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Aims/hypothesis: Insulitis, a hallmark of inflammation preceding autoimmune type 1 diabetes, leads to the eventual loss of functional beta cells. However, functional beta cells can persist even in the face of continuous insulitis. Despite advances in immunosuppressive treatments, maintaining functional beta cells to prevent insulitis progression and hyperglycaemia remains a challenge. The cannabinoid type 1 receptor (CB1R), present in immune cells and beta cells, regulates inflammation and beta cell function. Here, we pioneer an ex vivo model mirroring human insulitis to investigate the role of CB1R in this process., Methods: CD4 + T lymphocytes were isolated from peripheral blood mononuclear cells (PBMCs) from male and female individuals at the onset of type 1 diabetes and from non-diabetic individuals, RNA was extracted and mRNA expression was analysed by real-time PCR. Single beta cell expression from donors with type 1 diabetes was obtained from data mining. Patient-derived human islets from male and female cadaveric donors were 3D-cultured in solubilised extracellular matrix gel in co-culture with the same donor PBMCs, and incubated with cytokines (IL-1β, TNF-α, IFN-γ) for 24-48 h in the presence of vehicle or increasing concentrations of the CB1R blocker JD-5037. Expression of CNR1 (encoding for CB1R) was ablated using CRISPR/Cas9 technology. Viability, intracellular stress and signalling were assayed by live-cell probing and real-time PCR. The islet function measured as glucose-stimulated insulin secretion was determined in a perifusion system. Infiltration of immune cells into the islets was monitored by microscopy. Non-obese diabetic mice aged 7 weeks were treated for 1 week with JD-5037, then euthanised. Profiling of immune cells infiltrated in the islets was performed by flow cytometry., Results: CNR1 expression was upregulated in circulating CD4 + T cells from individuals at type 1 diabetes onset (6.9-fold higher vs healthy individuals) and in sorted islet beta cells from donors with type 1 diabetes (3.6-fold higher vs healthy counterparts). The peripherally restricted CB1R inverse agonist JD-5037 arrested the initiation of insulitis in humans and mice. Mechanistically, CB1R blockade prevented islet NO production and ameliorated the ATF6 arm of the unfolded protein response. Consequently, cyto/chemokine expression decreased in human islets, leading to sustained islet cell viability and function., Conclusions/interpretation: These results suggest that CB1R could be an interesting target for type 1 diabetes while highlighting the regulatory mechanisms of insulitis. Moreover, these findings may apply to type 2 diabetes where islet inflammation is also a pathophysiological factor., Data Availability: Transcriptomic analysis of sorted human beta cells are from Gene Expression Omnibus database, accession no. GSE121863, available at https://www.ncbi.nlm.nih.gov/geo/query/acc.cgi?acc=GSM3448161 ., (© 2024. The Author(s).)

Introduction and Objectives: Impact of gender on long-term outcomes after transcatheter aortic valve implantation (TAVI) remains uncertain. We aimed to investigate gender-specific differences in TAVI and its impact on outcomes., Methods: This analysis used data from the prospective Spanish TAVI registry, which included consecutive TAVI patients treated in 46 Spanish centers from 2009 to 2021. The primary endpoint was all-cause mortality at 12 months. Secondary endpoints included in-hospital and 30-day mortality and TAVI-related complications. Adjusted logistic and Cox regression analyses were performed., Results: The study included 12 253 consecutive TAVI patients with a mean age of 81.2±6.4 years. Women (53.9%) were older, and had a higher STS-PROM score (7.0±7.0 vs 6.2±6.7; P < .001) than men. Overall, the TAVI-related complication rate was similar between women and men, with specific gender-related complications. While women more frequently developed in-hospital vascular complications (13.6% vs 9.8%; P <.001) and cardiac tamponade (1.5% vs 0.6%; P=.009), men showed a higher incidence of permanent pacemaker implantation (14.5% vs 17.4%; P=.009). There was no difference in all-cause mortality either in hospital (3.6% vs 3.6%, adjusted OR, 1.01; 95%CI, 0.83-1.23; P=.902), at 30 days (4.2% vs 4.2%, adjusted OR, 0.90; 95%CI, 0.65-1.25; P=.564) or at 1 year (11% vs 13%, adjusted HR, 0.94; 95%CI, 0.80-1.11; P=.60)., Conclusions: Women treated with TAVI are older and have more comorbidities than men, leading to distinct complications between genders. Nevertheless, all-cause mortality in the short-term and at 1-year was similar between men and women., (Copyright © 2024 Sociedad Española de Cardiología. Published by Elsevier España, S.L.U. All rights reserved.)

Neuropathic pain is a severe and chronic condition widely found in the general population. The reason for this is the extensive variety of damage or diseases that can spark this unpleasant constant feeling in patients. During the processing of pain, the dorsal root ganglia constitute an important region where dorsal root ganglion neurons play a crucial role in the transmission and propagation of sensory electrical stimulation. Furthermore, the dorsal root ganglia have recently exhibited a regenerative capacity that should not be neglected in the understanding of the development and resolution of neuropathic pain and in the elucidation of innovative therapies. Here, we will review the complex interplay between cells (satellite glial cells and inflammatory cells) and factors (cytokines, neurotrophic factors and genetic factors) that takes place within the dorsal root ganglia and accounts for the generation of the aberrant excitation of primary sensory neurons occurring in neuropathic pain. More importantly, we will summarize an updated view of the current pharmacologic and nonpharmacologic therapies targeting the dorsal root ganglia for the treatment of neuropathic pain., Competing Interests: None

Introduction and Objectives: Significant tricuspid regurgitation (TR) is associated with increased morbidity and mortality. Clinical evaluation of TR patients is challenging. Our aim was to establish a new clinical classification specific for patients with TR, the 4A classification, and evaluate its prognostic performance., Methods: We included patients with isolated TR that was at least severe and without previous episodes of heart failure (HF) who were assessed in the heart valve clinic. We registered signs and symptoms of asthenia, ankle swelling, abdominal pain or distention and/or anorexia and followed up the patients every 6 months. The 4A classification ranged from A0 (no A) to A3 (3 or 4 As present). We defined a combined endpoint consisting of hospital admission due to right HF or cardiovascular mortality., Results: We included 135 patients with significant TR between 2016 and 2021 (69% females, mean age 78±7 years). During a median follow-up of 26 [IQR, 10-41] months, 39% (n=53) patients had the combined endpoint: 34% (n=46) were admitted for HF and 5% (n=7) died. At baseline, 94% of the patients were in NYHA I or II, while 24% were in classes A2 or A3. The presence of A2 or A3 conferred a high incidence of events. The change in 4A class remained an independent marker of HF and cardiovascular mortality (adjusted HR per unit of change of 4A class, 1.95 [1.37-2.77]; P<.001)., Conclusions: This study reports a novel clinical classification specifically for patients with TR that is based on signs and symptoms of right HF and has prognostic value for events., (Copyright © 2023. Published by Elsevier España, S.L.U.)

