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Floating-Harbor syndrome (FHS) is a rare autosomal dominant syndrome characterized by short stature with delayed bone age, retarded speech development, intellectual disability and dysmorphic facial features. Recently, dominant mutations almost exclusively clustered in the final exon of the Snf2-related CREBBP activator protein (SRCAP) gene were identified to cause FHS. Here, we report a boy with short stature, speech delay, mild intellectual disability, dysmorphic features, and with genetically confirmed FHS. To the best of our knowledge, this is the first molecularly confirmed case with this syndrome reported in Romania. An intensive program of cognitive and speech stimulation, as well as yearly neurological, psychological, ophthalmological, otorhinolaryngological, pediatric and endocrinological monitoring for our patient were designed. We propose a checklist of clinical features suggestive of FHS, based on the main clinical features, in order to facilitate the diagnosis and clinical management of this rare condition.

Alexandre Rey,1 Martin Thoenes,1,2 Rolf Fimmers,3 Christoph A Meier,4 Peter Bramlage51Sanofi Aventis, Medical Department, Meyrin, Switzerland; 2Institute for Clinical Pharmacology, Medical Faculty Carl Gustav Carus, Technical University Dresden, Germany; 3Institut für Medizinische Biometrie, Informatik und Epidemiologie, Universität Bonn, Germany; 4Klinik für Innere Medizin, Stadtspital Triemli, Zürich, Switzerland; 5Institut für Pharmakologie und präventive Medizin, Mahlow, GermanyBackground: Diabetes represents one of the major health challenges in Switzerland, and early diagnosis and treatment is mandatory to prevent or delay diabetes-related morbidity and mortality. For the purpose of identifying affected individuals, early screening in pharmacies is a valuable option. In this survey, we aimed to determine blood glucose and metabolic control in an unselected population of individuals visiting Swiss pharmacies.Methods: The subjects responded to a short questionnaire and underwent a single capillary blood glucose test for screening purposes. They were classified as normal, indeterminate, impaired fasting glucose, and diabetes according to predefined blood glucose levels.Results: A total of 3135 individuals (mean age 56 years) in 18 cantons were screened in November 2010; of these, 4.2% (95% confidence interval [CI] 3.5–4.9) had previously been diagnosed with diabetes. Diabetes was newly diagnosed in 1.9% (95% CI 1.5–2.4), and 11.5% (95% CI 10.4–12.6) had impaired fasting glucose. Subjects with impaired glucose control had an increased body mass index, a frequent family history of diabetes, hypertension, hypercholesterolemia, smoking, and a low level of physical activity. Prevalence of impaired glucose control was different between the French/Italian-speaking part of Switzerland (new diabetes 4.9%; impaired fasting glucose 12.7%) and the German-speaking part (new diabetes 1.9%; impaired fasting glucose 10.3%).Conclusion: Our study shows a 6.1% prevalence of diabetes, of which about a third (1.9%) was previously undiagnosed, and 11.5% had impaired fasting glucose. Therefore, screening initiatives in pharmacies may be suitable for detecting people with undiagnosed diabetes.Keywords: diabetes, pharmacy, epidemiology, screening

Abstract Objectives The metabolic syndrome is a cluster of cardiovascular risk factors leading to an increased risk for the subsequent development of diabetes and cardiovascular morbidity and mortality. Blocking the renin-angiotensin system has been shown to prevent cardiovascular disease and delay the onset of diabetes. Irbesartan is an angiotensin receptor blocker (ARB) which has been shown to possess peroxisome proliferator-activated receptor gamma (PPARγ) activating properties, and to have a favorable metabolic profile. Current discussion is whether the addition of small doses of hydrochlorothiazide changes this profile. Therefore the efficacy, safety and metabolic profile of Irbesartan either as monotherapy or in combination therapy was assessed in patients with the metabolic syndrome in a large observational cohort in primary care. Research design and methods Multicenter, prospective, two-armed, post authorization study over 9 months in 14,200 patients with uncontrolled hypertension with and without the metabolic syndrome (doctors' diagnosis based on the Adult Treatment Panel III criteria 2001). Blood pressure was measured sphygmomanometrically and cardiovascular risk factors making up the criteria for the metabolic syndrome were assessed. Main outcome measures Systolic (SBP) and diastolic (DBP) blood pressure reduction, – response, and – normalization (systolic and diastolic), changes in fasting glucose, waist circumference (abdominal obesity), serum triglycerides and HDL cholesterol as well as the proportion of patients fulfilling the criteria for the metabolic syndrome. Number and nature of adverse events (AEs). Results After 9 month the use of Irbesartan in monotherapy resulted in a significant reduction of blood pressure (SBP: -26.3 ± 10.1 mmHg/DBP-13.0 ± 6.6 mmHg, both p < 0.0001) in patients with the metabolic syndrome. This was accompanied by a reduction in cardiovascular risk factors: HDL cholesterol (+3.6 ± 7.2 mg/dl in men, +3.8 ± 6.5 mg/dl in women, both p < 0.0001), serum triglycerides (-28.6 ± 52.1 mg/dl, p < 0.0001), fasting blood glucose (-8.4 ± 25.1 mg/dl, p < 0.0001) and waist circumference (-2.4 ± 11.9 cm in men, -1.2 ± 14.2 in women, both p < 0.0001) were significantly improved. Irbesartan combination therapy (12.5 mg HCTZ) in patients with the metabolic syndrome: blood pressure reduction (SBP: -27.5 ± 10.1 mmHg/DBP: -14.1 ± 6.6 mmHg, both p < 0.0001), improvement in HDL cholesterol (+4.0 ± 6.8 mg/dl in men, +3.4 ± 6.8 in women, both p < 0.0001), triglycerides (-34.1 ± 52.6 mg/dl, p < 0.0001), fasting blood glucose (-10.0 ± 24.7, p < 0.0001) and waist circumference (-3.2 ± 12.7 cm in men, -1.7 ± 14.4 in women, both p < 0.0001). Tolerability was excellent: only 0.6% of patients experienced an AE. Conclusion There was a significant improvement in blood pressure and metabolic risk factors as a result of Irbesartan treatment. There was no evidence of a difference between monotherapy and combination therapy with regard to the cardiovascular risk profile.

