Sigma Receptor Ligands Are Potent Antiprion Compounds that Act Independently of Sigma Receptor Binding.

Prion diseases are invariably fatal neurodegenerative diseases of humans and other animals for which there are no effective treatment options. Previous work from our laboratory identified phenethylpiperidines as a novel class of anti-prion compounds. While working to identify the molecular target(s) of these molecules, we unexpectedly discovered ten novel antiprion compounds based on their known ability to bind to the sigma receptors, σ1R and σ2R, which are currently being tested as therapeutic or diagnostic targets for cancer and neuropsychiatric disorders. Surprisingly, however, knockout of the respective genes encoding σ1R and σ2R (Sigmar1 and Tmem97) in prion-infected N2a cells did not alter the antiprion activity of these compounds, demonstrating that these receptors are not the direct targets responsible for the antiprion effects of their ligands. Further investigation of the most potent molecules established that they are efficacious against multiple prion strains and protect against downstream prion-mediated synaptotoxicity. While the precise details of the mechanism of action of these molecules remain to be determined, the present work forms the basis for further investigation of these compounds in preclinical studies. Given the therapeutic utility of several of the tested compounds, including rimcazole and haloperidol for neuropsychiatric conditions, (+)-pentazocine for neuropathic pain, and the ongoing clinical trials of SA 4503 and ANAVEX2-73 for ischemic stroke and Alzheimer's disease, respectively, this work has immediate implications for the treatment of human prion disease.

Clinical Impact of Standardized TAVR Technique and Care Pathway: Insights From the Optimize PRO Study.

BACKGROUND: Procedural success and clinical outcomes after transcatheter aortic valve replacement (TAVR) have improved, but residual aortic regurgitation (AR) and new permanent pacemaker implantation (PPI) rates remain variable because of a lack of uniform periprocedural management and implantation. OBJECTIVES: The Optimize PRO study evaluates valve performance and procedural outcomes using an "optimized" TAVR care pathway and the cusp overlap technique (COT) in patients receiving the Evolut PRO/PRO+ (Medtronic) self-expanding valves. METHODS: Optimize PRO, a nonrandomized, prospective, postmarket study conducted in the United States, Canada, Europe, Middle East, and Australia, is enrolling patients with severe symptomatic aortic stenosis and no pre-existing pacemaker. Sites follow a standardized TAVR care pathway, including early discharge and a conduction disturbance management algorithm, and transfemoral deployment using the COT. RESULTS: A total of 400 attempted implants from the United States and Canada comprised the main cohort of this second interim analysis. The mean age was 78.7 ± 6.6 years, and the mean Society of Thoracic Surgeons predictive risk of mortality was 3.0 ± 2.4. The median length of stay was 1 day. There were no instances of moderate or severe AR at discharge. At 30 days, all-cause mortality or stroke was 3.8%, all-cause mortality was 0.8%, disabling stroke was 0.7%, hospital readmission was 10.1%, and cardiovascular rehospitalization was 6.1%. The new PPI rate was 9.8%, 5.8% with 4-step COT compliance. In the multivariable model, right bundle branch block and the depth of the implant increased the risk of PPI, whereas using the 4-step COT lowered 30-day PPI. CONCLUSIONS: The use of the TAVR care pathway and COT resulted in favorable clinical outcomes with no moderate or severe AR and low PPI rates at 30 days while facilitating early discharge and reproducible outcomes across various sites and operators. (Optimize PRO; NCT04091048).

Effect of Transcatheter Aortic Valve Implantation vs Surgical Aortic Valve Replacement on All-Cause Mortality in Patients With Aortic Stenosis: A Randomized Clinical Trial.