Alzheimer's disease (AD) is a common neurodegenerative disease. In AD-associated neuroinflammation, astrocytes play a key role, finding glial activation both in patients and in animal models. The endocannabinoid system (ECS) is a neurolipid signaling system with anti-inflammatory and neuroprotective properties implicated in AD. Astrocytes respond to external cannabinoid signals and also have their own cannabinoid signaling. Our main objective is to describe the cannabinoid signaling machinery present in hippocampal astrocytes from 3×Tg-AD mice to determine if they are actively involved in the neurodegenerative process. Primary cultures of astrocytes from the hippocampus of 3×Tg-AD and non-Tg offspring were carried out. We analyzed the gene expression of astrogliosis markers, the main components of the ECS and Ca 2+ signaling. 3×Tg-AD hippocampal astrocytes show low inflammatory activity ( Il1b , Il6 , and Gls ) and Ca 2+ flow ( P2rx5 and Mcu ), associated with low cannabinoid signaling ( Cnr1 and Cnr2 ). These results were more evident in females. Our study corroborates glial involvement in AD pathology, in which cannabinoid signaling plays an important role. 3×Tg-AD mice born with hippocampal astrocytes with differential gene expression of the ECS associated with an innate attenuation of their activity. In addition, we show that there are sex differences from birth in this AD animal, which should be considered when investigating the pathogenesis of the disease.

Background: A small aortic annulus (SAA) is a risk factor for prosthesis-patient mismatch (PPM) in patients undergoing surgical or transcatheter aortic valve implantation (TAVI). Data regarding TAVI in patients with extra-SAA are scarce., Aims: The aim of this study was to analyse the safety and efficacy of TAVI in patients with extra-SAA., Methods: A multicentre registry study including patients with extra-SAA (defined as an aortic annulus area <280 mm 2 and/or perimeter <60 mm) undergoing TAVI was established. Primary efficacy and safety endpoints were defined as device success and early safety at 30 days, respectively, using the Valve Academic Research Consortium-3 criteria, and were analysed according to valve type: self-expanding (SEV) versus balloon-expandable (BEV)., Results: A total of 150 patients were included, of which 139 (92.7%) were women, and 110 (73.3%) received an SEV. Intraprocedural technical success was 91.3%, with a higher rate in patients receiving an SEV (96.4% vs 77.5% with BEV; p=0.001). Overall, 30-day device success was 81.3%, (85.5% with SEV vs 70.0% with BEV; p=0.032). The primary safety endpoint occurred in 72.0% of patients (with no difference between groups; p=0.118). Severe PPM occurred in 12% (9.0% with SEV and 24.0% with BEV; p=0.039), with no impact on all-cause mortality, cardiovascular mortality, or heart failure readmission at 2-year follow-up., Conclusions: TAVI is a safe and feasible treatment in patients with extra-SAA with a high rate of technical success. The use of SEV was associated with a lower rate of intraprocedural complications, higher device success at 30 days and better haemodynamic outcomes compared to BEV.

Background: Coronary obstruction (CO) following transcatheter aortic valve replacement (TAVR) is a life-threatening complication, scarcely studied., Objectives: The authors analyzed the incidence of CO after TAVR, presentation, management, and in-hospital and 1-year clinical outcomes in a large series of patients undergoing TAVR., Methods: Patients from the Spanish TAVI (Transcatheter Aortic Valve Implantation) registry who presented with CO in the procedure, during hospitalization or at follow-up were included. Computed tomography (CT) risk factors were assessed. In-hospital, 30-day, and 1-year all-cause mortality rates were analyzed and compared with patients without CO using logistic regression models in the overall cohort and in a propensity score-matched cohort., Results: Of 13,675 patients undergoing TAVR, 115 (0.80%) presented with a CO, mainly during the procedure (83.5%). The incidence of CO was stable throughout the study period (2009-2021), with a median annual rate of 0.8% (range 0.3%-1.3%). Preimplantation CT scans were available in 105 patients (91.3%). A combination of at least 2 CT-based risk factors was less frequent in native than in valve-in-valve patients (31.7% vs 78.3%; P < 0.01). Percutaneous coronary intervention was the treatment of choice in 100 patients (86.9%), with a technical success of 78.0%. In-hospital, 30-day, and 1-year mortality rates were higher in CO patients than in those without CO (37.4% vs 4.1%, 38.3% vs 4.3%, and 39.1% vs 9.1%, respectively; P < 0.001)., Conclusions: In this large, nationwide TAVR registry, CO was a rare, but often fatal, complication that did not decrease over time. The lack of identifiable predisposing factors in a subset of patients and the frequently challenging treatment when established may partly explain these findings., Competing Interests: Funding Support and Author Disclosures The Spanish TAVI registry is managed and maintained with funding from the Interventional Cardiology Association of the Spanish Cardiology Society. Dr Ojeda has received consulting fees from Medtronic and Edwards Lifesciences; has received speaker fees from Philips and World Medical; and holds a research grant (PI21/00949) from the Spanish Ministry of Science and Innovation (Instituto de Salud Carlos III). Dr Asmarats is proctor for Abbott Vascular; and has received speaker fees from Edwards Lifesciences. Dr Amat-Santos is a proctor for Medtronic, Boston Scientific, and Meril Life. Dr Romaguera is proctor for Biosensor. Dr Moreno is a proctor for Boston Scientific and Biosensor. Dr Pan has received speaker fees from Abbott, Boston Scientific, World Medical, and Philips; and holds a research grant (PI21/00949) from the Spanish Ministry of Science and Innovation (Instituto de Salud Carlos III). All other authors have reported that they have no relationships relevant to the contents of this paper to disclose., (Copyright © 2023 American College of Cardiology Foundation. Published by Elsevier Inc. All rights reserved.)

Cocaine is a widely used psychostimulant drug whose repeated exposure induces persistent cognitive/emotional dysregulation, which could be a predictor of relapse in users. However, there is scarce evidence on effective treatments to alleviate these symptoms. Environmental enrichment (EE) has been shown to be associated with improved synaptic function and cellular plasticity changes related to adult hippocampal neurogenesis (AHN), resulting in cognitive enhancement. Therefore, EE could mitigate the negative impact of chronic administration of cocaine in mice and reduce the emotional and cognitive symptoms present during cocaine abstinence. In this study, mice were chronically administered with cocaine for 14 days, and control mice received saline. After the last cocaine or saline dose, mice were submitted to control or EE housing conditions, and they stayed undisturbed for 28 days. Subsequently, mice were evaluated with a battery of behavioural tests for exploratory activity, emotional behaviour, and cognitive performance. EE attenuated hyperlocomotion, induced anxiolytic-like behaviour and alleviated cognitive impairment in spatial memory in the cocaine-abstinent mice. The EE protocol notably upregulated AHN in both control and cocaine-treated mice, though cocaine slightly reduced the number of immature neurons. Altogether, these results demonstrate that EE could enhance hippocampal neuroplasticity ameliorating the behavioural and cognitive consequences of repeated administration of cocaine. Therefore, environmental stimulation may be a useful strategy in the treatment cocaine addiction., (© 2022 The Authors. Addiction Biology published by John Wiley & Sons Ltd on behalf of Society for the Study of Addiction.)