Introduction: Genome-wide association studies (GWAS) are fundamental for identifying loci associated with diseases. However, they require replication in other ethnicities., Methods: We performed GWAS on sporadic Alzheimer's disease (AD) including 539 patients and 854 controls from Argentina and Chile. We combined our results with those from the European Alzheimer and Dementia Biobank (EADB) in a meta-analysis and tested their genetic risk score (GRS) performance in this admixed population., Results: We detected apolipoprotein E ε4 as the single genome-wide significant signal (odds ratio  = 2.93 [2.37-3.63], P = 2.6 × 10 -23 ). The meta-analysis with EADB summary statistics revealed four new loci reaching GWAS significance. Functional annotations of these loci implicated endosome/lysosomal function. Finally, the AD-GRS presented a similar performance in these populations, despite the score diminished when the Native American ancestry rose., Discussion: We report the first GWAS on AD in a population from South America. It shows shared genetics modulating AD risk between the European and these admixed populations., Highlights: This is the first genome-wide association study on Alzheimer's disease (AD) in a population sample from Argentina and Chile. Trans-ethnic meta-analysis reveals four new loci involving lysosomal function in AD. This is the first independent replication for TREM2L, IGH-gene-cluster, and ADAM17 loci. A genetic risk score (GRS) developed in Europeans performed well in this population. The higher the Native American ancestry the lower the GRS values., (© 2023 The Authors. Alzheimer's & Dementia published by Wiley Periodicals LLC on behalf of Alzheimer's Association.)

The transcatheter aortic valve implantation (TAVI) treatment pathway is complex, leading to procedure-related delays. Dedicated TAVI coordinators can improve pathway efficiency. COORDINATE was a pilot observational prospective registry at three German centers that enrolled consecutive elective patients with severe aortic stenosis undergoing TAVI to investigate the impact a TAVI coordinator program. Pathway parameters and clinical outcomes were assessed before (control group) and after TAVI coordinator program implementation (intervention phase). The number of repeated diagnostics remained unchanged after implementation. Patients with separate hospitalizations for screening and TAVI had long delays, which increased after implementation (65 days pre- vs. 103 days post-implementation); hospitalizations combining these were more efficient. The mean time between TAVI and hospital discharge remained constant. Nurse ( p = 0.001) and medical technician ( p = 0.008) working hours decreased. Patient satisfaction increased, and more consistent/intensive contact between patients and staff was reported. TAVI coordinators provided more post-TAVI support, including discharge management. No adverse effects on post-procedure or 30-day outcomes were seen. This pilot suggests that TAVI coordinator programs may improve aspects of the TAVI pathway, including post-TAVI care and patient satisfaction, without compromising safety. These findings will be further investigated in the BENCHMARK registry.

Background: The Toronto Aortic Stenosis Quality of Life Questionnaire (TASQ) is a validated instrument for assessing quality of life (QoL) in patients with severe aortic stenosis (AS). In this study, we evaluated health status outcomes, based on the TASQ, in patients with severe AS undergoing transcatheter aortic valve replacement (TAVR) or surgical aortic valve replacement (SAVR)., Methods: The TASQ registry was a prospective observational registry. Patients with severe AS from nine centres in Europe and one in Canada underwent either SAVR or transfemoral TAVR. Patients completed the TASQ, Kansas City Cardiomyopathy Questionnaire and Short Form-12 V.2 prior to the intervention, predischarge, and at 30-day and 3-month follow-ups. Primary end point was the TASQ score., Results: In both the TAVR (n=137) and SAVR (n=137) cohorts, significant increases were observed in all three scores. The overall TASQ score improved as did all but one of the individual domains at 3 months after the intervention (p<0.001). TASQ health expectations were the only domain which worsened (p<0.001). Across TASQ subscores, significant changes were evident from the time of discharge in the TAVR and 30-day follow-up in the SAVR cohort. In a categorical analysis of the TASQ, 39.7% of the TAVR group and 35.0% of the SAVR group had a substantially improved health status at 3 months compared with baseline., Conclusions: The TASQ captured changes in QoL among patients with severe AS who were treated with TAVR or SAVR. QoL improved substantially after either intervention, as indicated by changes in the TASQ overall score at 3 months., Trial Registration Number: NCT03186339., Competing Interests: Competing interests: PB is the representative of the Institute for Pharmacology and Preventive Medicine, Cloppenburg, Germany. LS, JK and MT are employees of the funder. All centres were paid by IPPMed for the enrolment and documentation of patients., (© Author(s) (or their employer(s)) 2021. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Background: Degenerative aortic stenosis (AS), the most common valvular heart disease in the Western world, is often diagnosed late when the mortality risk becomes substantial. We determined the feasibility of AS screening during influenza vaccination at general practitioner (GP) surgeries in the UK., Methods: Consecutive subjects aged >65 years presenting to a GP for influenza vaccination underwent heart auscultation and 2D echocardiography (V-scan). Based on these findings, a patient management strategy was determined (referral to cardiologist, review within own practice or no follow-up measures) and status at 3 months was determined., Results: 167 patients were enrolled with a mean age of 75 years. On auscultation, a heart murmur was detected in 30 of 167 (18%) patients (6 subjects with an AS-specific and 24 with a non-specific murmur). 75.2% of those with no murmur had a negative V-scan finding. Conversely, 16 of 30 (53%) patients with any murmur had an abnormal V-scan finding that was largely related to the aortic valve. Using clinical auscultation and V-scan screening, a decision not to pursue follow-up measures was taken in 147 (88%) cases, whereas 18 (10.8%) subjects were referred onward; with 5 of 18 (27.8%) and 3 of 18 (16.7%) being diagnosed with mild and moderate AS., Conclusions: Our pilot study confirms feasibility of valvular heart disease screening in the elderly in a primary care setting. Using simple and inexpensive diagnostic measures and 7.3 million UK inhabitants undergoing influenza vaccination, nationwide screening could potentially identify 130 000 patients with moderate AS and a significant number of patients with severe AS., Competing Interests: Competing interests: PB is the representative of the IPPMed, Cloppenburg, Germany. RPS received honoraria for advisory board meetings and speakers’ honoraria from Edwards Lifesciences. MT is an employee of Edwards Lifesciences. AP, NM and CD have no conflicts of interest to disclose., (© Author(s) (or their employer(s)) 2021. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

APOE genotype is the strongest genetic risk factor for Alzheimer's Disease (AD). The low degree of homology between mouse and human APOE is a concerning issue in preclinical models currently used to study the role of this gene in AD pathophysiology. A key objective of ADAPTED (Alzheimer's Disease Apolipoprotein Pathology for Treatment Elucidation and Development) project was to generate in vitro models that better recapitulate human APOE biology. We describe a new set of induced pluripotent stem cells (iPSC) lines carrying common APOE variants (Ɛ2, Ɛ3, and Ɛ3/Ɛ4) and a knock-out isogenic to the parental APOE Ɛ4/Ɛ4 line (UKBi011-A)., (Copyright © 2021 Janssen Pharmaceutica, NV. Published by Elsevier B.V. All rights reserved.)

