Understanding the role of the left atrial appendage on the flow in the atrium.

BACKGROUND: The exclusion/occlusion of the left atrial appendage (LAA) is a treatment option for atrial fibrillation (AF) patients who are at high risk of stroke and high risk of bleeding. As the role of the LAA is not well understood or explored, this study aims to assess its role on flow dynamics in the left atrium. METHODS: Computational fluid dynamics (CFD) simulations were carried out for nine AF patients before and after LAA exclusion. The flow parameters investigated included the LA velocities, Time Averaged Wall Shear Stress (TAWSS), Oscillatory Shear Index (OSI), Relative Residence Time (RRT), and Pressure in the LA. RESULTS: This study shows that, on average, a decrease in TAWSS (1.82 ± 1.85 Pa to 1.27 ± 0.96 Pa, p < 0.05) and a slight increase in OSI (0.16 ± 0.10 to 0.17 ± 0.10, p < 0.05), RRT (1.87 ± 1.84 Pa-1 to 2.11 ± 1.78 Pa-1, p < 0.05), and pressure (-19.2 ± 6.8 mmHg to -15.3 ± 8.3 mmHg, p < 0.05) were observed in the LA after the exclusion of the LAA, with a decrease in low-magnitude velocities. CONCLUSION: The exclusion of the LAA seems to be associated with changes in LA flow dynamics. Further studies are needed to elucidate the clinical implications of these changes.

Predictors of permanent pacemaker implantation for transcatheter self-expandable aortic valve implant in the cusp overlap era.

BACKGROUND: Predictors of permanent pacemaker implantation (PPMI) after self-expanding transcatheter aortic valve implant (TAVI) were described. Is unknown if PPMI predictors remain in the era of high implants using the cusp overlap (COP). METHODS: Single-center, prospective, consecutive case series of patients undergoing self-expanding TAVI with the COP approach. The status of PPMI and other clinical events were ascertained at 30 days. RESULTS: A total of 261 patients were included (84% with Evolut, n = 219). Implant depth >4 mm was infrequent (13.8%). TAVI depth (OR 1.259; p = 0.005), first or second-degree auriculo-ventricular block (OR 3.406; p = 0.033), right-bundle (OR 15.477; p < 0.0001), and incomplete left-bundle branch block (OR 7.964; p = 0.036) were found to be independent predictors of PPMI. The risk of PPMI with deep implant and no electrical disturbances was 3%, and 0% with high implant and no prior electrical disturbances. Those who received PPMI had no statistically significant increased risk of death, myocardial infarction, stroke, bleeding events, or vascular complications at 30 days, but longer hospital stay (mean difference 1.43 days more, p = 0.003). CONCLUSIONS: Implant depth and prior conduction abnormalities remain the main predictors of PPMI using self-expanding TAVI in the COP era. Patients with high implants and no prior conduction abnormalities may be candidates for early discharge after uneventful self-expanding TAVI, while the rest may need inpatient monitoring regardless of achieving a high implant. The need for PPMI was associated with longer hospital stays.

Recurrent hypo-attenuated leaflet thickening after TAVR: Clinical implications.

Subclinical bioprosthetic valve thrombosis (BPVT) is a relatively common finding in asymptomatic patients during follow-up imaging. However, its clinical significance is unclear. Data from registries associate BPVT with elevated valve gradients, thromboembolic complications, recurrence, and valve degeneration. Given the dynamic nature of the disease process, management is challenging. The duration of anticoagulation is unpredictable, and the need for frequent monitoring of BPVT, even in subclinical scenarios, is unclear. Our report is shedding the light on the clinical implications BPVT.

Importance of B-Type Natriuretic Peptide in the Detection of Patients With Structural Heart Disease in a Primary Care Setting.

