis

Sacubitrilo-valsartán tiene demostrada eficacia en disminuir las hospitalizaciones y las muertes por insuficiencia cardiaca en los ensayos clínicos, y los datos de práctica clínica real corroboran su efectividad y su seguridad. Asimismo su uso temprano durante la hospitalización, incluso en pacientes con insuficiencia cardiaca de inicio y/o sin tratamiento previo, también parece ser seguro y recomendable para simplificar el tratamiento del paciente y facilitar la transición de cuidados. También tiene un efecto favorable sobre el remodelado cardiaco, como demuestran los resultados del estudio PROVE-HF, que es mayor con un inicio temprano y a dosis más altas en estudios observacionales. Información sobre el suplemento: este artículo forma parte del suplemento titulado «Controversias para una nueva era en el tratamiento de la insuficiencia cardiaca», que ha sido patrocinado por Novartis

Clinical trials have found that sacubitril-valsartan is effective in reducing the risk of hospitalization and death from heart failure and real-life data have confirmed the drug combination's effectiveness and safety. Moreover, early use during hospitalization, in both patients with de novo heart failure and previously untreated patients, also appears to be safe and is recommended for simplifying patient management and easing transitional care. In addition, sacubitril-valsartan has a beneficial effect on cardiac remodeling, as demonstrated by the results of the PROVE-HF study, which is greater with an early onset and at higher doses in observational studies. Supplement information: this article is part of a supplement entitled "Questions on a new era for heart failure treatment" which is sponsored by Novartis

Subcutaneous implantable cardioverter-defibrillator in primary and secondary prevention of sudden cardiac death: A meta-analysis.

BACKGROUND: Subcutaneous implantable cardioverter-defibrillator (S-ICD) is gaining in popularity for primary and secondary prevention of sudden cardiac death. The objective was to evaluate the safety and clinical effectiveness of the S-ICD for prevention of sudden cardiac death compared to transvenous cardioverter-defibrillator (TV-ICD). METHODS: A systematic review with meta-analyses was performed. The electronic databases MEDLINE, EMBASE, SCI, and Cochrane Central Register of Controlled Trials were consulted in March 2018 with no restrictions on publication date. Predefined criteria were used to determine inclusion of studies and to assess their methodologic quality. RESULTS: Ten longitudinal-observational studies with comparison group presenting moderate methodologic flaws were included (N = 7820). The combination of results indicates that health-related quality of life is not significantly different between S-ICD and TV-ICD groups (Physical health: MD = 2.90; 95% CI = -3.88, 9.68/Mental health: MD = 0.13; 95% CI = -2.11, 2.37). Mortality occurred in 4.4% of S-ICD patients and 5.9% of TV-ICD patients died (OR = 0.79; 95% CI = 0.50, 1.24). The incidence of infections (OR = 1.79; 95% CI = 0.93, 3.43) and inappropriate shocks (OR = 1.28, 95% CI = 0.91, 1.78) is not significantly different between both groups. The S-ICD reduces complications related to electrodes/leads (OR = 0.13, 95% CI = 0.05, 0.29) and has lower electrodes/leads movement compared with TV-ICD (OR = 0.26; 95% CI 0.10, 0.67). In contrast, pneumothorax is more likely in TV-ICD than S-ICD (OR = 0.17; 95% CI = 0.03, 0.97). CONCLUSIONS: S-ICD reduces electrodes/leads movement, electrodes/leads related complications, and pneumothorax. Our study did not demonstrate a statistically significant difference in mortality, health-related quality of life, and infection rate between S-ICD and TV-ICD.

Pulmonary Arterial Hypertension in Systemic Lupus Erythematosus: Prevalence and Predictors.