Aims: There is no quality of life tool specifically developed for patients with severe aortic stenosis (AS) to assess how this chronic condition and its treatment affect patients. The Toronto Aortic Stenosis Quality of Life Questionnaire (TASQ) has been developed to overcome this gap. The results of the validation of the TASQ in patients undergoing treatment for severe AS are presented., Methods and Results: Prospective study at 10 centres in Europe and Canada, which enrolled 274 patients with severe symptomatic AS undergoing surgical or transcatheter aortic valve replacement. Mean TASQ score at baseline was 71.2 points and increased to 88.9 three months after aortic valve implantation (P < 0.001). Increases were seen for the emotional impact (32.0 to 39.0; P < 0.001), physical limitations (14.8 to 22.0; P < 0.001), and physical symptoms (8.5 vs. 11.0; P < 0.001) domains. Internal consistency was good/excellent for overall TASQ score (α = 0.891) and for the physical limitation, emotional impact, and social limitation domains (α = 0.815-0.950). Test-retest reliability was excellent or strong for the overall TASQ (intraclass correlation coefficient of 0.883) and for the physical symptoms, physical limitation, emotional impact, and social limitation domains (intraclass correlation coefficient of 0.791-0.895). Responsiveness was medium overall (Cohen's d = 0.637) and medium/large for physical symptoms, emotional impact, and physical limitations (0.661-0.812). Sensitivity to change was significant for physical symptoms, physical limitations (both P < 0.001), emotional impact (P = 0.003), and social limitations (P = 0.038)., Conclusions: The TASQ is a new, brief, self-administered, and clinically relevant health-specific tool to measure changes in quality of life in patients with AS undergoing an intervention., (© 2020 The Authors. ESC Heart Failure published by John Wiley & Sons Ltd on behalf of the European Society of Cardiology.)

Objective: Approximately 3.4% of adults aged >75 years suffer from aortic stenosis (AS). Guideline indications for aortic valve replacement (AVR) distinguish between patients with symptomatic and asymptomatic severe AS. The present analysis aims to assess contemporary practice in the treatment of severe AS across Europe and identify characteristics associated with treatment decisions, namely denial of AVR in symptomatic patients and assignment of asymptomatic patients to AVR., Methods: Participants of the prospective, multinational IMPULSE database of patients with severe AS were grouped according to AS symptoms, and stratified into subgroups based on assignment to/denial of AVR., Results: Of 1608 symptomatic patients, 23.8% did not undergo AVR and underwent medical treatment. Denial was independently associated with multiple factors, including severe frailty (p=0.024); mitral (p=0.002) or tricuspid (p=0.004) regurgitation grade III/IV, and the presence of renal impairment (p=0.017). Of 392 asymptomatic patients, 86.5% had no prespecified indication for AVR. Regardless, 36.3% were assigned to valve replacement. Those with an indexed aortic valve area (AVA; p=0.045) or left ventricular ejection fraction (LVEF; p<0.001) below the study median; or with a left ventricular end systolic diameter above the study median (p=0.007) were more likely to be assigned to AVR., Conclusions: There may be considerable discrepancies between guideline-based recommendations and clinical practice decision-making in the treatment of AS. It appears that guidelines may not fully capture the complete clinical spectrum of patients with AS. Thus, there is a need to find ways to increase their acceptance and the rate of adoption., Competing Interests: Competing interests: Peter Bramlage received research funding from Edwards Lifesciences, Nyon, Switzerland. Norbert Frey, Rick Steeds and David Messika-Zeitoun have received honoraria for advisory board meetings and Tanja Rudolph speakers’ honoraria from Edwards Lifesciences. The institutions of these three and those of the remaining authors representing study centres have received funding for employing a study nurse., (© Author(s) (or their employer(s)) 2021. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Valvular heart disease (VHD) is a chronic progressive condition with an increasing prevalence in the Western world due to aging populations. VHD is often diagnosed at a late stage when patients are symptomatic and the outcomes of therapy, including valve replacement, may be sub-optimal due the development of secondary complications, including left ventricular (LV) dysfunction. The clinical application of artificial intelligence (AI), including machine learning (ML), has promise in supporting not only early and more timely diagnosis, but also hastening patient referral and ensuring optimal treatment of VHD. As physician auscultation lacks accuracy in diagnosis of significant VHD, computer-aided auscultation (CAA) with the help of a commercially available digital stethoscopes improves the detection and classification of heart murmurs. Although used little in current clinical practice, CAA can screen large populations at low cost with high accuracy for VHD and faciliate appropriate patient referral. Echocardiography remains the next step in assessment and planning management and AI is delivering major changes in speeding training, improving image quality by pattern recognition and image sorting, as well as automated measurement of multiple variables, thereby improving accuracy. Furthermore, AI then has the potential to hasten patient disposal, by automated alerts for red-flag findings, as well as decision support in dealing with results. In management, there is great potential in ML-enabled tools to support comprehensive disease monitoring and individualized treatment decisions. Using data from multiple sources, including demographic and clinical risk data to image variables and electronic reports from electronic medical records, specific patient phenotypes may be identified that are associated with greater risk or modeled to the estimate trajectory of VHD progression. Finally, AI algorithms are of proven value in planning intervention, facilitating transcatheter valve replacement by automated measurements of anatomical dimensions derived from imaging data to improve valve selection, valve size and method of delivery., Competing Interests: Conflicts of Interest: All authors have completed the ICMJE uniform disclosure form (available at http://dx.doi.org/10.21037/jtd-20-1837). M Thoenes reports other from Edwards Lifesciences, outside the submitted work. P Bramlage reports grants and personal fees from Edwards Lifesciences, outside the submitted work. RP Steeds reports grants and personal fees from Edwards Lifesciences, outside the submitted work. The other authors have no conflict of interest to declare., (2021 Journal of Thoracic Disease. All rights reserved.)