BACKGROUND: Early detection and intervention for preclinical heart failure (HF) are crucial for restraining the potential increase in patients with HF. Thus, we designed and conducted a single-center retrospective cohort study to confirm the efficacy of B-type natriuretic peptide (BNP) for the early detection of preclinical HF in a primary care setting. METHODS AND RESULTS: We investigated 477 patients with no prior diagnosis of HF who were under the care of general practitioners. These patients were categorized into 4 groups based on BNP concentrations: Category 1, 0 pg/mL≤BNP≤35 pg/mL; Category 2, 35 pg/mL200 pg/mL. There was a marked and statistically significant increase in the prevalence of preclinical HF with increasing BNP categories: 19.9%, 57.9%, 87.5%, and 96.0% in Categories 1, 2, 3, and 4, respectively. Compared with Category 1, the odds ratio of preclinical HF in Categories 2, 3, and 4 was determined to be 5.56 (95% confidence interval [CI] 3.57-8.67), 23.70 (95% CI 8.91-63.11), and 171.77 (95% CI 10.31-2,861.93), respectively. CONCLUSIONS: Measuring BNP is a valuable tool for the early detection of preclinical HF in primary care settings. Proactive testing in patients at high risk of HF could play a crucial role in addressing the impending HF pandemic.

Clinical Advances in Cardiovascular Computed Tomography: From Present Applications to Promising Developments.

PURPOSE OF THE REVIEW: This review aims to provide a profound overview on most recent studies on the clinical significance of Cardiovascular Computed Tomography (CCT) in diagnostic and therapeutic pathways. Herby, this review helps to pave the way for a more extended but yet purposefully use in modern day cardiovascular medicine. RECENT FINDINGS: In recent years, new clinical applications of CCT have emerged. Major applications include the assessment of coronary artery disease and structural heart disease, with corresponding recommendations by major guidelines of international societies. While CCT already allows for a rapid and non-invasive diagnosis, technical improvements enable further in-depth assessments using novel imaging parameters with high temporal and spatial resolution. Those developments facilitate diagnostic and therapeutic decision-making as well as improved prognostication. This review determined that recent advancements in both hardware and software components of CCT allow for highly advanced examinations with little radiation exposure. This particularly strengthens its role in preventive care and coronary artery disease. The addition of functional analyses within and beyond coronary artery disease offers solutions in wide-ranging patient populations. Many techniques still require improvement and validation, however, CCT possesses potential to become a "one-stop-shop" examination.

Postextrasystolic repolarization changes of ventricular premature beats correlate with structural heart disease and suggest prognostic implications.

Ventricular premature beats (VPBs) can potentially lead to life-threatening arrhythmias, especially in patients with structural heart disease (SHD). However, identifying dangerous VPBs has always been a topic and challenge in clinical research. This study aimed to evaluate the relationship of postextrasystolic repolarization changes of VPBs with SHD and its possible additional prognostic value. 125 cases of frequent VPBs with SHD and 156 cases without SHD were included. VPBs were stratified selected from 24 h Holter recording according to the scale of heart rate. Average QTDV (difference value of QT interval between the first beat follow VPB with beats preceding VPB) and max QTDV were significantly longer in SHD group than that in the non-SHD group. For identifying patients with SHD, the best cutoff value were 19 ms for average QTDV (AUC = 0.931) and 29 ms for max QTDV (AUC = 0.910) respectively. For Tu morphology analysis, PT2 (postextrasystolic T wave amplitude change ≥2 mV), reversed T wave, and Pu (postextrasystolic u wave) change were all highly specific, but low sensitive as identification of SHD. Compared with average QTDV < 19 ms patients, average QTDV ≥ 19 ms patients had significantly larger left heart size and wores left cardiac function. The presence of non-persistent ventricular tachycardia runs was higher in average QTDV ≥ 19 ms group and positive Pu change group than that in control groups. The findings indicated that postextrasystolic repolarization changes of VPBs correlated with SHD and suggested potential value in prognosis asssessment.

Whispers of the Cath lab: "Cases we would rather forget".

In the dynamic field of interventional cardiology, significant strides have been made in reducing periprocedural complications. Echocardiography, particularly transesophageal echocardiography, plays a key role in ensuring the safety and success of structural heart interventions. Its real-time imaging capabilities allow for precise monitoring of device positioning, deployment, and procedural outcomes. By adhering to established imaging protocols and acquiring standard imaging planes, periprocedural echocardiography has become an essential tool for the successful performance of many structural heart interventions. In this manuscript, we present a series of unusual yet significant complications that we encountered during structural interventional procedures in our catheter laboratory. These complications, detected through echocardiography, underscore the critical role of imaging guidance in recognizing, and addressing unforeseen challenges, such as device malposition, thrombus formation in cardiac chambers during structural heart interventions, and cardiac tamponade during transcatheter mitral valve procedures. Through these cases, we highlight the effectiveness of transesophageal echocardiography in promptly identifying complications, allowing for timely intervention and resolution.