Background: Infective endocarditis (IE) following transcatheter aortic valve replacement (TAVR) has been associated with a dismal prognosis. However, scarce data exist on IE perivalvular extension (PEE) in such patients., Methods: This multicenter study included 579 patients who had the diagnosis of definite IE at a median of 171 (53-421) days following TAVR. PEE was defined as the presence of an intracardiac abscess, pseudoaneurysm, or fistula., Results: A total of 105 patients (18.1%) were diagnosed with PEE (perivalvular abscess, pseudoaneurysm, fistula, or a combination in 87, 7, 7, and 4 patients, respectively). A history of chronic kidney disease (adjusted odds ratio [ORadj], 2.08; 95% confidence interval [CI]: 1.27-3.41; P = .003) and IE secondary to coagulase-negative staphylococci (ORadj, 2.71; 95% CI: 1.57-4.69; P < .001) were associated with an increased risk of PEE. Surgery was performed at index IE episode in 34 patients (32.4%) with PEE (vs 15.2% in patients without PEE, P < .001). In-hospital and 2-year mortality rates among PEE-IE patients were 36.5% and 69.4%, respectively. Factors independently associated with an increased mortality were the occurrence of other complications (stroke post-TAVR, acute renal failure, septic shock) and the lack of surgery at index IE hospitalization (padj < 0.05 for all)., Conclusions: PEE occurred in about one-fifth of IE post-TAVR patients, with the presence of coagulase-negative staphylococci and chronic kidney disease determining an increased risk. Patients with PEE-IE exhibited high early and late mortality rates, and surgery during IE hospitalization seemed to be associated with better outcomes., Competing Interests: Potential conflicts of interest. J. R.-C. has received institutional research grants from Edwards Lifesciences, Medtronic, and Boston Scientific. V. P. has received institutional research grants from Medtronic, Boston Scientific, and Microport. D. T. has received consulting fees from Abbott Vascular, Boston Scientific, Edwards Lifesciences, and Medtronic. H. C. H. has received institutional research grants from Abbott, Boston Scientific, Edwards Lifesciences, and Medtronic and consulting fees from Edwards Lifesciences and Medtronic. J. G. W. has received consulting fees from Edwards Lifesciences and St. Jude Medical. R. M. has received research grants from Edwards Lifesciences, Medtronic, Abbott, Capricor, and St. Jude Medical; has served as a proctor for Edwards Lifesciences; and has received consulting fees from Medtronic. F. S. de B. has received honoraria from Medtronic and Edwards Lifesciences for symposium speeches and proctoring cases. S. L. has received consulting fees from Edwards Lifesciences. H. Le B. has received lecture fees from Edwards Lifesciences outside the submitted work. J. M. S. has received speaker honoraria from Abbott, Boston Scientific, Edwards Lifesciences, and Medtronic and research grants from Boston Scientific, Edwards Lifesciences, and Medtronic outside the submitted work. K. W.-K. has received personal fees from Boston Scientific, Edwards Lifesciences, Abbott, Medtronic, and Meril outside the submitted work. S. S. reports grants to their institution from Edwards Lifesciences, Medtronic, Boston Scientific, and Abbott and has received personal fees from Boston Scientific, BTG, and Teleflex outside the submitted work. O. H. has received personal fees from Boston Scientific and payments from Abbott. N. M. has received personal fees from Edwards Lifesciences, Medtronic, Biotronik, Novartis, Sanofi Genzyme, AstraZeneca, Pfizer, and Bayer outside the submitted work. All remaining authors: No reported conflicts of interest. All authors have submitted the ICMJE Form for Disclosure of Potential Conflicts of Interest. Conflicts that the editors consider relevant to the content of the manuscript have been disclosed., (© The Author(s) 2021. Published by Oxford University Press for the Infectious Diseases Society of America. All rights reserved. For permissions, e-mail: journals.permissions@oup.com.)

Introduction and Objectives: Transaxillary access (TXA) has become the most widely used alternative to transfemoral access (TFA) in patients undergoing transcatheter aortic valve implantation (TAVI). The aim of this study was to compare total in-hospital and 30-day mortality in patients included in the Spanish TAVI registry who were treated by TXA or TFA access., Methods: We analyzed data from patients treated with TXA or TFA and who were included in the TAVI Spanish registry. In-hospital and 30-day events were defined according to the recommendations of the Valve Academic Research Consortium. The impact of the access route was evaluated by propensity score matching according to clinical and echocardiogram characteristics., Results: A total of 6603 patients were included; 191 (2.9%) were treated via TXA and 6412 via TFA access. After adjustment (n=113 TXA group and n=3035 TFA group) device success was similar between the 2 groups (94%, TXA vs 95%, TFA; P=.95). However, compared with the TFA group, the TXA group showed a higher rate of acute myocardial infarction (OR, 5.3; 95%CI, 2.0-13.8); P=.001), renal complications (OR, 2.3; 95%CI, 1.3-4.1; P=.003), and pacemaker implantation (OR, 1.6; 95%CI, 1.01-2.6; P=.03). The TXA group also had higher in-hospital and 30-day mortality rates (OR, 2.2; 95%CI, 1.04-4.6; P=.039 and OR, 2.3; 95%CI, 1.2-4.5; P=.01, respectively)., Conclusions: Compared with ATF, TXA is associated with higher total mortality, both in-hospital and at 30 days. Given these results, we believe that TXA should be considered only in those patients who are not suitable candidates for TFA., (Copyright © 2021 Sociedad Española de Cardiología. Published by Elsevier España, S.L.U. All rights reserved.)