Importance: Transcatheter aortic valve implantation (TAVI) is a less invasive alternative to surgical aortic valve replacement and is the treatment of choice for patients at high operative risk. The role of TAVI in patients at lower risk is unclear. Objective: To determine whether TAVI is noninferior to surgery in patients at moderately increased operative risk. Design, Setting, and Participants: In this randomized clinical trial conducted at 34 UK centers, 913 patients aged 70 years or older with severe, symptomatic aortic stenosis and moderately increased operative risk due to age or comorbidity were enrolled between April 2014 and April 2018 and followed up through April 2019. Interventions: TAVI using any valve with a CE mark (indicating conformity of the valve with all legal and safety requirements for sale throughout the European Economic Area) and any access route (n = 458) or surgical aortic valve replacement (surgery; n = 455). Main Outcomes and Measures: The primary outcome was all-cause mortality at 1 year. The primary hypothesis was that TAVI was noninferior to surgery, with a noninferiority margin of 5% for the upper limit of the 1-sided 97.5% CI for the absolute between-group difference in mortality. There were 36 secondary outcomes (30 reported herein), including duration of hospital stay, major bleeding events, vascular complications, conduction disturbance requiring pacemaker implantation, and aortic regurgitation. Results: Among 913 patients randomized (median age, 81 years [IQR, 78 to 84 years]; 424 [46%] were female; median Society of Thoracic Surgeons mortality risk score, 2.6% [IQR, 2.0% to 3.4%]), 912 (99.9%) completed follow-up and were included in the noninferiority analysis. At 1 year, there were 21 deaths (4.6%) in the TAVI group and 30 deaths (6.6%) in the surgery group, with an adjusted absolute risk difference of -2.0% (1-sided 97.5% CI, -∞ to 1.2%; P < .001 for noninferiority). Of 30 prespecified secondary outcomes reported herein, 24 showed no significant difference at 1 year. TAVI was associated with significantly shorter postprocedural hospitalization (median of 3 days [IQR, 2 to 5 days] vs 8 days [IQR, 6 to 13 days] in the surgery group). At 1 year, there were significantly fewer major bleeding events after TAVI compared with surgery (7.2% vs 20.2%, respectively; adjusted hazard ratio [HR], 0.33 [95% CI, 0.24 to 0.45]) but significantly more vascular complications (10.3% vs 2.4%; adjusted HR, 4.42 [95% CI, 2.54 to 7.71]), conduction disturbances requiring pacemaker implantation (14.2% vs 7.3%; adjusted HR, 2.05 [95% CI, 1.43 to 2.94]), and mild (38.3% vs 11.7%) or moderate (2.3% vs 0.6%) aortic regurgitation (adjusted odds ratio for mild, moderate, or severe [no instance of severe reported] aortic regurgitation combined vs none, 4.89 [95% CI, 3.08 to 7.75]). Conclusions and Relevance: Among patients aged 70 years or older with severe, symptomatic aortic stenosis and moderately increased operative risk, TAVI was noninferior to surgery with respect to all-cause mortality at 1 year. Trial Registration: isrctn.com Identifier: ISRCTN57819173.

Chest Pain Post-Transcatheter Aortic Valve Implantation: Don't Forget the Uncommon Complication.

Transesophageal echocardiography guides a range of structural heart disease interventions, especially in older adult and frail patients who are deemed not suitable to undergo surgical repair. Although rare, transesophageal echocardiography can be associated with esophageal trauma, including perforation. Treating physicians should be cognizant of such a complication. (Level of Difficulty: Intermediate.).

Transcatheter Aortic Valve Replacement via the Right Subclavian Artery Approach: A Case Series.

The right subclavian artery (RSA) approach is an infrequently used alternative-access method for transcatheter aortic valve replacement (TAVR), which may be considered when transfemoral and left subclavian artery (LSA) access routes are contraindicated. The double arterial bend encountered along the course of the RSA to the aortic root makes advancement of the TAVR delivery system more challenging, but can be overcome using a steerable delivery system over an ultra-stiff guidewire. We report 5 cases from our institution of TAVRs performed via the RSA approach in patients with severe aortic stenosis that were unsuitable for transfemoral or LSA access. The procedures were performed under general anesthesia, using a 5-cm infraclavicular incision. In each case, an Edwards Commander Delivery System was advanced through an eSheath over an Innowi guidewire, and an Edwards SAPIEN 3 valve was successfully deployed. The mean fluoroscopy time was 19.5 ± 3.8 minutes. No aortic regurgitation (AR) was present postprocedure for 4 out of 5 cases, and 1 had mild to moderate AR. The length of hospital stay was 2 to 3 days for 4 patients. All patients had an excellent outcome at 12 months post-procedure. The RSA approach is a safe and feasible access method for TAVR, and we recommend that it be considered as the next best access method if transfemoral and LSA approaches are unsuitable.