Impact of Sex on Long-Term Outcomes Following Surgical Aortic Valve Replacement.

BACKGROUND: The impact of sex on outcomes following surgical aortic valve replacement (SAVR) remains unclear. It has been proposed that females experience inferior outcomes, but this has yet to be conclusively established, particularly in the long term. The objective of this study is to identify discrepancies in postoperative outcomes between males and females following SAVR to better inform consideration for surgical intervention. METHOD: We retrospectively reviewed the outcomes of 4,927 patients who underwent SAVR from 2004 to 2018 at our centre. In total, 531 propensity-matched males and females were included in the final analysis. The primary outcome was mortality at any point during the follow-up period. Secondary outcomes included various measures of postoperative morbidity. Follow-up duration was 15 years. RESULTS: In SAVR all-comers, females experienced inferior short-term mortality, but equivalent mid-term and long-term mortality. Rates of mediastinal bleeding, sternal wound infections, sepsis, heart failure, and pacemaker insertion were all equivalent between the sexes; however, males experienced a higher rate of acute kidney injury and readmission for stroke at the longest follow-up while females experienced a longer intensive care unit and hospital length of stay. In a sub-analysis of isolated SAVR, males and females experienced equivalent early, mid, and late mortality. Of note, a trend towards increased aortic valve reoperation was noted in females at the longest follow-up. CONCLUSIONS: Males and females experience equivalent long-term mortality following isolated SAVR. Sex is not an independent risk factor of poor outcomes post-SAVR; however, the increased preoperative risk profile of females requires diligent consideration.

Electroanatomical mapping after cardiac radioablation for treatment of incessant electrical storm: a case report from the RAVENTA trial.

BACKGROUND: Electroanatomical mapping (EAM)-guided stereotactic arrhythmia radioablation (STAR) is a novel noninvasive therapy option for patients with monomorphic ventricular tachycardia (VT) refractory to antiarrhythmic drugs and/or urgent catheter ablation (CA). Data on success rates in an emergency situation such as electrical storm (ES) are rare. We present a case of a patient with an initially very poor life expectancy after extensive myocardial infarction with therapy-resistant ES, not amendable for further antiarrhythmic drug therapy, implantable cardioverter-defibrillator implantation, or repeated CA who was introduced to the radiation oncology department for emergency STAR as a bail-out therapy. METHODS: Target volume definition and transfer from EAM to CT were validated and quality assured with a semi-automatic, dedicated visualization tool (CARDIO-RT). Emergency STAR was performed with 25 Gy in the framework of the RAVENTA study. The VT burden gradually decreased after STAR; however, a second VT morphology occurred, which was successfully treated with EAM-guided CA 12 days after STAR. RESULTS: The second EAM-guided CA showed areas of low voltage in the irradiated segments, indicating a precise targeting and early functional response to STAR. The patient remained free of any VT recurrence or any radiation-related toxicities and in good general condition during the recent follow-up of 18 months. CONCLUSION: The case highlights the possible approach, caveats, difficulties, and prognosis of a patient severely affected by therapy-resistant VT in whom CA could not lead to VT suppression. Further studies of putative mechanisms of STAR in the acute and chronic phase of this novel therapy are warranted.

Radiosurgery for ventricular tachycardia (RAVENTA): interim analysis of a multicenter multiplatform feasibility trial.

BACKGROUND: Single-session cardiac stereotactic radiation therapy (SBRT) has demonstrated promising results for patients with refractory ventricular tachycardia (VT). However, the full safety profile of this novel treatment remains unknown and very limited data from prospective clinical multicenter trials are available. METHODS: The prospective multicenter multiplatform RAVENTA (radiosurgery for ventricular tachycardia) study assesses high-precision image-guided cardiac SBRT with 25 Gy delivered to the VT substrate determined by high-definition endocardial and/or epicardial electrophysiological mapping in patients with refractory VT ineligible for catheter ablation and an implanted cardioverter defibrillator (ICD). Primary endpoint is the feasibility of full-dose application and procedural safety (defined as an incidence of serious [grade ≥ 3] treatment-related complications ≤ 5% within 30 days after therapy). Secondary endpoints comprise VT burden, ICD interventions, treatment-related toxicity, and quality of life. We present the results of a protocol-defined interim analysis. RESULTS: Between 10/2019 and 12/2021, a total of five patients were included at three university medical centers. In all cases, the treatment was carried out without complications. There were no serious potentially treatment-related adverse events and no deterioration of left ventricular ejection fraction upon echocardiography. Three patients had a decrease in VT episodes during follow-up. One patient underwent subsequent catheter ablation for a new VT with different morphology. One patient with local VT recurrence died 6 weeks after treatment in cardiogenic shock. CONCLUSION: The interim analysis of the RAVENTA trial demonstrates early initial feasibility of this new treatment without serious complications within 30 days after treatment in five patients. Recruitment will continue as planned and the study has been expanded to further university medical centers. TRIAL REGISTRATION NUMBER: NCT03867747 (clinicaltrials.gov). Registered March 8, 2019. Study start: October 1, 2019.