Aims: There is an increasing awareness of gender-related differences in patients with severe aortic stenosis and their outcomes after surgical aortic valve replacement (SAVR) and transcatheter aortic valve implantation (TAVI)., Methods: Data from the IMPULSE registry were analysed. Patients with severe aortic stenosis (AS) were enrolled between March 2015 and April 2017 and stratified by gender. A subgroup analysis was performed to assess the impact of age., Results: Overall, 2171 patients were enrolled, and 48.0% were female. Women were characterised by a higher rate of renal impairment (31.7 vs 23.3%; p<0.001), were at higher surgical risk (EuroSCORE II: 4.5 vs 3.6%; p=0.001) and more often in a critical preoperative state (7.0vs 4.2%; p=0.003). Men had an increased rate of previous cardiac surgery (9.4 vs 4.7%; p<0.001) and a reduced left ventricular ejection fraction (4.9 vs 1.3%; p<0.001). Concomitant mitral and tricuspid valve disease was substantially more common among women. Symptoms were highly prevalent in both women and men (83.6 vs 77.3%; p<0.001). AVR was planned in 1379 cases. Women were more frequently scheduled to undergo TAVI (49.3 vs 41.0%; p<0.001) and less frequently for SAVR (20.3 vs 27.5%; p<0.001)., Conclusions: The present data show that female patients with severe AS have a distinct patient profile and are managed in a different way to males. Gender-based differences in the management of patients with severe AS need to be taken into account more systematically to improve outcomes, especially for women., Competing Interests: Competing interests: PB is the representative of the IPPMed, Cloppenburg, Germany. NF, RPS and DM-Z have received honoraria for advisory board meetings and TKR speakers’ honoraria from Edwards Lifesciences. The institutions of these three and those of the remaining authors representing study centres have received funding for employing a study nurse. JK and MT are employees of the funder of this registry. As this is a disease registry, neither the type of intervention (SAVR, TAVI or medical management) nor on the valves to be used was pre-specified., (© Author(s) (or their employer(s)) 2021. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Background: An investigation into differences in the management and treatment of severe aortic stenosis (AS) between Germany, France and the UK may allow benchmarking of the different healthcare systems and identification of levers for improvement., Methods: Patients with a diagnosis of severe AS under management at centres within the IMPULSE and IMPULSE enhanced registries were eligible., Results: Data were collected from 2052 patients (795 Germany; 542 France; 715 UK). Patients in Germany were older (79.8 years), often symptomatic (89.5%) and female (49.8%) and had a lower EF (53.8%) than patients in France and UK. Comorbidities were more common and they had a higher mean Euroscore II.Aortic valve replacement (AVR) was planned within 3 months in 70.2%. This was higher (p<0.001) in Germany than France/ UK. Of those with planned AVR, 82.3% received it within 3 months with a gradual decline (Germany>France> UK; p<0.001). In 253 patients, AVR was not performed, despite planned. Germany had a strong transcatheter aortic valve implantation (TAVI) preference (83.2%) versus France/ UK (p<0.001). Waiting time for TAVI was shorter in Germany (24.9 days) and France (19.5 days) than UK (40.3 days).Symptomatic patients were scheduled for an AVR in 79.4% (Germany> France> UK; p<0.001) and performed in 83.6% with a TAVI preference (73.1%). 20.4% of the asymptomatic patients were intervened., Conclusion: Patients in Germany had more advanced disease. The rate of intervention within 3 months after diagnosis was startlingly low in the UK. Asymptomatic patients without a formal indication often underwent an intervention in Germany and France., Competing Interests: Competing interests: PB has received research funding for the present project and honoraria for consultancy from Edwards Lifesciences. NF, RPS and DM-Z have received honoraria for advisory board meetings and TKR speakers’ honoraria from Edwards Lifesciences. The institutions of these three and those of the remaining authors representing study centers have received funding for employing a study nurse., (© Author(s) (or their employer(s)) 2020. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Background Despite the availability of guidelines for the performance of transcatheter aortic valve implantation (TAVI), current treatment pathways vary between countries and institutions, which impact on the mean duration of postprocedure hospitalization. Methods and Results This was a prospective, multicenter registry of 502 patients to validate the appropriateness of discharge timing after transfemoral TAVI, using prespecified risk criteria from FAST-TAVI (Feasibility and Safety of Early Discharge After Transfemoral [TF] Transcatheter Aortic Valve Implantation), based on hospital events within 1-year after discharge. The end point-a composite of all-cause mortality, vascular access-related complications, permanent pacemaker implantation, stroke, cardiac rehospitalization, kidney failure, and major bleeding-was reached in 27.0% of patients (95% CI, 23.3-31.2) within 1 year after intervention; 7.5% (95% CI, 5.5-10.2) had in-hospital complications before discharge and 19.6% (95% CI, 16.3-23.4) within 1 year after discharge. Overall mortality within 1 year after discharge was 7.3% and rates of cardiac rehospitalization 13.5%, permanent pacemaker implantation 4.2%, any stroke 1.8%, vascular-access-related complications 0.7%, life-threatening bleeding 0.7%, and kidney failure 0.4%. Composite events within 1 year after discharge were observed in 18.8% and 24.3% of patients with low risk of complications/early (≤3 days) discharge and high risk and discharged late (>3 days) (concordant discharge), respectively. Event rate in patients with discordant discharge was 14.3% with low risk but discharged late and increased to 50.0% in patients with high risk but discharged in ≤3 days. Conclusions The FAST-TAVI risk assessment provides a tool for appropriate, risk-based discharge that was validated with the 1-year event rate after transfemoral TAVI. Registration URL: https://www.ClinicalTrials.gov; Unique identifier: NCT02404467.