Scarce data exist on mitral valve (MV) infective endocarditis (IE) after transcatheter aortic valve implantation (TAVI). This multicenter study included a total of 579 patients with a diagnosis of definite IE after TAVI from the IE after TAVI International Registry and aimed to evaluate the incidence, characteristics, management, and outcomes of MV-IE after TAVI. A total of 86 patients (14.9%) had MV-IE. These patients were compared with 284 patients (49.1%) with involvement of the transcatheter heart valve (THV) only. Two factors were found to be associated with MV-IE: the use of self-expanding valves (adjusted odds ratio 2.49, 95% confidence interval [CI] 1.23 to 5.07, p = 0.012), and the presence of an aortic regurgitation ≥2 at discharge (adjusted odds ratio 3.33; 95% CI 1.43 to 7.73, p <0.01). There were no differences in IE timing and causative microorganisms between groups, but surgical management was significantly lower in patients with MV-IE (6.0%, vs 21.6% in patients with THV-IE, p = 0.001). All-cause mortality rates at 2-year follow-up were high and similar between patients with MV-IE (51.4%, 95% CI 39.8 to 64.1) and patients with THV-IE (51.5%, 95% CI 45.4 to 58.0) (log-rank p = 0.295). The factors independently associated with increased mortality risk in patients with MV-IE were the occurrence of heart failure (adjusted p <0.001) and septic shock (adjusted p <0.01) during the index hospitalization. One of 6 IE episodes after TAVI is localized on the MV. The implantation of a self-expanding THV and the presence of an aortic regurgitation ≥2 at discharge were associated with MV-IE. Patients with MV-IE were rarely operated on and had a poor prognosis at 2-year follow-up., (Copyright © 2022 Elsevier Inc. All rights reserved.)

Background: The optimal treatment of patients developing infective endocarditis (IE) after transcatheter aortic valve implantation (TAVI) is uncertain., Objectives: The goal of this study was to investigate the clinical characteristics and outcomes of patients with TAVI-IE treated with cardiac surgery and antibiotics (IE-CS) compared with patients treated with antibiotics alone (IE-AB)., Methods: Crude and inverse probability of treatment weighting analyses were applied for the treatment effect of cardiac surgery vs medical therapy on 1-year all-cause mortality in patients with definite TAVI-IE. The study used data from the Infectious Endocarditis after TAVI International Registry., Results: Among 584 patients, 111 patients (19%) were treated with IE-CS and 473 patients (81%) with IE-AB. Compared with IE-AB, IE-CS was not associated with a lower in-hospital mortality (HR unadj : 0.85; 95% CI: 0.58-1.25) and 1-year all-cause mortality (HR unadj : 0.88; 95% CI: 0.64-1.22) in the crude cohort. After adjusting for selection and immortal time bias, IE-CS compared with IE-AB was also not associated with lower mortality rates for in-hospital mortality (HR adj : 0.92; 95% CI: 0.80-1.05) and 1-year all-cause mortality (HR adj : 0.95; 95% CI: 0.84-1.07). Results remained similar when patients with and without TAVI prosthesis involvement were analyzed separately. Predictors for in-hospital and 1-year all-cause mortality included logistic EuroSCORE I, Staphylococcus aureus, acute renal failure, persistent bacteremia, and septic shock., Conclusions: In this registry, the majority of patients with TAVI-IE were treated with antibiotics alone. Cardiac surgery was not associated with an improved all-cause in-hospital or 1-year mortality. The high mortality of patients with TAVI-IE was strongly linked to patients' characteristics, pathogen, and IE-related complications., Competing Interests: Funding Support and Author Disclosures Dr Mangner has received personal fees from Edwards Lifesciences, Medtronic, Biotronik, Novartis, Sanofi Genzyme, AstraZeneca, Pfizer, Bayer, Abbott, Abiomed, and Boston Scientific, outside the submitted work. Dr del Val was supported by a research grant from the Fundación Alfonso Martin Escudero (Madrid, Spain). Dr Tchetche has received consulting fees from Abbott Vascular, Boston Scientific, Edwards Lifesciences, and Medtronic. Dr Herrmann has received institutional research grants from Abbott, Boston Scientific, Edwards Lifesciences, and Medtronic; and has received consulting fees from Edwards Lifesciences and Medtronic. Dr Webb has received consulting fees from Edwards Lifesciences and St. Jude Medical. Dr Makkar has received research grants from Edwards Lifesciences, Medtronic, Abbott, Capricor, and St. Jude Medical; has served as a proctor for Edwards Lifesciences; and has received consulting fees from Medtronic. Dr de Brito has received honoraria from Medtronic and Edwards Lifesciences for symposium speeches and proctoring cases. Dr Lerakis has received consulting fees from Edwards Lifesciences. Dr Le Breton has received lecture fees from Edwards Lifesciences, outside the submitted work. Dr Sinning has received speaker honoraria from Abbott, Boston Scientific, Edwards Lifesciences, and Medtronic; and has received research grants from Boston Scientific, Edwards Lifesciences, and Medtronic, outside the submitted work. Dr Kim has received proctor/speaker fees/served on the advisory board for Abbott, Boston Scientific, Edwards Lifesciences, Medtronic, Meril Life Sciences, and Shockwave Medical, outside the submitted work. Dr Stortecky has received grants to the institution from Edwards Lifesciences, Medtronic, Boston Scientific, and Abbott; and has received personal fees from Boston Scientific, BTG, and Teleflex, outside the submitted work. Dr Søndergaard has received consultant fees and/or institutional research grants from Abbott, Boston Scientific, Medtronic, and SMT. Dr Husser has received personal fees from Boston Scientific; and payments from Abbott. Dr Linke has received personal fees from Medtronic, Abbott, Edwards Lifesciences, Boston Scientific, AstraZeneca, Novartis, Pfizer, Abiomed, Bayer, and Boehringer outside the submitted work. Dr Rodés-Cabau has received institutional research grants from Edwards Lifesciences, Medtronic, and Boston Scientific. All other authors have reported that they have no relationships relevant to the contents of this paper to disclose., (Copyright © 2022 American College of Cardiology Foundation. Published by Elsevier Inc. All rights reserved.)

Background: The Supreme healing-targeted drug-eluting stent (DES) is designed to promote endothelial healing to reduce stent-related adverse events. This may be particularly relevant among complex lesions that have a higher rate of adverse events. We sought to compare 1-year outcomes of percutaneous coronary intervention in complex lesions between the Supreme DES and contemporary durable-polymer, everolimus-eluting stents (DP-EES)., Methods: PIONEER III was a multicenter, prospective, single-blind clinical trial, randomizing 1629 patients with either an acute or chronic coronary syndrome in a 2:1 ratio to the Supreme DES or DP-EES. Complex lesions (American College of Cardiology/American Heart Association type B2/C) were found in 1137 patients. Outcomes were also compared for specific parameters of lesion complexity: severe calcification, long length (>20 ​mm), and severe tortuosity. The primary end point was target lesion failure at 1 ​year., Results: At 1 ​year, there was no difference in target lesion failure between the Supreme DES and DP-EES: (5.7% vs 5.6%; hazard ratio 1.00, 95% confidence interval 0.59-1.68, P = .99). Similarly, there were no differences in the secondary end points of lesion success (99.7% vs 99.4%, P = .41), device success (97.0% vs 98.5%, P = .14), target vessel failure (6.5% vs 7.4%, P = .50), major adverse cardiac events (7.8% vs 8.5%, P = .64), or stent thrombosis (0.7% vs 1.1%, P = .48). A trend was observed toward a higher rate of target lesion revascularization with the Supreme DES (2.5% vs 0.9%, P = .06)., Conclusions: This study suggests that the Supreme DES is as effective and safe at 1 ​year compared with the standard DP-EES across a broad spectrum of lesion complexity., (Crown Copyright © 2021 Published by Elsevier Inc. on behalf of the Society for Cardiovascular Angiography and Interventions Foundation.)