Reversible PCET and Ambient Catalytic Oxidative Alcohol Dehydrogenation by {V=O} Perfluoropinacolate Complexes.

A new air-stable catalyst for the oxidative dehydrogenation of benzylic alcohols under ambient conditions has been developed. The synthesis and characterization of this compound and the related monomeric and dimeric V(IV)- and V(V)-pinF (pinF = perfluoropinacolate) complexes are reported herein. Monomeric V(IV) complex (Me4N)2[V(O)(pinF)2] (1) and dimeric (µ-O)2-bridged V(V) complex (Me4N)2[V2(O)2(µ-O)2(pinF)2] (3a) are prepared in water under ambient conditions. Monomeric V(V) complex (Me4N)[V(O)(pinF)2] (2) may be generated via chemical oxidation of 1 under an inert atmosphere, but dimerizes to 3a upon exposure to air. Complexes 1 and 2 display a perfectly reversible VIV/V couple at 20 mV (vs Ag/AgNO3), whereas a quasi-reversible VIV/V couple at -865 mV is found for 3a. Stoichiometric reactions of 3a with both fluorenol and TEMPOH result in the formation of (Me4N)2[V2(O)2(µ-OH)2(pinF)2] (4a), which contains two V(IV) centers that display antiferromagnetic coupling. In order to structurally characterize the dinuclear anion of 4a, {K(18C6)}+ countercations were employed, which formed stabilizing K···O interactions between the counterion and each terminal oxo moiety and H-bonding between the oxygen atoms of the crown ether and µ-OH bridges of the dimer, resulting in {K(18C6)}2[V2(O)2(µ-OH)2(pinF)2] (4b). The formal storage of H2 in 4a is reversible and proton-coupled electron transfer (PCET) from crystals of 4a regenerates 3a upon exposure to air over the course of several days. Furthermore, the reaction of 3a (2%) under ambient conditions with excess fluorenol, cinnamyl alcohol, or benzyl alcohol resulted in the selective formation of fluorenone (82% conversion), cinnamaldehyde (40%), or benzaldehyde (7%), respectively, reproducing oxidative alcohol dehydrogenation (OAD) chemistry known for VOx surfaces and demonstrating, in air, the thermodynamically challenging selective oxidation of alcohols to aldehydes/ketones.

Initial experience of a self-expanding transcatheter aortic valve with an outer pericardial wrap: The United Kingdom and Ireland Implanters' registry.

OBJECTIVES: The United Kingdom and Ireland Implanters' registry is a multicenter registry which reports on real-world experience with new transcatheter heart valves. BACKGROUND: The Evolut PRO (Medtronic, Minneapolis, MN) transcatheter aortic valve is a self-expanding transcatheter aortic valve with an outer pericardial wrap, designed to minimize paravalvular regurgitation. METHODS: Between July 2017 and December 2018, clinical, procedural, and 30-day outcome data were prospectively collected from all patients receiving the Evolut PRO valve across nine participating centers in the United Kingdom and Ireland. The primary efficacy outcome was the Valve Academic Research Consortium-2 (VARC-2)-defined endpoint of device success. The primary safety outcome was the VARC-2-defined composite endpoint of early safety at 30 days. RESULTS: A total of 317 patients underwent implantation. Mean age was 81.8 ± 6.4 years and Society of Thoracic Surgeons Predicted Risk of Mortality Score 5.5 ± 1.8%. Iliofemoral access was used in 99.1% of patients. Device success was 91.2%. Mean gradient was 7.6 ± 4.7 mmHg and effective orifice area 1.9 ± 0.7 cm2 . The incidence of moderate paravalvular regurgitation was 1.7% and there was no severe paravalvular regurgitation. A new permanent pacemaker was implanted in 17.8% of patients without a pacemaker at baseline. Early safety was demonstrated in 92.7%. At 30 days, all-cause mortality was 0.6%, stroke 3.8%, and major vascular complication 2.8%. CONCLUSIONS: Real-world experience of the Evolut PRO transcatheter aortic valve demonstrated favorable procedural success, safety, valve function, and incidence of new permanent pacemaker implantation.