Aortic stenosis (AS) is a progressive and degenerative disease that necessitates valve replacement through either surgical aortic valve replacement (SAVR) or transcatheter aortic valve replacement (TAVR). Various studies have shown that, unlike for TAVR, SAVR is associated with an elevated risk for women as compared to men. The aim of this review is to better understand the risks and their possible causes, associated with the use of both TAVR and SAVR in female patients. Our systematic review included studies published between 2012 and 2020, identified through specific searches of PubMed. Compatibility of publications, determined by the use of pre-defined inclusion/exclusion criteria, resulted in 15 articles being used in our review. Overall, more men than women undergo SAVR, but our findings confirmed that SAVR is associated with worse outcomes in women in the short-term. Reasons for a higher 30-day mortality post-SAVR in women include an increased age, higher in-hospital mortality and, possibly baseline comorbidities and anatomical differences. There was no difference observed in 30-day mortality between men and women undergoing TAVR. Female patients appear to have a better longer-term survival post-TAVR than their male counterparts. Understanding the reasons why women have worse outcomes post-SAVR is essential for ensuring appropriate treatment selection for patients with AS, as well as for achieving the best possible long-term and safety outcomes for these patients., Competing Interests: Conflicts of Interest: All authors have completed the ICMJE uniform disclosure form (available at http://dx.doi.org/10.21037/jtd-20-700). MT is an employee of Edwards Lifesciences. PB reports grants and other from Edwards Lifesciences, outside the submitted work.The authors have no other conflicts of interest to declare., (2020 Journal of Thoracic Disease. All rights reserved.)

Background: Contemporary data regarding the impact of comorbidities on the clinical presentation and management of patients with severe aortic stenosis (AS) are scarce., Methods: Prospective registry of severe patients with AS across 23 centres in nine European countries., Results: Of the 2171 patients, chronic kidney disease (CKD 27.3%), left ventricular ejection fraction (LVEF) <50% (22.0%), atrial fibrillation (15.9%) and chronic obstructive pulmonary disease (11.4%) were the most prevalent comorbidities (49.3% none, 33.9% one and 16.8% ≥2 of these). The decision to perform aortic valve replacement (AVR) was taken in a comparable proportion (67%, 72% and 69%, in patients with 0, 1 and ≥2 comorbidities; p=0.186). However, the decision for TAVI was more common with more comorbidities (35.4%, 54.0% and 57.0% for no, 1 and ≥2; p<0.001), while the decision for surgical AVR (SAVR) was decreased with increasing comorbidity burden (31.9%, 17.4% and 12.3%; p<0.001). The proportion of patients with planned AVRs that were performed within 3 months was significantly higher in patients with 1 or ≥2 comorbidities than in those without (8.7%, 10.0% and 15.7%; p<0.001). Furthermore, the mean time to AVR was significantly shorter in patients with one (30.5 days) or ≥2 comorbidities (30.8 days) than in those without (35.7 days; p=0.012). Patients with reduced LVEF tended to be offered an AVR more frequently and with a shorter delay while patients with CKD were less frequently treated., Conclusions: Comorbidities in severe patients with AS affect the presentation and management of patients with severe AS. TAVI was offered more often than SAVR and performed within a shorter time period., Competing Interests: Competing interests: PB is the representative of the IPPMed, Cloppenburg, Germany. NF, RPS, DM-Z and TKR are consultants to Edwards Lifesciences. The institutions of these three and those of the remaining authors representing study centres have received funding for employing a study nurse., (© Author(s) (or their employer(s)) 2020. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Background: Predilation of the native valve has long been deemed necessary in transfemoral transcatheter aortic valve implantation (TF-TAVI), despite little trial evidence to support its clinical use. As most evidence is derived from retrospective analyses of observational studies, we conducted a two-armed, prospective multicentre registry., Methods: Patients undergoing TF-TAVI with the Edwards SAPIEN 3 valve, with or without balloon aortic valvuloplasty (BAV), were included and their procedural characteristics, short-term safety and short-term efficacy outcomes compared. We hypothesised that BAV may be safely omitted in many patients and omission could be associated with procedural benefits., Results: Overall, 196 consecutive patients underwent TF-TAVI, 56 with BAV and 140 without. The mean age was 81.2±6.2 years, and the mean logistic EuroSCORE I was 17.1±13.6. Device success according to Valve Academic Research Consortium-2 (VARC-2) was achieved in 96.4%. The median procedural duration was shorter without BAV (56 min vs 90 min; p=0.001), as was fluoroscopy time (10 min vs 13 min; p=0.001). The need for balloon postdilation was less frequent in patients without BAV (15.7% vs 30.4%, p=0.029). There was no difference in the proportion of patients meeting the VARC-2 defined composite safety endpoint at 30 days (9.3% without vs 8.9% with BAV; adjusted OR (adjOR) 2.55; 95% CI 0.56 to 18.84) and at 6 months (15.2% without vs 16.4% with BAV; adjOR 1.66; 95% CI 0.49 to 6.55)., Conclusions: In the majority of patients, BAV can be safely omitted from the TAVI procedure without adverse effects. The omission of BAV is associated with shorter procedural duration and could be advantageous for the majority of patients., Trial Registration Number: NCT02760771., Competing Interests: Competing interests: PB is the representative of the Institute for Pharmacology and Preventive Medicine, Cloppenburg (IPPMed), Germany. A research grant was provided by Edwards Lifescience, Nyon, Switzerland, to the Sponsor IPPMed. CB, TR, CJ, JR, HT, SK, DF and GS have received consultancy fees from different companies producing heart valves. LS and MTs are employees of Edwards Lifesciences., (© Author(s) (or their employer(s)) 2019. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Background Many patients with severe aortic stenosis are referred late with advanced symptoms or inappropriately denied intervention. The objective was to investigate whether a structured communication to referring physicians (facilitated data relay) might improve the rate and timeliness of intervention. Methods and Results A prospective registry of consecutive patients with severe aortic stenosis at 23 centers in 9 European countries with transcatheter as well as surgical aortic valve replacement being available was performed. The study included a 3-month documentation of the status quo (phase A), a 6-month intervention phase (implementing facilitated data relay), and a 3-month documentation of a legacy effect (phase-B). Two thousand one hundred seventy-one patients with severe aortic stenoses were enrolled (phase A: 759; intervention: 905; phase-B: 507). Mean age was 77.9±10.0 years, and 80% were symptomatic, including 52% with severe symptoms. During phase A, intervention was planned in 464/696 (67%), 138 (20%) were assigned to watchful waiting, 8 (1%) to balloon aortic valvuloplasty, 60 (9%) were listed as not for active treatment, and in 26 (4%), no decision was made. Three hundred sixty-three of 464 (78%) patients received the planned intervention within 3 months. Timeliness of the intervention improved as shown by the higher number of aortic valve replacements performed within 3 months (59% versus 51%, P =0.002) and a significant decrease in the time to intervention (36±38 versus 30±33 days, P =0.002). Conclusions A simple, low-cost, facilitated data relay improves timeliness of treatment for patients diagnosed with severe aortic stenosis, resulting in a shorter time to transcatheter aortic valve replacement. This effect was mainly driven by a significant improvement in timeliness of intervention in transcatheter aortic valve replacement but not surgical aortic valve replacement. Clinical Trial Registration URL: https://www.clinicaltrials.gov/. Unique identifier: NCT02241447.