Background: Staphylococcus aureus (SA) has been extensively studied as causative microorganism of surgical prosthetic-valve infective endocarditis (IE). However, scarce evidence exists on SA IE after transcatheter aortic valve replacement (TAVR)., Methods: Data were obtained from the Infectious Endocarditis After TAVR International Registry, including patients with definite IE after TAVR from 59 centres in 11 countries. Patients were divided into 2 groups according to microbiologic etiology: non-SA IE vs SA IE., Results: SA IE was identified in 141 patients out of 573 (24.6%), methicillin-sensitive SA in most cases (115/141, 81.6%). Self-expanding valves were more common than balloon-expandable valves in patients presenting with early SA IE. Major bleeding and sepsis complicating TAVR, neurologic symptoms or systemic embolism at admission, and IE with cardiac device involvement (other than the TAVR prosthesis) were associated with SA IE (P < 0.05 for all). Among patients with IE after TAVR, the likelihood of SA IE increased from 19% in the absence of those risk factors to 84.6% if ≥ 3 risk factors were present. In-hospital (47.8% vs 26.9%; P < 0.001) and 2-year (71.5% vs 49.6%; P < 0.001) mortality rates were higher among patients with SA IE vs non-SA IE. Surgery at the time of index SA IE episode was associated with lower mortality at follow-up compared with medical therapy alone (adjusted hazard ratio 0.46, 95% CI 0.22-0.96; P = 0.038)., Conclusions: SA IE represented approximately 25% of IE cases after TAVR and was associated with very high in-hospital and late mortality. The presence of some features determined a higher likelihood of SA IE and could help to orientate early antibiotic regimen selection. Surgery at index SA IE was associated with improved outcomes, and its role should be evaluated in future studies., (Copyright © 2021 Canadian Cardiovascular Society. Published by Elsevier Inc. All rights reserved.)

The atypical cannabinoid Abn-CBD improves the inflammatory status in preclinical models of several pathologies, including autoimmune diseases. However, its potential for modulating inflammation in autoimmune type 1 diabetes (T1D) is unknown. Herein we investigate whether Abn-CBD can modulate the inflammatory response during T1D onset using a mouse model of T1D (non-obese diabetic- (NOD)-mice) and of beta cell damage (streptozotocin (STZ)-injected mice). Six-week-old female NOD mice were treated with Abn-CBD (0.1-1 mg/kg) or vehicle during 12 weeks and then euthanized. Eight-to-ten-week-old male C57Bl6/J mice were pre-treated with Abn-CBD (1 mg/kg of body weight) or vehicle for 1 week, following STZ challenge, and euthanized 1 week later. Blood, pancreas, pancreatic lymph nodes (PLNs) and T cells were collected and processed for analysis. Glycemia was also monitored. In NOD mice, treatment with Abn-CBD significantly reduced the severity of insulitis and reduced the pro-inflammatory profile of CD4 + T cells compared to vehicle. Concomitantly, Abn-CBD significantly reduced islet cell apoptosis and improved glucose tolerance. In STZ-injected mice, Abn-CBD decreased circulating proinflammatory cytokines and ameliorated islet inflammation reducing intra-islet phospho-NF-κB and TXNIP. Abn-CBD significantly reduced 2 folds intra-islet CD8 + T cells and reduced Th1/non-Th1 ratio in PLNs of STZ-injected mice. Islet cell apoptosis and intra-islet fibrosis were also significantly reduced in Abn-CBD pre-treated mice compared to vehicle. Altogether, Abn-CBD reduces circulating and intra-islet inflammation, preserving islets, thus delaying the progression of insulitis. Hence, Abn-CBD and related compounds emerge as new candidates to develop pharmacological strategies to treat the early stages of T1D., (Copyright © 2021 The Authors. Published by Elsevier Masson SAS.. All rights reserved.)

Background: Procedural improvements combined with the contemporary clinical profile of patients undergoing transcatheter aortic valve replacement (TAVR) may have influenced the incidence and outcomes of infective endocarditis (IE) following TAVR. We aimed to determine the temporal trends, characteristics, and outcomes of IE post-TAVR., Methods: Observational study including 552 patients presenting definite IE post-TAVR. Patients were divided in 2 groups according to the timing of TAVR (historical cohort [HC]: before 2014; contemporary cohort [CC]: after 2014)., Results: Overall incidence rates of IE were similar in both cohorts (CC vs HC: 5.45 vs 6.52 per 1000 person-years; P = .12), but the rate of early IE was lower in the CC (2.29‰ vs 4.89‰, P < .001). Enterococci were the most frequent microorganism. Most patients presented complicated IE ( CC: 67.7%; HC: 69.6%; P = .66), but the rate of surgical treatment remained low (CC: 20.7%; HC: 17.3%; P = .32). The CC exhibited lower rates of in-hospital acute kidney injury (35.1% vs 44.6%; P = .036) and in-hospital (26.6% vs 36.4%; P = .016) and 1-year (37.8% vs 53.5%; P < .001) mortality. Higher logistic EuroScore, Staphylococcus aureus etiology, and complications (stroke, heart failure, and acute renal failure) were associated with in-hospital mortality in multivariable analyses (P < .05 for all)., Conclusions: Although overall IE incidence has remained stable, the incidence of early IE has declined in recent years. The microorganism, high rate of complications, and very low rate of surgical treatment remained similar. In-hospital and 1-year mortality rates were high but progressively decreased over time., (© The Author(s) 2021. Published by Oxford University Press for the Infectious Diseases Society of America. All rights reserved. For permissions, e-mail: journals.permissions@oup.com.)

Maternal malnutrition in critical periods of development increases the risk of developing short- and long-term diseases in the offspring. The alterations induced by this nutritional programming in the hypothalamus of the offspring are of special relevance due to its role in energy homeostasis, especially in the endocannabinoid system (ECS), which is involved in metabolic functions. Since astrocytes are essential for neuronal energy efficiency and are implicated in brain endocannabinoid signaling, here we have used a rat model to investigate whether a moderate caloric restriction (R) spanning from two weeks prior to the start of gestation to its end induced changes in offspring hypothalamic (a) ECS, (b) lipid metabolism (LM) and/or (c) hypothalamic astrocytes. Monitorization was performed by analyzing both the gene and protein expression of proteins involved in LM and ECS signaling. Offspring born from caloric-restricted mothers presented hypothalamic alterations in both the main enzymes involved in LM and endocannabinoids synthesis/degradation. Furthermore, most of these changes were similar to those observed in hypothalamic offspring astrocytes in culture. In conclusion, a maternal low caloric intake altered LM and ECS in both the hypothalamus and its astrocytes, pointing to these glial cells as responsible for a large part of the alterations seen in the total hypothalamus and suggesting a high degree of involvement of astrocytes in nutritional programming.