Longitudinal deformation bench testing using a coronary artery model: a new standard?

Objectives: To compare susceptibility of five different stent platforms with longitudinal stent deformation (LSD) using a clinically relevant bench testing model simulating both short and long malapposed lengths. Background: Recent data suggest that design modifications to the Promus Element stent which led to the Promus Premier stent has reduced susceptibility to LSD. However, susceptibility to LSD at long malapposed lengths has not been tested. Furthermore, the mechanisms behind susceptibility to LSD are as yet unclear. Methods: The Omega, Integrity, Multilink 8, Biomatrixand Promus Premier stent platforms were tested. The Omega, Integrity and Multilink 8 platforms were used in place of their drug-eluting equivalents. 3.5 mm stents were deployed in a stepped tube with the distal portion fixed and the proximal test section exposed. The force required to compress stents by a fixed distance at different exposed lengths was compared. Symmetrical and point loading were used. Results: The Promus Premier was longitudinally as strong as Multilink and Integrity at a short exposed length (4 mm) but weaker, in between Omega and the other platforms, at longer exposed lengths (12 mm). As previously noted, the Omega (Promus Element) platform was significantly weaker than the other stents and Biomatrix was the strongest stent. Conclusion: Susceptibility to LSD varies depending on length of malapposed segment when tested using a clinically relevant model as in this study. The mechanisms behind the susceptibility are likely multifactorial, including connector number, strut thickness, connector alignment and ring orientation but remain to be elucidated.

Development and validation of a clinical risk score to predict mortality after percutaneous coronary intervention.

OBJECTIVE: To develop and validate a contemporary clinical risk score to predict mortality after percutaneous coronary intervention (PCI). METHODS: Using data collected from patients undergoing PCI at the South Yorkshire Cardiothoracic Centre, Sheffield, UK, between January 2007 and September 2013, a risk score was developed to predict mortality. Logistic regression was used to evaluate the effect of each variable upon 30-day mortality. A backwards stepwise logistic regression model was then used to build a predictive model. The results were validated both internally and externally with data from Manchester Royal Infirmary, UK. 30-Day mortality status was determined from the UK Office of National Statistics. RESULTS: The development data set comprised 6522 patients from Sheffield. Five risk factors, including cardiogenic shock, procedural urgency, history of renal disease, diabetes mellitus and age, were statistically significant to predict 30-day mortality. The risk score was validated internally on a further 3290 patients from Sheffield and externally on 3230 patients from Manchester. The discrimination of the model was high in the development (C-statistic=0.82, 95% CI 0.79 to 0.85), internal (C-statistic=0.81, 95% CI 0.76 to 0.86) and external (C statistics=0.90, 95% CI 0.87 to 0.93) cohorts. There was no significant difference between observed and predicted mortality in any group. CONCLUSION: This contemporary risk score reliably predicts 30-day mortality after PCI using a small number of clinical variables obtainable prior to the procedure, without knowledge of the coronary anatomy.

Forward and back aspiration during ST-elevation myocardial infarction: a feasibility study.