OBJECTIVE: Pulmonary arterial hypertension (PAH) prevalence has been reported to be between 0.5% and 17% in systemic lupus erythematosus (SLE). This study assessed PAH prevalence and predictors in an SLE cohort. METHODS: The Borg dyspnea scale, DLCO, N-terminal pro-brain natriuretic peptide (NT-proBNP), and Doppler echocardiographic (DE) were performed. An echocardiographic Doppler exercise test was conducted in selected patients. When DE systolic pulmonary arterial pressure was ≥ 45 mmHg or increased during exercise > 20 mmHg, a right heart catheterization was performed. Hemodynamic during exercise was measured if rest mean pulmonary arterial pressure was < 25 mmHg. RESULTS: Of the 203 patients with SLE, 152 were included. The mean age was 44.9 ± 12.3 years, and 94% were women. Three patients had known PAH. The algorithm diagnosed 1 patient with chronic thromboembolic pulmonary hypertension and 5 with exercise-induced pulmonary artery pressure increase (4 with occult left diastolic dysfunction). These patients had significantly more dyspnea, higher NT-proBNP, and lower DLCO. CONCLUSION: These data confirm the low prevalence of PAH in SLE. In our cohort, occult left ventricular diastolic dysfunction was a frequent diagnosis of unexplained dyspnea. Dyspnea, DLCO, and NT-proBNP could be predictors of pulmonary hypertension in patients with SLE.

Economic evaluations of implantable cardioverter defibrillators: a systematic review.

The aim of this paper was to review the cost-effectiveness studies of implantable cardioverter defibrillators (ICD) for primary or secondary prevention of sudden cardiac death (SCD). A systematic review of the literature published in English or Spanish was performed by electronically searching MEDLINE and MEDLINE in process, EMBASE, NHS-EED, and EconLit. Some keywords were implantable cardioverter defibrillator, heart failure, heart arrest, myocardial infarction, arrhythmias, syncope, sudden death. Selection criteria were the following: (1) full economic evaluations published after 1995, model-based studies or alongside clinical trials (2) that explored the cost-effectiveness of ICD with or without associated treatment compared with placebo or best medical treatment, (3) in adult patients for primary or secondary prevention of SCD because of ventricular arrhythmias. Studies that fulfilled these criteria were reviewed and data were extracted by two reviewers. The methodological quality of the studies was assessed and a narrative synthesis was prepared. In total, 24 studies were included: seven studies on secondary prevention and 18 studies on primary prevention. Seven studies were performed in Europe. For secondary prevention, the results showed that the ICD is considered cost-effective in patients with more risk. For primary prevention, the cost-effectiveness of ICD has been widely studied, but uncertainty about its cost-effectiveness remains. The cost-effectiveness ratios vary between studies depending on the patient characteristics, methodology, perspective, and national settings. Among the European studies, the conclusions are varied, where the ICD is considered cost-effective or not dependent on the study.

Long-term inhaled nitric oxide plus phosphodiesterase 5 inhibitors for severe pulmonary hypertension.

BACKGROUND: Inhaled nitric oxide (iNO) is a potent pulmonary vasodilator, but therapeutic experience in patients with severe pulmonary hypertension is scarce. METHODS: Eleven patients with severe pulmonary hypertension, 6 due to pulmonary arterial hypertension and 4 due to chronic thromboembolic disease, were selected for iNO therapy. A phosphodiesterase type 5 inhibitor (PDE5i) was added in cases of clinical worsening. In this study we evaluate the clinical effectiveness and safety of long-term treatment with iNO either alone or combined with a PDE5i. RESULTS: After 1 month of iNO administration, improvements were observed in World Health Organization functional class, Borg scale (p = 0.003), brain natriuretic peptide levels (p = 0.002) and 6-minute walk test (p = 0.003). After 6 months of treatment, 7 patients had clinical deterioration that was reversed upon adding a PDE5i. One of these patients died in Month 8 and another underwent pulmonary transplantation in Month 9. The clinical condition of the remaining 9 patients was unchanged after 1 year. A second right catheterization showed improvement in mean pulmonary arterial pressure (66 +/- 15 mm Hg to 56 +/- 18 mm Hg; p = 0.01), pulmonary vascular resistance (1,234 +/- 380 dyn/s/cm(5) to 911 +/- 410 dyn/s/cm(5); p = 0.008) and cardiac index (2.0 +/- 0.4 liters/min/m(2) to 2.5 +/- 0.4 liters/min/m(2); p = 0.04). There was no significant increase in methemoglobin, no worsening of pulmonary function and no sudden withdrawal syndrome. CONCLUSIONS: We suggest that iNO therapy alone or in combination with a PDE5i could be a therapeutic alternative for severe pulmonary hypertension.

Usefulness of hyperemic venous return angiography for studying coronary venous anatomy prior to cardiac resynchronization device implantation.