Defects in GABAergic function can cause anxiety- and depression-like behaviors among other neuropsychiatric disorders. Therapeutic strategies using the transplantation of GABAergic interneuron progenitors derived from the medial ganglionic eminence (MGE) into the adult hippocampus reversed the symptomatology in multiple rodent models of interneuron-related pathologies. In turn, the lysophosphatidic acid receptor LPA 1 has been reported to be essential for hippocampal function. Converging evidence suggests that deficits in LPA 1 receptor signaling represent a core feature underlying comparable hippocampal dysfunction and behaviors manifested in common neuropsychiatric conditions. Here, we first analyzed the GABAergic interneurons in the hippocampus of wild-type and maLPA 1 -null mice, lacking the LPA 1 receptor. Our data revealed a reduction in the number of neurons expressing GABA, calcium-binding proteins, and neuropeptides such as somatostatin and neuropeptide Y in the hippocampus of maLPA 1 -null mice. Then, we used interneuron precursor transplants to test links between hippocampal GABAergic interneuron deficit, cell-based therapy, and LPA 1 receptor-dependent psychiatric disease-like phenotypes. For this purpose, we transplanted MGE-derived interneuron precursors into the adult hippocampus of maLPA 1 -null mice, to test their effects on GABAergic deficit and behavioral symptoms associated with the absence of the LPA 1 receptor. Transplant studies in maLPA 1 -null mice showed that grafted cells were able to restore the hippocampal host environment, decrease the anxiety-like behaviors and neutralize passive coping, with no abnormal effects on motor activity. Furthermore, grafted MGE-derived cells maintained their normal differentiation program. These findings reinforce the use of cell-based strategies for brain disorders and suggest that the LPA 1 receptor represents a potential target for interneuron-related neuropsychiatric disorders.

Background: Stroke is one of the most common and potentially disabling complications of infective endocarditis (IE). However, scarce data exist about stroke complicating IE after transcatheter aortic valve replacement (TAVR)., Objectives: The purpose of this study was to determine the incidence, risk factors, clinical characteristics, management, and outcomes of patients with definite IE after TAVR complicated by stroke during index IE hospitalization., Methods: Data from the Infectious Endocarditis after TAVR International Registry (including 569 patients who developed definite IE following TAVR from 59 centers in 11 countries) was analyzed. Patients were divided into two groups according to stroke occurrence during IE admission (stroke [S-IE] vs. no stroke [NS-IE])., Results: A total of 57 (10%) patients had a stroke during IE hospitalization, with no differences in causative microorganism between groups. S-IE patients exhibited higher rates of acute renal failure, systemic embolization, and persistent bacteremia (p < 0.05 for all). Previous stroke before IE, residual aortic regurgitation ≥moderate after TAVR, balloon-expandable valves, IE within 30 days after TAVR, and vegetation size >8 mm were associated with a higher risk of stroke during the index IE hospitalization (p < 0.05 for all). Stroke rate in patients with no risk factors was 3.1% and increased up to 60% in the presence of >3 risk factors. S-IE patients had higher rates of in-hospital mortality (54.4% vs. 28.7%; p < 0.001) and overall mortality at 1 year (66.3% vs. 45.6%; p < 0.001). Surgical treatment was not associated with improved outcomes in S-IE patients (in-hospital mortality: 46.2% in surgical vs. 58.1% in no surgical treatment; p = 0.47)., Conclusions: Stroke occurred in 1 of 10 patients with IE post-TAVR. A history of stroke, short time between TAVR and IE, vegetation size, valve prosthesis type, and residual aortic regurgitation determined an increased risk. The occurrence of stroke was associated with increased in-hospital and 1-year mortality rates, and surgical treatment failed to improve clinical outcomes., Competing Interests: Funding Support and Author Disclosures Dr. del Val was supported by a research grant from the Fundación Alfonso Martin Escudero (Madrid, Spain). Dr. Mangner has received personal fees from Edwards Lifesciences, Medtronic, Biotronik, Novartis, Sanofi Genzyme, AstraZeneca, Pfizer, and Bayer, outside of the submitted work. Dr. Husser has received personal fees from Boston Scientific; and has received payments from Abbott. Dr. Sinning has received speaker honoraria from Abbott, Boston Scientific, Edwards Lifesciences, and Medtronic; and has received research grants from Boston Scientific, Edwards Lifesciences, and Medtronic, outside of the submitted work. Dr. Won-Keun has received personal fees from Boston Scientific, Edwards Lifesciences, Abbott, Medtronic, and Meril, outside of the submitted work. Dr. Herrmann has received institutional research grants from Abbott, Boston Scientific, Edwards Lifesciences, and Medtronic; and has received consulting fees from Edwards Lifesciences and Medtronic. Dr. Stortecky has received grants to the institution from Edwards Lifesciences, Medtronic, Boston Scientific, and Abbott; and has received personal fees from Boston Scientific, BTG, and Teleflex, outside of the submitted work. Dr. Tchetche has received consulting fees from Abbott Vascular, Boston Scientific, Edwards Lifesciences, and Medtronic. Dr. Webb has received consulting fees from Edwards Lifesciences and St. Jude Medical. Dr. Makkar has received research grants from Edwards Lifesciences, Medtronic, Abbott, Capricor, and St. Jude Medical; has served as a proctor for Edwards Lifesciences; and has received consulting fees from Medtronic. Dr. Lerakis has received consulting fees from Edwards Lifesciences. Dr. de Brito Jr. has received honoraria from Medtronic and Edwards Lifesciences for symposium speeches and proctoring cases. Dr. Le Breton has received lecture fees from Edwards Lifesciences, outside of the submitted work. Dr. Linke has received personal fees from Medtronic, Abbott, Edwards Lifesciences, Boston Scientific, AstraZeneca, Novartis, Pfizer, Abiomed, Bayer, and Boehringer, outside the submitted work. Dr. Rodés-Cabau holds the Research Chair “Fondation Famille Jacques Larivière” for the Development of Structural Heart Disease Interventions; and has received institutional research grants from Edwards Lifesciences, Medtronic, and Boston Scientific. All other authors have reported that they have no relationships relevant to the contents of this paper to disclose., (Copyright © 2021 American College of Cardiology Foundation. Published by Elsevier Inc. All rights reserved.)