Infective endocarditis after transcatheter edge-to-edge repair for severe mitral regurgitation; a case report and a systematic review.

Transcatheter edge-to-edge repair (TEER) is used extensively in patients with symptomatic severe mitral regurgitation and high surgical risk. While prosthetic valve endocarditis is well documented, infective endocarditis (IE) after TEER is a rare occurrence. To date, no study has been conducted on this complication. We report the case of an 85-year-old man who developed IE 3 months after undergoing TEER, and we systematically review 26 previously published cases of this complication. Our review findings indicate that discussion within the heart team is essential for the decision-making process and treatment strategy determination.

Prevalence and risk factors of cardiac thrombus prior to ventricular tachycardia catheter ablation in structural heart disease.

AIMS: Assess prevalence, risk factors, and management of patients with intra-cardiac thrombus referred for scar-related ventricular tachycardia (VT) ablation. METHODS AND RESULTS: Consecutive VT ablation referrals between January 2015 and December 2019 were reviewed (n = 618). Patients referred for de novo, scar-related VT ablation who underwent pre-procedure cardiac computed tomography (cCT) were included. We included 401 patients [61 ± 14 years; 364 male; left ventricular ejection fraction (LVEF) 40 ± 13%]; 45 patients (11%) had cardiac thrombi on cCT at 49 sites [29 LV; eight left atrial appendage (LAA); eight right ventricle (RV); four right atrial appendage]. Nine patients had pulmonary emboli. Overall predictors of cardiac thrombus included LV aneurysm [odds ratio (OR): 6.6, 95%, confidence interval (CI): 3.1-14.3], LVEF < 40% (OR: 3.3, CI: 1.5-7.3), altered RV ejection fraction (OR: 2.3, CI: 1.1-4.6), and electrical storm (OR: 2.9, CI: 1.4-6.1). Thrombus location-specific analysis identified LV aneurysm (OR: 10.9, CI: 4.3-27.7) and LVEF < 40% (OR: 9.6, CI: 2.6-35.8) as predictors of LV thrombus and arrhythmogenic right ventricular cardiomyopathy (OR: 10.6, CI: 1.2-98.4) as a predictor for RV thrombus. Left atrial appendage thrombi exclusively occurred in patients with atrial fibrillation. Ventricular tachycardia ablation was finally performed in 363 including 7 (16%) patients with thrombus but refractory electrical storm. These seven patients had tailored ablation with no embolic complications. Only one (0.3%) ablation-related embolic event occurred in the entire cohort. CONCLUSION: Cardiac thrombus can be identified in 11% of patients referred for scar-related VT ablation. These findings underscore the importance of systematic thrombus screening to minimize embolic risk.

Arrhythmias including atrial fibrillation and congenital heart disease in Kleefstra syndrome: a possible epigenetic link.