Background: Severe aortic stenosis (AS) is one of the most common and most serious valve diseases. Without timely intervention with surgical aortic valve replacement or transcatheter aortic valve replacement, patients have an estimated survival of 2-3 years. Guidelines for the treatment of AS have been developed, but studies suggest that as many as 42% of patients with AS are not treated according to these recommendations.The aims of this registry are to delineate the caseload of patients with AS, outline the management of these patients and determine appropriateness of treatments in participating centres with and without onsite access to surgery and percutaneous treatments., Methods/design: The IMPULSE enhanced registry is an international, multicentre, prospective, observational cohort registry conducted at four central full access centres (tertiary care hospitals) and at least two satellite centres per hub (primary/secondary care hospitals). An estimated 800 patients will be enrolled in the registry and patient follow-up will last for 12 months., Discussion: In addition to the primary aims determining the caseload management and outcome of patients with AS in primary, secondary and tertiary care settings, the registry will also determine a time course for the transition from asymptomatic to symptomatic status and the diagnostic steps, treatment decisions and the identification of decision-makers in tertiary versus primary/secondary care hospitals. The last patient will be enrolled in the registry in 2018 and results of the registry are anticipated in 2019., Registration Number: NCT03112629., Competing Interests: Competing interests: PB is the representative of the IPPMed, Cloppenburg, Germany. IPPMed has received research funding and honoraria for consultancy from Edwards Lifesciences. TKR, NF, ML, RPS and DM-Z received honoraria for advisory board meetings from Edwards Lifesciences. The institutions of these received funding for employing a study nurse.

Background: To evaluate the outcomes of transcatheter aortic valve implantation (TAVI) without balloon aortic valvuloplasty (BAV) in a real-world setting through a patient-level meta-analysis., Methods: The meta-analysis included patients of three European multicenter, prospective, observational registry studies that compared outcomes after Edwards SAPIEN 3 or XT TAVI with (n = 339) or without (n = 355) BAV. Unadjusted and adjusted pooled odds ratios (with 95% confidence intervals) were calculated for procedural and 30-day outcomes., Results: Median procedural time was shorter in the non-BAV group than in the BAV group (73 versus 93 min, p = 0.001), as was median fluoroscopy time (7 versus 11 min, p = 0.001). Post-delivery balloon dilation (15.5% versus 22.4%, p = 0.02) and catecholamine use (9.0% vs. 17.9%; p = 0.016) was required less often in the non-BAV group than in the BAV group with the difference becoming insignificant after multiple adjustment. There was a reduced risk for periprocedural atrioventricular block during the intervention (1.4% versus 4.1%, p = 0.035) which was non-significant after adjustment. The rate of moderate/severe paravalvular regurgitation post-TAVI was 0.6% in the no-BAV group versus 2.7% in the BAV group. There were no between-group differences in the risk of death, stroke or other adverse clinical outcomes at day 30., Conclusions: This patient-level meta-analysis of real-world data indicates that TAVI performed without BAV is advantageous as it has an adequate device success rate, reduced procedure time and no adverse effects on short-term clinical outcomes.

Background: In a three-month report from the CGA-TAVI registry, we found the Multidimensional Prognostic Index (MPI) and Short Physical Performance Battery (SPPB) to be of value for predicting short-term outcomes in elderly patients undergoing transcatheter aortic valve implantation (TAVI). In the present analysis, we examined the association of these tools with outcomes up to one year post-TAVI., Methods: CGA-TAVI is an international, observational registry of geriatric patients undergoing TAVI. Patients were assessed using the MPI and SPPB. Efficacy of baseline values and any postoperative change for predicting outcome were established using logistic regression. Kaplan-Meier analysis was carried out for each comprehensive geriatric assessment tool, with survival stratified by risk category., Results: One year after TAVI, 14.1% of patients deceased, while 17.4% met the combined endpoint of death and/or non-fatal stroke, and 37.7% the combined endpoint of death and/or hospitalisation and/or non-fatal stroke. A high-risk MPI score was associated with an increased risk of all-cause mortality (aOR = 36.13, 95% CI: 2.77-470.78, P = 0.006) and death and/or non-fatal stroke (aOR = 10.10, 95% CI: 1.48-68.75, P = 0.018). No significant associations were found between a high-risk SPPB score and mortality or two main combined endpoints. In contrast to a worsening SPPB, an aggravating MPI score at three months post-TAVI was associated with an increased risk of death and/or non-fatal stoke at one year (aOR = 95.16, 95% CI: 3.41-2657.01)., Conclusions: The MPI showed value for predicting the likelihood of death and a combination of death and/or non-fatal stroke by one year after TAVI in elderly patients.