Background and Aim: Recent randomized data comparing percutaneous mitral valve repair (PMVR) versus optimal medical treatment in patients with functional MR (FMR) seemed to highlight the importance of the learning curve not only for procedural outcomes but also for patient selection. The aim of the study was to compare a contemporary series of patients undergoing PMVR using a second-generation Mitraclip device (Mitraclip NT) with previous cohorts treated with a first-generation system., Methods: This multicenter study collected individual data from 18 centers between 2012 and 2017. The cohort was divided into three groups according to the use of the first-generation Mitraclip during the first (control-1) or second half (control-2) or the Mitraclip NT system., Results: A total of 545 consecutive patients were included in the study. Among all, 182 (33.3%), 183 (33.3%), and 180 (33.3%) patients underwent mitral repair in the control-1, control-2, and NT cohorts, respectively. Procedural success was achieved in 93.3% of patients without differences between groups. Major adverse events did not statistically differ among groups, but there was a higher rate of pericardial effusion in the control-1 group (4.3%, 0.6%, and 2.6%, respectively; p = 0.025). The composite endpoint of death, surgery, and admission for congestive heart failure (CHF) at 12 months was lower in the NT group (23.5% in control-1, 22.5% in control-2, and 8.3% in the NT group; p = 0.032)., Conclusions: The present paper shows that contemporary clinical outcomes of patients undergoing PMVR with the Mitraclip system have improved over time.

Pigment epithelium-derived factor (PEDF) is a multifunctional protein which was initially described in the retina, although it is also present in other tissues. It functions as an antioxidant agent promoting neuronal survival. Recently, a PEDF receptor has shown an elevated binding affinity for PEDF. There are no relevant data regarding the distribution of both proteins in the brain, therefore the main goal of this work was to investigate the spatiotemporal presence of PEDF and PEDFR in the adult mouse brain, and to determine the PEDF blood level in mouse and human. The localization of both proteins was analyzed by different experimental methods such as immunohistochemistry, western-blotting, and also by enzyme-linked immunosorbent assay. Differential expression was found in some telencephalic structures and positive signals for both proteins were detected in the cerebellum. The magnitude of the PEDFR labeling pattern was higher than PEDF and included some cortical and subventricular areas. Age-dependent changes in intensity of both protein immunoreactions were found in the cortical and hippocampal areas with greater reactivity between 4 and 8 months of age, whilst others, like the subventricular zones, these differences were more evident for PEDFR. Although ubiquitous presence was not found in the brain for these two proteins, their relevant functions must not be underestimated. It has been described that PEDF plays an important role in neuroprotection and data provided in the present work represents the first extensive study to understand the relevance of these two proteins in specific brain areas., (© 2020 Wiley Periodicals, Inc.)

Introduction: Limited data are available regarding the evaluation of right ventricular (RV) performance in patients with aortic stenosis (AS) undergoing transcatheter aortic valve implantation (TAVI)., Objective: To evaluate the prevalence of RV dysfunction in patients with severe AS undergoing TAVI and long-term changes., Methods: Consecutive patients with severe AS undergoing TAVI from January 2016 to July 2017 were included. RV anatomical and functional parameters were analyzed: RV diameters, fractional area change, tricuspid annular plane systolic excursion (TAPSE), S-wave tissue Doppler of the tricuspid annulus (RV-S'TDI), global longitudinal strain (RV-GLS), and free wall strain (RV-FWS). Preprocedure and 1-year echo were analyzed., Results: Final population included 114 patients, mean age 83.63 ± 6.31 years, and 38.2% women. The prevalence of abnormal RV function was high, variable depending on the parameter that we analyzed, and it showed a significant reduction 1 year after TAVI implantation: 13.9% vs 6.8% (TAPSE < 17mm), P = .04; 26.3% vs 20% (fractional area change < 35%), P = .048; 41.2% vs 29.2% (RV-S'TDI < 9.5cm/s), P = .04; 48.7% vs 39.5% (RV-GLS > [20]), P = .049; and 48.7% vs 28.9% (RV-FWS > [20]), P = .03. Significant differences were noted between patients with low-flow (LF) vs normal-flow (NF) AS in RV dysfunction prevalence as well as in RV function recovery which is less evident in LF compared with NF patients., Conclusions: RV dysfunction is high among symptomatic AS patients undergoing TAVI, with variable prevalence depending on the echocardiographic parameter used., (© 2020 Wiley Periodicals, Inc.)

Background and Aims: The synthetic atypical cannabinoid Abn-CBD, a cannabidiol (CBD) derivative, has been recently shown to modulate the immune system in different organs, but its impact in obesity-related meta-inflammation remains unstudied. We investigated the effects of Abn-CBD on metabolic and inflammatory parameters utilizing a diet-induced obese (DIO) mouse model of prediabetes and non-alcoholic fatty liver disease (NAFLD). Materials and Methods: Ten-week-old C57Bl/6J mice were fed a high-fat diet for 15 weeks, following a 2-week treatment of daily intraperitoneal injections with Abn-CBD or vehicle. At week 15 mice were obese, prediabetic and developed NAFLD. Body weight and glucose homeostasis were monitored. Mice were euthanized and blood, liver, adipose tissue and pancreas were collected and processed for metabolic and inflammatory analysis. Results: Body weight and triglycerides profiles in blood and liver were comparable between vehicle- and Abn-CBD-treated DIO mice. However, treatment with Abn-CBD reduced hyperinsulinemia and markers of systemic low-grade inflammation in plasma and fat, also promoting white adipose tissue browning. Pancreatic islets from Abn-CBD-treated mice showed lower apoptosis, inflammation and oxidative stress than vehicle-treated DIO mice, and beta cell proliferation was induced. Furthermore, Abn-CBD lowered hepatic fibrosis, inflammation and macrophage infiltration in the liver when compared to vehicle-treated DIO mice. Importantly, the balance between hepatocyte proliferation and apoptosis was improved in Abn-CBD-treated compared to vehicle-treated DIO mice. Conclusions: These results suggest that Abn-CBD exerts beneficial immunomodulatory actions in the liver, pancreas and adipose tissue of DIO prediabetic mice with NAFLD, thus protecting tissues. Therefore, Abn-CBD and related compounds could represent novel pharmacological strategies for managing obesity-related metabolic disorders., (Copyright © 2020 Romero-Zerbo, García-Fernández, Espinosa-Jiménez, Pozo-Morales, Escamilla-Sánchez, Sánchez-Salido, Lara, Cobo-Vuilleumier, Rafacho, Olveira, Rojo-Martínez, Gauthier, González-Mariscal and Bermúdez-Silva.)