AIMS: Kleefstra syndrome (KS), often diagnosed in early childhood, is a rare genetic disorder due to haploinsufficiency of EHMT1 and is characterized by neuromuscular and intellectual developmental abnormalities. Although congenital heart disease (CHD) is common, the prevalence of arrhythmias and CHD subtypes in KS is unknown. METHODS AND RESULTS: Inspired by a novel case series of KS patients with atrial tachyarrhythmias in the USA, we evaluate the two largest known KS registries for arrhythmias and CHD: Radboudumc (50 patients) based on health record review at Radboud University Medical Center in the Netherlands and GenIDA (163 patients) based on worldwide surveys of patient families. Three KS patients (aged 17-25 years) presented with atrial tachyarrhythmias without manifest CHD. In the international KS registries, the median [interquartile range (IQR)] age was considerably younger: GenIDA/Radboudumc at 10/13.5 (12/13) years, respectively. Both registries had a 40% prevalence of cardiovascular abnormalities, the majority being CHD, including septal defects, vascular malformations, and valvular disease. Interestingly, 4 (8%) patients in the Radboudumc registry reported arrhythmias without CHD, including one atrial fibrillation (AF), two with supraventricular tachycardias, and one with non-sustained ventricular tachycardia. The GenIDA registry reported one patient with AF and another with chronic ectopic atrial tachycardia (AT). In total, atrial tachyarrhythmias were noted in six young KS patients (6/213 or 3%) with at least four (three AF and one AT) without structural heart disease. CONCLUSION: In addition to a high prevalence of CHD, evolving data reveal early-onset atrial tachyarrhythmias in young KS patients, including AF, even in the absence of structural heart disease.

3D print and multi-modality imaging guided transcatheter closure of multiple left ventricular pseudoaneurysms.

Left ventricular pseudoaneurysm (PSA) after surgical aortic valve replacement (AVR) is a known but uncommon complication. It is associated with risks such as thromboembolism and life-threatening rupture. Surgical repair has traditionally been utilized in low-risk patients but transcatheter closure has become a promising therapeutic option. This case report describes the utility of multimodality imaging in pre-, intra-, and post-procedural evaluation of transcatheter PSA closure and is among the first to demonstrate the utility of 3D print model.

Real-Time Multiplanar Reconstruction Imaging Using 3-Dimensional Transesophageal Echocardiography in Structural Heart Interventions.

The complexity of structural heart interventions has led to a demand for sophisticated periprocedural imaging guidance. Although traditional 2-dimensional (2D) transesophageal techniques are used widely, new-generation 3D ultrasound probes enable high temporal and spatial resolution. Multiplanar reconstruction of acquired 3D datasets has gained considerable momentum for precise imaging and to increase the validity of measurements. Previously, this technique was used after the acquisition of suitable 3D datasets. Recent advances in technology have enabled the use of live mode for multiplanar reconstruction across different ultrasound vendor platforms. The use of live multiplanar reconstruction can enhance the precision in real-time imaging, enable simultaneous visualization of structures of interest in multiple planes, reduce the need for probe manipulation, and thereby contribute to the success of the procedures. In this narrative review, the authors describe the rationale and utility for 3D transesophageal live multiplanar reconstruction, and outline its use for the structural heart interventions of mitral and tricuspid valve edge-to-edge repair, left atrial appendage occlusion, and the Lampoon procedure. A 3D transesophageal echocardiogram with live-multiplanar reconstruction has the potential to advance guidance of these complex interventions.

Overview of the Interatrial Septum: Review of Cardiac Nomenclature for Transseptal Puncture.

Transseptal puncture is an increasingly common procedure undertaken to gain access to the left side of the heart during structural heart disease interventions. Precision guidance during this procedure is paramount to ensure success and patient safety. As such, multimodality imaging, such as echocardiography, fluoroscopy, and fusion imaging, is routinely used to guide safe transseptal puncture. Despite the use of multimodal imaging, there is currently no uniform nomenclature of cardiac anatomy between the various imaging modes and proceduralists, and echocardiographers tend to use imaging modality-specific terminology when communicating among the various imaging modes. This variability in nomenclature among imaging modes stems from differing anatomic descriptions of cardiac anatomy. Given the required level of precision in performing transseptal puncture, a clearer understanding of the basis of cardiac anatomic nomenclature is required by both echocardiographers as well as proceduralists; enhanced understanding can help facilitate communication across specialties and possibly improve communication and safety. In this review, the authors highlight the variation in cardiac anatomy nomenclature among various imaging modes.

Evolution of interventional imaging in structural heart disease.

Treatments for structural heart diseases (SHD) have been considerably evolved by the widespread of transcatheter approach in the last decades. The progression of transcatheter treatments for SHD was feasible due to the improvement of devices and the advances in imaging techniques. In this setting, the cardiovascular imaging is pivotal not only for the diagnosis but even for the treatment of SHD. With the aim of fulfilling these tasks, a multimodality imaging approach with new imaging tools for pre-procedural planning, intra-procedural guidance, and follow-up of SHD was developed. This review will describe the current state-of-the-art imaging techniques for the most common percutaneous interventions as well as the new imaging tools. The imaging approaches will be addressed describing the use in pre-procedural planning, intra-procedural guidance, and follow-up.