AIMS: The inability to optimise stent expansion fully whilst simultaneously preventing distal embolisation during ST-elevation myocardial infarction (STEMI) remains a clinical conundrum. We aimed to describe a newly devised angiographic strategy of "forward" and "back" aspiration that leads to more complete thrombus removal and prevention of distal embolisation, to allow high-pressure post-dilatation of the implanted stent to be performed. METHODS AND RESULTS: Forward aspiration was conducted with a conventional aspiration thrombectomy catheter, with bail-out aspiration thrombectomy for angiographically persistent thrombus utilising the larger bore 6 Fr (0.056") guide catheter extension system (GuideLiner; Vascular Solutions, Inc., Minneapolis, MN, USA). Back aspiration was undertaken with a deeply intubated GuideLiner or guide catheter with a vacuum induced within, extending to the inflated angioplasty balloon, to allow for proximal embolic protection during balloon deflation during all stages of the PCI procedure, including high-pressure post-dilatation of the stent to the visually estimated reference vessel diameter (RVD). Over a six-month period 30 consecutive cases were undertaken during working hours. Bail-out GuideLiner-assisted aspiration thrombectomy was performed in 9/30 cases because of inadequate thrombus removal with a conventional aspiration thrombectomy catheter. Back aspiration was performed in all cases. In 27/30 cases high-pressure post-dilatation of the stent was performed. The mean maximum post-dilatation balloon size and mean proximal reference vessel diameter did not significantly differ (3.60±0.41 mm vs. 3.65±0.45 mm, p=0.68). In all cases, implantation +/- post-dilatation of the stent to the visually estimated RVD was achievable without any deterioration in TIMI blood flow or myocardial blush grade. CONCLUSIONS: The strategy of forward and back aspiration to facilitate stent implantation and high-pressure post-dilatation during STEMI appears to be safe and effective. Randomised controlled trials are required to confirm the safety and efficacy of this newly devised angiographic strategy.

Nanometre-thick single-crystalline nanosheets grown at the water-air interface.

To date, the preparation of free-standing 2D nanomaterials has been largely limited to the exfoliation of van der Waals solids. The lack of a robust mechanism for the bottom-up synthesis of 2D nanomaterials from non-layered materials has become an obstacle to further explore the physical properties and advanced applications of 2D nanomaterials. Here we demonstrate that surfactant monolayers can serve as soft templates guiding the nucleation and growth of 2D nanomaterials in large area beyond the limitation of van der Waals solids. One- to 2-nm-thick, single-crystalline free-standing ZnO nanosheets with sizes up to tens of micrometres are synthesized at the water-air interface. In this process, the packing density of surfactant monolayers adapts to the sub-phase metal ions and guides the epitaxial growth of nanosheets. It is thus named adaptive ionic layer epitaxy (AILE). The electronic properties of ZnO nanosheets and AILE of other materials are also investigated.

Does the CHA2DS2-Vasc score predict procedural and short-term outcomes in patients undergoing transcatheter aortic valve implantation?

BACKGROUND: Transcatheter aortic valve implantation (TAVI) is associated with periprocedural and postprocedural morbidity and mortality. Currently, there is a paucity of risk stratification models for potential TAVI candidates. We employed the CHA2DS2-Vasc score to quantify the risk of 30-day mortality and morbidity in patients undergoing TAVI. METHODS AND RESULTS: A retrospective analysis of registry data for consecutive patients undergoing TAVI at 3 tertiary centres in Northwest England between 2008 and 2013. The CHA2DS2-Vasc score and its modification-the R2CHA2DS2-Vasc score, which includes pre-existing renal impairment and pre-existing conduction abnormality (right bundle branch block/left bundle branch block, RBBB/LBBB)-were calculated for all patients. A total of 313 patients with a mean age of 80 (79.1-80.8) years underwent TAVI. The implanted devices were either the CoreValve or the Edwards-SAPIEN prosthesis. The 30-day mortality was 14.3% in those with a CHA2DS2-Vasc score ≥6, whereas it was only 6.2% in those with a score <6 (p=0.04). Using the R2-CHA2DS2-Vasc score, the difference was more pronounced with a 30-day mortality of 22.6% in those patients with an R2-CHA2DS2-Vasc score ≥7 compared to 6.0% in those with a R2-CHA2DS2-Vasc score <7 (p=0.001). In multivariable Cox regression analyses, there was a significant and independent relationship between the CHA2DS2-Vasc score (hazard ratio (HR)= 2.71, (1.01 to 7.31); p<0.05) and the modified R2CHA2DS2-Vasc score (HR=4.27 (1.51 to 12.07); p=0.006) with 30-day mortality. CONCLUSIONS: Our study demonstrates the potential use of the CHA2DS2-Vasc or the R2CHA2DS2-Vasc score to quantify the risk of mortality in patients undergoing TAVI. This could have significant implications in terms of clinical as well as patients' decision-making.