LH-21 is a triazol derivative that has been described as a low-permeant neutral CB1 antagonist, though its pharmacology is still unclear. It has been associated with anti-obesity actions in obese rats. However, its role in preventing type 2 diabetes (T2D) onset have not been studied yet. Given CB1 receptors remain as potential pharmacological targets to fight against obesity and T2D, we wanted to explore the metabolic impact of this compound in an animal model of obesity and pre-diabetes as well as the lack of relevant actions in related central processes such as anxiety. C57BL/6J mice were rendered obese and pre-diabetic by feeding a high-fat diet for 15 weeks and then treated with LH-21 or vehicle for two weeks. Food intake, body weight and glucose handling were assessed, together with other relevant parameters. Behavioural performance was evaluated by the open field test and the elevated plus maze. LH-21 did not affect food intake nor body weight but it improved glucose handling, displaying tissue-specific beneficial actions. Unexpectedly, LH-21 induced anxiolysis and reverted obesity-induced anxiety, apparently through GPR55 receptor. These results suggest that LH-21 can be a new candidate to fight against diabetes onset. Indeed, this compound shows potential in counteracting obesity-related anxiety.

Persistent pulmonary hypertension (P-PH) after mitral valve replacement (MVR) leads to an increased risk of morbidity and mortality. We sought to determine which factors were involved in its occurrence. Patients undergoing MVR for a 3-year period were collected in a retrospective way. We excluded those with an available follow-up shorter than 3 months. Sample size was 111 patients. PH was diagnosed if systolic pulmonary artery pressure (sPAP) estimated by Doppler echocardiography was >40 mmHg. Clinical, echocardiographic, and surgical factors were analyzed. P-PH was present in 42.3 % of patients after 12.6 months of mean follow-up. P-PH was more frequently observed in elderly and female patients, in those with severe degrees of PH before surgery, and significant tricuspid regurgitation (TR). On multivariable analysis, significant TR (OR 1.739; p = 0.01) and more severe degrees of PH before surgery (OR 1.761; p = 0.03) were significantly associated with the presence of P-PH after MVR. Surgical factors related to P-PH were prosthesis size and tricuspid annuloplasty: no need for the performing of tricuspid annuloplasty (OR 0.345; p = 0.025) and the implantation of a smaller prosthesis (OR 0.656; p = 0.004) were related to higher rates of P-PH after MVR. MVR was associated with high prevalence of P-PH after mid-term follow-up. Both PH and significant TR before surgery were associated with P-PH. Our data point out that MVR should be planned before the development of PH and greater TR. Smaller prosthetic size is also a risk factor for P-PH and bigger prostheses are desirable when possible.

Objective: Angiographic thrombus burden (TB) can be assessed early and enable a decision on intervention. The aim of this study was to analyze its effect on the incidence of cardiac events after a primary percutaneous coronary intervention., Patients and Methods: We carried out a prospective study of 480 consecutive ST-segment elevation myocardial infarction patients treated by systematic primary percutaneous coronary intervention. Large TB was defined as thrombus length at least 2 vessel diameters or as solid thrombus obtained through catheter aspiration. The primary outcome measure was a composite of death, reinfarction, or target vessel revascularization., Results: A total of 205 (47%) patients fulfilled the criteria for large TB. These patients were more frequently treated with abciximab (62.0 vs. 35.8%, P<0.001), showed more angiographic complications (26.6 vs. 13.7%, P=0.001), and had larger infarcts (peak troponin I, 74 vs. 50 ng/ml, P=0.015). During a follow-up of 19 ± 5 months, the rates of primary outcome were similar between groups of small and large TB (16.2 vs. 12.8%, hazard ratio: 0.88, 95% confidence interval: 0.46-1.67, P=0.691). There were no differences in the rates of definite stent thrombosis (0.5 vs. 2.2%, P=0.190)., Conclusion: Large TB is associated with larger infarct size, but not with worse mid-term outcomes. Selective use of adjuvant therapies according to TB may be an effective approach to reduce thrombotic complications.

Background: Fragile X syndrome is the most common genetic cause of mental disability. Although many research has been performed, the mechanism underlying the pathogenesis is unclear and needs further investigation. Oxidative stress played major roles in the syndrome. The aim was to investigate the nitric oxide metabolism, protein nitration level, the expression of NOS isoforms, and furthermore the activation of the nuclear factor NF-κB-p65 subunit in different brain areas on the fragile X mouse model., Methods: This study involved adult male Fmr1-knockout and wild-type mice as controls. We detected nitric oxide metabolism and the activation of the nuclear factor NF-κBp65 subunit, comparing the mRNA expression and protein content of the three NOS isoforms in different brain areas., Results: Fmr1-KO mice showed an abnormal nitric oxide metabolism and increased levels of protein tyrosine nitrosylation. Besides that, nuclear factor NF-κB-p65 and inducible nitric oxide synthase appeared significantly increased in the Fmr1-knockout mice. mRNA and protein levels of the neuronal nitric oxide synthase appeared significantly decreased in the knockout mice. However, the epithelial nitric oxide synthase isoform displayed no significant changes., Conclusions: These data suggest the potential involvement of an abnormal nitric oxide metabolism in the pathogenesis of the fragile X syndrome.

A patient with severe aortic valve disease and high surgical risk underwent Direct Flow (DF) valve implantation. Anatomical assessment (Trans-esophageal echocardiography (TEE) and CT scan) revealed a 3-leaflet aortic valve (annulus diameter 23.4 mm) that was functionally bicuspid because of complete and linearly calcified fusion of noncoronary and right cusps. The valve had severe stenosis (peak/mean gradients of 70/45 mm Hg) and moderate to severe regurgitation. A balloon valvuloplasty (semicompliant 23 mm × 45 mm balloon, 2 inflations) was performed with persistence of balloon waist. A 25 DF valve was positioned in the aortic annulus, with both rings well expanded. A mild deformity in the vertical supporting tubes was observed but considered nonrelevant because valve function (peak/mean gradients of 25/12 mm Hg respectively and no aortic regurgitation) was acceptable. Then the polymer was injected and the valve released from its attachments. Postoperative course was uneventful without clinical complications; nevertheless 3 days later Doppler peak/mean transaortic gradients were 80/45 mm Hg. These high gradients were confirmed by direct invasive measurements while CT scan documented a severe geometrical deformation of the valve cuff. Since patient was in good clinical condition, a conservative strategy was adopted. Eight months later, patient functional status had improved (NYHA class II), left ventricular dimensions decreased, left ventricular ejection fraction (LVEF) increased, and valve gradients remained unchanged; therefore surgical aortic valve replacement has been deferred until clinical indication. Such a favorable course can be explained by disappearance of aortic regurgitation. Patient anatomical and procedural features that conditioned this very rare phenomenon are discussed as well as clues to prevent it., (© 2015 Wiley Periodicals, Inc.)