Cardiac CT Beyond Coronaries: Focus on Structural Heart Disease.

PURPOSE OF REVIEW: Cardiac computed tomography (CT) is an established non-invasive imaging tool for the assessment of coronary artery disease. Furthermore, it plays a key role in the preinterventional work-up of patients presenting with structural heart disease. RECENT FINDINGS: CT is the gold standard for preprocedural annular assessment, device sizing, risk determination of annular injury, coronary occlusion or left ventricular outflow tract obstruction, calcification visualization and quantification of the target structure, and prediction of a co-planar fluoroscopic angulation for transcatheter interventions in patients with structural heart disease. It is further a key imaging modality in postprocedural assessment for prosthesis thrombosis, degeneration, or endocarditis. CT plays an integral part in the imaging work-up of novel transcatheter therapies for structural heart disease and postprocedural assessment for prosthesis thrombosis or endocarditis. This review provides a comprehensive overview of the key role of CT in the context of structural heart interventions.

Successful percutaneous closure of a recurrent aorto-left ventricular tunnel with an Amplatzer Vascular Plug II.

Aorto-left ventricular tunnel is an extremely rare CHD clinically impressing as aortic regurgitation. This is usually corrected surgically, sometimes by percutaneous catheter intervention. Recurrent aorto-left ventricular tunnel has been reported occasionally. Reports of percutaneous closure of such recurrent aorto-left ventricular tunnels are rare. We hereby describe successful closure of a recurrent aorto-left ventricular tunnel with an Amplatzer Vascular Plug II.

A Prospective, Multicentre Randomised Controlled Trial Comparing Catheter Ablation Versus Antiarrhythmic Drugs in Patients With Structural Heart Disease Related Ventricular Tachycardia: The CAAD-VT Trial Protocol.

IMPORTANCE: Randomised trials have shown that catheter ablation (CA) is superior to medical therapy for ventricular tachycardia (VT) largely in patients with ischaemic heart disease. Whether this translates to patients with all forms and stages of structural heart disease (SHD-e.g., non-ischaemic heart disease) is unclear. This trial will help clarify whether catheter ablation offers superior outcomes compared to medical therapy for VT in all patients with SHD. OBJECTIVE: To determine in patients with SHD and spontaneous or inducible VT, if catheter ablation is more efficacious than medical therapy in control of VT during follow-up. DESIGN: Randomised controlled trial including 162 patients, with an allocation ratio of 1:1, stratified by left ventricular ejection fraction (LVEF) and geographical region of site, with a median follow-up of 18-months and a minimum follow-up of 1 year. SETTING: Multicentre study performed in centres across Australia. PARTICIPANTS: Structural heart disease patients with sustained VT or inducible VT (n=162). INTERVENTION: Early treatment, within 30 days of randomisation, with catheter ablation (intervention) or initial treatment with antiarrhythmic drugs only (control). MAIN OUTCOMES, MEASURES, AND RESULTS: Primary endpoint will be a composite of recurrent VT, VT storm (≥3 VT episodes in 24 hrs or incessant VT), or death. Secondary outcomes will include each of the individual primary endpoints, VT burden (number of VT episodes in the 6 months preceding intervention compared to the 6 months after intervention), cardiovascular hospitalisation, mortality (including all-cause mortality, cardiac death, and non-cardiac death) and LVEF (assessed by transthoracic echocardiography from baseline to 6-, 12-, 24- and 36-months post intervention). CONCLUSIONS AND RELEVANCE: The Catheter Ablation versus Anti-arrhythmic Drugs for Ventricular Tachycardia (CAAD-VT) trial will help determine whether catheter ablation is superior to antiarrhythmic drug therapy alone, in patients with SHD-related VT. TRIAL REGISTRY: Australian New Zealand Clinical Trials Registry (ANZCTR) TRIAL REGISTRATION ID: ACTRN12620000045910 TRIAL REGISTRATION URL: https://www.anzctr.org.au/Trial/Registration/TrialReview.aspx?id=377617&isReview=true.