Major Bleeding and Adverse Outcome following Percutaneous Coronary Intervention.

Advances in anti-thrombotic and anti-platelet therapies have improved outcomes in patients undergoing percutaneous coronary interventions (PCIs) through a reduction in ischaemic events, at the expense of peri-procedural bleeding complications. These may occur through either the access site through which the PCI was performed or through non-access-related sites. There are currently over 10 definitions of major bleeding events consisting of clinical events, changes in laboratory parameters and clinical outcomes, where different definitions will differentially influence the reported incidence of major bleeding events. Use of different major bleeding definitions has been shown to change the reported outcome of a number of therapeutic strategies in randomised controlled trials but as yet a universal bleeding definition has not gained widespread adoption in assessing the efficacy of such therapeutic interventions. Major bleeding complications are independently associated with adverse mortality and major adverse cardiovascular event (MACE) outcomes, irrespective of the definition of major bleeding used, with the worst outcomes associate with non-access-site related bleeds. We consider the mechanisms through which bleeding complications may affect longer-term outcomes and discuss bleeding avoidance strategies, including access site choice, pharmacological considerations and formal bleeding risk assessment to minimise such bleeding events.

Severe catheter kinking and entrapment during transradial coronary angiography: percutaneous retrieval using a sheathless guide catheter.

The transradial (TR) approach for coronary angiography and intervention is increasingly used worldwide because of several advantages such as reduced bleeding and vascular complications. During TR procedures, aggressive catheter manipulation in the setting of complex and tortuous arterial anatomy can lead to catheter kinking and entrapment. Several percutaneous retrieval techniques using either homolateral radial access or femoral access have been described previously. We demonstrate, for the first time, the use of a sheathless guide catheter as a rescue technique to successfully retrieve a severely kinked and entrapped diagnostic catheter during TR access. © 2014 Wiley Periodicals, Inc.

Baseline bleeding risk and arterial access site practice in relation to procedural outcomes after percutaneous coronary intervention.

BACKGROUND: Transradial access (TRA) has been associated with reduced access site-related bleeding complications and mortality after percutaneous coronary intervention (PCI). It is unclear, however, whether these observed benefits are influenced by baseline bleeding risk. OBJECTIVES: This study investigated the relationship between baseline bleeding risk, TRA utilization, and procedure-related outcomes in patients undergoing PCI enrolled in the British Cardiovascular Intervention Society database. METHODS: Baseline bleeding risk was calculated by using modified Mehran bleeding risk scores in 348,689 PCI procedures performed between 2006 and 2011. Four categories for bleeding risk were defined for the modified Mehran risk score (MMRS): low (<10), moderate (10 to 14), high (15 to 19), and very high (≥20). The impact of baseline bleeding risk on 30-day mortality and its relationship with access site were studied. RESULTS: TRA was independently associated with a 35% reduction in 30-day mortality risk (odds ratio [OR]: 0.65 [95% confidence interval (CI): 0.59 to 0.72]; p < 0.0001), with the magnitude of mortality reduction related to baseline bleeding risk (MMRS <10, OR: 0.73 [95% CI: 0.62 to 0.86]; MMRS ≥20, OR: 0.53 [95% CI: 0.47 to 0.61]). In patients with an MMRS <10, TRA was used in 71,771 (43.2%) of 166,083 PCI procedures; TRA was used in 8,655 (40.1%) of 21,559 PCI procedures in patients with an MMRS ≥20, illustrating that TRA was used less in those at highest risk from bleeding complications (p < 0.0001). CONCLUSIONS: TRA was independently associated with reduced 30-day mortality, and the magnitude of this effect was related to baseline bleeding risk; those at highest risk of bleeding complications gained the greatest benefit from adoption of TRA during PCI.