Background: Patients with severe aortic stenosis (AS) have a reduced life expectancy and quality of life (QoL), owing to advanced age and the presence of multiple comorbidities. Currently, there is no AS-specific QoL measurement tool, which prevents an accurate assessment of how this chronic condition and its treatment affect patients. The Toronto Aortic Stenosis Quality of Life Questionnaire (TASQ) was developed in order to address this deficiency., Methods: The present trial protocol was designed to enable validation of the TASQ, which has been produced in five languages (English, French, German, Italian and Spanish) to increase usability. Patients with severe AS who are undergoing surgical aortic valve replacement (SAVR) or transcatheter aortic valve implantation (TAVI) will be asked to complete the TASQ and, for comparative purposes, the Kansas City Cardiomyopathy Questionnaire and the general health-related QoL Short Form-12 questionnaire. The questionnaires will be completed prior to the intervention, at discharge, as well as at 30 days and 3 months follow-up. A total of 290 patients will be recruited across one Canadian and nine European centres. Overall, the protocol validation aims to include 120 patients undergoing transfemoral TAVI (TF-TAVI), 120 undergoing SAVR and up to 50 being treated medically. The primary objective of the registry is to validate the TASQ in five different languages. The secondary objective is to assess the utility of the TASQ for assessing differences in QoL outcome between patients undergoing TF-TAVI, SAVR or medical management for their AS., Discussion: Validation and roll-out of the TASQ will enable clinicians to capture an accurate assessment of how AS and its management affects the QoL of patients and will help them to determine the most appropriate treatment strategy for individual patients., Trial Registration Number: NCT03186339., Competing Interests: Competing interests: PB is the representative of the Institute for Pharmacology and Preventive Medicine, Cloppenburg, Germany. All centres were paid by IPPMed for the enrolment and documentation of patients.

Objectives: There is lack of data regarding the longer-term outcomes of patients undergoing transaortic (TAo) transcatheter aortic valve implantation (TAVI). We aimed to provide a contemporary snapshot of the types and frequencies of events in the year following TAo-TAVI., Methods: The Registry of the Utilization of the TAo-TAVI approach using the Edwards SAPIEN Valve (ROUTE) is a multicentre, European, prospective, observational registry of aortic stenosis patients undergoing TAo-TAVI. Patients were grouped according to the composite end point death, myocardial infarction, stroke/transient ischaemic attack, major vascular complications, life-threatening bleeding, acute kidney injury (AKI) and/or cardiovascular rehospitalization., Results: Two hundred and fifty-three patients with a mean age of 81.5 ± 5.8 years were included, of whom 89 (35.2%) patients met the composite end point (the event group) and 164 (64.8%) patients did not (the event-free group). New York Heart Association (NYHA) class III/IV (85.2% vs 71.8%, P = 0.017), Canadian Cardiovascular Society angina class III/IV (22.6% vs 11.4%; P = 0.021), pulmonary disease (32.6% vs 18.9%; P = 0.015) and renal insufficiency (15.7% vs 3.0%; P < 0.001) were more common in the event group. At 1 year, the most common event was death (19.1%), followed by AKI stage II or III (14.7%). The baseline renal insufficiency was the strongest independent predictor of composite end point achievement [odds ratio (OR) 7.55, 95% confidence interval (CI) 2.33-24.56], followed by NYHA class III/IV (OR 2.316, 95% CI 1.06-5.06) and pulmonary disease (OR 2.91, 95% CI 1.45-5.85). Pulmonary disease was also an independent predictor of 1-year mortality (OR 3.01, 95% CI 1.34-6.75)., Conclusions: Long-term outcomes after TAo-TAVI appear to be similar to those for TAVI via other non-transfemoral access routes. Awareness of characteristics associated with poorer outcomes may aid patient selection and identification of those requiring closer post-procedural monitoring., Clinical Trial Registration Number: ClinicalTrials.gov identifier: NCT01991431., (© The Author(s) 2018. Published by Oxford University Press on behalf of the European Association for Cardio-Thoracic Surgery. All rights reserved.)

Transcatheter heart valve interventions have transformed the outcomes of patients with valvular heart disease (VHD) who are unfavourable candidates for surgery. Technological advances have allowed extension of these interventions to younger or lower risk patients and those with other forms of VHD and may in the future permit earlier treatment of VHD in less symptomatic patients or those with moderate disease. The balance of risks and benefits is likely to differ between lower and higher risk patients, and more evidence is needed to evaluate the net benefit of transcatheter technology in these groups. As academic researchers, clinicians, industry, and patient stakeholders collaborate to research these broader indications for transcatheter valve interventions, it is essential to address (i) device durability and deliverability, (ii) specific anatomical needs (e.g. bicuspid aortic valves, aortic regurgitation, mitral and tricuspid valve disease), (iii) operator training, and (iv) the reinforced importance of the multidisciplinary Heart Team.

In Europe, approximately one million people over 75 years suffer from severe aortic stenosis (AS), one of the most serious and most common valve diseases, and this disease burden is increasing with the aging population. A diagnosis of severe symptomatic AS is associated with an average life expectancy of 2-3 years and necessitates a timely valve intervention. Guidelines for valve replacement therapy have been established but only a proportion of patients with symptomatic AS actually receive this life-saving treatment. The decision for valve intervention in asymptomatic patients with severe AS is often more challenging and likely results in fewer patients receiving treatment in comparison to their symptomatic counterparts. This article reviews the epidemiology and clinical manifestations of AS, the associated economic burden of AS to the healthcare system, the diagnosis of AS and the possible mechanisms for the introduction of routine screening in elderly patients. Elderly patients typically visit healthcare providers more frequently than younger patients, thereby providing increased opportunities for ad hoc AS screening and this, along with raising patient awareness of the symptoms of AS, has the potential to result in the earlier diagnosis and treatment of AS and increased patient survival., Competing Interests: Conflicts of Interest: M Thoenes and J Kurucova are employees of Edwards Lifesciences. The other authors have no conflicts of interest to declare.

Background: Transcatheter aortic valve implantation (TAVI) is the standard therapy for high-risk patients with aortic stenosis (AS). TAVI-outcomes are widely investigated in comparison to surgical aortic valve replacement (SAVR), but less is known about infectious complications after TAVI. We aimed to compare early and mid-term infectious outcomes of patients undergoing TAVI or SAVR., Methods: The present study is a prospective single-centre study including 200 consecutive patients between 06/2014-03/2015 undergoing TAVI (either transfemoral or transapical and transaortic, n=47+53=100) or SAVR (either isolated or concomitant with CABG, n=52+48=100). The mean age and log. EuroSCORE were significantly different between both groups (81±6 versus 69±11 years, P<0.001 and 23.1%±13.8% versus 8.7%±9.5%, P<0.001). Primary endpoints included wound healing disorders, respiratory and urinary tract infections and incidence of endocarditis or sepsis within hospital stay. Secondary endpoints included infectious parameters, infectious related rehospitalisation and 2-year mortality., Results: Primary endpoints showed no difference in overall TAVI- versus SAVR-groups regarding respiratory- (14% versus 19%, P=0.45), urinary-tract (7% versus 4%, P=0.54) infections, sepsis (5% versus 6%, P=1.0), endocarditis (0% versus 1%, P=1.0) or 30-day mortality (10% versus 4%, P=0.09), except for wound disorders, which were significantly lower in the TAVI-group (1% versus 8%, P=0.035), respectively. Secondary endpoints reported no difference regarding infectious related rehospitalisation (4% versus 4%, P=1.0), but significantly higher 2-year mortality (28% versus 16%, P=0.048) in the TAVI-group., Conclusions: So far, little has been studied about infectious complications after TAVI. This study reports no difference between the overall TAVI and SAVR groups regarding infectious complications. However, SAVR group show more wound healing disorders but less mortality than TAVI group., Competing Interests: Conflicts of Interest: This work was presented at the 65th annual meeting of the European Society of Cardiovascular Surgery, April 2016, Belgrade, Serbia.