INTRODUCTION AND OBJECTIVES: Implantation of electrodes via the coronary sinus (CS) can be very challenging because access to the target vessel is restricted by anatomical obstacles. Consequently, prior knowledge of coronary venous anatomy is crucial. The objective of this study was to evaluate the usefulness of hyperemic venous return angiography relative to that of occlusive retrograde venography prior to cardiac resynchronization device implantation. METHODS: Coronary venous anatomy was studied in 200 patients both by videoing venous coronary return, which was optimized by inducing hyperemia, and by occlusive venography. The visibility of different portions of the coronary venous system was scored. RESULTS: Overall, sufficient anatomic information was obtained in 99.5% of patients. Visibility scores for the CS and the lateral vein of the left ventricle were slightly higher in the group studied using occlusive venography, though there was no significant difference between the two techniques. In contrast, the middle cardiac vein and the anterior interventricular vein could be visualized in greater detail using venous return angiography. There were no complications in the group studied using venous return angiography whereas dissection of the great cardiac vein occurred in three patients studied using occlusive venous angiography, though this did not prevent electrode implantation. CONCLUSIONS: With venous return angiography, it was possible to visualize accurately the venous anatomy of the lateral wall of the left ventricle and, consequently, to anticipate the level of difficulty posed by electrode implantation.

Utilidad de la senovenografía de retorno con hiperemia para el estudio de la anatomía venosa coronaria previo al implante de dispositivos de resincronización cardiaca / Usefulness of hyperemic venous return angiography for studying coronary venous anatomy prior to cardiac resynchronization device implantation

Introducción y objetivos. El implante de un electrodo a través del seno coronario (SC) puede ser dificultoso debido a obstáculos anatómicos que limitan el acceso a la vena. Por ello es fundamental conocer la anatomía venosa coronaria. El objetivo es analizar la utilidad de la senovenografía de retorno con hiperemia en el implante de dispositivos de resincronización cardiaca comparándolo con la senovenografía oclusiva retrógrada. Métodos. Se estudió la anatomía venosa coronaria en 200 pacientes, mediante la filmación del retorno venoso coronario optimizado con la inducción de hiperemia y mediante senovenografía oclusiva, puntuándose la visibilidad de las distintas porciones del sistema venoso coronario. Resultados. En general, se obtuvo una información anatómica adecuada en el 99,5% de los individuos. Las puntuaciones de visibilidad para el SC y la vena lateral fueron ligeramente superiores en el grupo estudiado mediante senovenografía oclusiva retrógrada, aunque no hubo diferencias significativas entre ambas técnicas. Por el contrario, la vena cardiaca media y la vena interventricular anterior se visualizaron con mayor detalle mediante la senovenografía de retorno. No hubo complicaciones en el grupo estudiado mediante senovenografía de retorno, mientras que en 3 pacientes estudiados con senovenografía oclusiva se produjo la disección de la gran vena cardiaca, aunque no impidió el implante del electrodo. Conclusiones. La angiografía coronaria de retorno define con precisión la anatomía venosa de la región lateral del ventrículo izquierdo y permite anticipar el nivel de dificultad del implante del electrodo (AU)

Introduction and objectives. Implantation of electrodes via the coronary sinus (CS) can be very challenging because access to the target vessel is restricted by anatomical obstacles. Consequently, prior knowledge of coronary venous anatomy is crucial. The objective of this study was to evaluate the usefulness of hyperemic venous return angiography relative to that of occlusive retrograde venography prior to cardiac resynchronization device implantation. Methods. Coronary venous anatomy was studied in 200 patients both by videoing venous coronary return, which was optimized by inducing hyperemia, and by occlusive venography. The visibility of different portions of the coronary venous system was scored. Results. Overall, sufficient anatomic information was obtained in 99.5% of patients. Visibility scores for the CS and the lateral vein of the left ventricle were slightly higher in the group studied using occlusive venography, though there was no significant difference between the two techniques. In contrast, the middle cardiac vein and the anterior interventricular vein could be visualized in greater detail using venous return angiography. There were no complications in the group studied using venous return angiography whereas dissection of the great cardiac vein occurred in three patients studied using occlusive venous angiography, though this did not prevent electrode implantation. Conclusions. With venous return angiography, it was possible to visualize accurately the venous anatomy of the lateral wall of the left ventricle and, consequently, to anticipate the level of difficulty posed by electrode implantation (AU)