Objectives: To assess safety and efficacy of transapical transcatheter aortic valve implantation (TA-TAVI) in the absence of predilation using balloon aortic valvuloplasty (BAV). Predilation of the stenosed valve using BAV is a routine step in TA-TAVI; however, evidence supporting its clinical value is lacking, and several studies have linked it with higher complication rates., Methods: A prospective, two-armed, multicentre registry (EASE-IT TA) to gather data on patients undergoing TA-TAVI with or without BAV, using the Edwards SAPIEN 3 valve was designed. The primary evaluation criterion was a composite of all-cause mortality, non-fatal stroke, non-fatal myocardial infarction, acute kidney injury and pacemaker implantation [per Valve Academic Research Consortium-2 (VARC-2)] within 30 days after TAVI., Results: A total of 198 subjects underwent TA-TAVI, 61 with and 137 without BAV. Patient characteristics were comparable at baseline (mean ± SD: age 80.3 ± 5.7 years; logistic EuroSCORE 20.2 ± 12.6). Similar reductions in peak and mean transvalvular gradients were observed post-procedurally. There was a significant reduction of fluoroscopy time without BAV (4.7 vs 7.9 min; P = 0.039) and significantly decreased odds of catecholamine administration (17.5% vs 32.8%; P = 0.017). A decreased odds of the primary evaluation criterion in patients without BAV after 30 days (adjusted odds ratio 0.71; 95% confidence interval 0.34-1.82) and the same composite end-point after 6 months (adjusted odds ratio 0.74; 95% confidence interval 0.37-1.47) were not significant even after multivariable adjustment., Conclusions: TA-TAVI without BAV appears to be at least equal to its conventional counterpart in terms of efficacy and may offer advantages in terms of safety. Thus, there appears to be little justification for maintaining the BAV step in TA-TAVI for many patients.

Objective: It has been reported that balloon aortic valvuloplasty immediately before transfemoral or transapical transcatheter aortic valve implantation has mostly little to no clinical value. We aimed to provide data on the need for balloon aortic valvuloplasty in patients undergoing transaortic transcatheter aortic valve implantation., Methods: Patients undergoing transaortic transcatheter aortic valve implantation with the Edwards SAPIEN XT (Nyon, Switzerland) or 3 transcatheter heart valve were prospectively included at 18 sites across Europe. In the present analysis, we compare the periprocedural and 30-day outcomes of patients undergoing conventional (+ balloon aortic valvuloplasty) versus direct (- balloon aortic valvuloplasty) transaortic transcatheter aortic valve implantation., Results: Of the 300 patients enrolled, 222 underwent conventional and 78 underwent direct transaortic transcatheter aortic valve implantation. Peak and mean transvalvular gradients were improved in both groups with no significant difference between groups. Procedural duration, contrast agent volume, and requirement for postdilation were also comparable. A trend toward fewer periprocedural complications was evident in the direct group (3.9% vs 11.3%; P = .053), with significantly lower rates of permanent pacemaker implantation (0% vs 5.0%; P = .034). Balloon aortic valvuloplasty omission had no significant effect on any of the 30-day safety and efficacy outcomes, including Valve Academic Research Consortium-2 composite end points (early safety events: 22.7% vs 17.4%, odds ratio, 1.17, 95% confidence interval, 0.53-2.62; clinical efficacy events: 20.5% vs 18.7%, odds ratio, 1.14, 95% confidence interval, 0.51-2.55)., Conclusions: For many patients, balloon aortic valvuloplasty predilation seems to have little clinical value in transaortic transcatheter aortic valve implantation using a balloon expandable transcatheter valve and may result in a higher rate of periprocedural complications, particularly in terms of permanent pacemaker implantation., (Copyright © 2017 The American Association for Thoracic Surgery. Published by Elsevier Inc. All rights reserved.)

Background: In older patients with aortic stenosis (AS) undergoing TAVI, the potential role of prior CGA is not well established. To explore the value of comprehensive geriatric assessment (CGA) for predicting mortality and/or hospitalisation within the first 3 months after transcatheter aortic valve implantation (TAVI)., Methods: An international, multi-centre, prospective registry (CGA-TAVI) was established to gather data on CGA results and medium-term outcomes in geriatric patients undergoing TAVI. Logistic regression was used to evaluate the predictive value of a multidimensional prognostic index (MPI); a short physical performance battery (SPPB); and the Silver Code, which was based on administrative data, for predicting death and/or hospitalisation in the first 3 months after TAVI (primary endpoint)., Results: A total of 71 TAVI patients (mean age 85.4 years; mean log EuroSCORE I 22.5%) were enrolled. Device success according to VARC criteria was 100%. After adjustment for selected baseline characteristics, a higher (poorer) MPI score (OR: 3.34; 95% CI: 1.39-8.02; p = 0.0068) and a lower (poorer) SPPB score (OR: 1.15; 95% CI: 1.01-1.54; p = 0.0380) were found to be associated with an increased likelihood of the primary endpoint. The Silver Code did not show any predictive ability in this population., Conclusions: Several aspects of the CGA have shown promise for being of use to physicians when predicting TAVI outcomes. While the MPI may be useful in clinical practice, the SPPB may be of particular value, being simple and quick to perform. Validation of these findings in a larger sample is warranted., Trial Registration: The trial was registered in ClinicalTrials.gov on November 7, 2013 ( NCT01991444 ).