T-Type Ca2+ Channels Mediate a Critical Period of Plasticity in Adult-Born Granule Cells.

Adult-born granule cells (abGCs) exhibit a transient period of elevated synaptic plasticity that plays an important role in hippocampal function. Various mechanisms have been implicated in this critical period for enhanced plasticity, including minimal GABAergic inhibition and high intrinsic excitability conferred by T-type Ca2+ channels. Here we assess the contribution of synaptic inhibition and intrinsic excitability to long-term potentiation (LTP) in abGCs of adult male and female mice using perforated patch recordings. We show that the timing of critical period plasticity is unaffected by intact GABAergic inhibition such that 4-6-week-old abGCs exhibit LTP that is absent by 8 weeks. Blocking GABAA receptors, or partial blockade of GABA release from PV and nNos-expressing interneurons by a µ-opioid receptor agonist, strongly enhances LTP in 4-week-old GCs, suggesting that minimal inhibition does not underlie critical period plasticity. Instead, the closure of the critical period coincides with a reduction in the contribution of T-type Ca2+ channels to intrinsic excitability, and a selective T-type Ca2+ channel antagonist prevents LTP in 4-week-old but not mature GCs. Interestingly, whole-cell recordings that facilitate T-type Ca2+ channel activity in mature GCs unmasks LTP (with inhibition intact) that is also sensitive to a T-type Ca2+ channel antagonist, suggesting T-type channel activity in mature GCs is suppressed by native intracellular signaling. Together these results show that abGCs use T-type Ca2+ channels to overcome inhibition, providing new insight into how high intrinsic excitability provides young abGCs a competitive advantage for experience-dependent synaptic plasticity.

Three-dimensional mapping of neurofibrillary tangle burden in the human medial temporal lobe.

Tau protein neurofibrillary tangles are closely linked to neuronal/synaptic loss and cognitive decline in Alzheimer's disease and related dementias. Our knowledge of the pattern of neurofibrillary tangle progression in the human brain, critical to the development of imaging biomarkers and interpretation of in vivo imaging studies in Alzheimer's disease, is based on conventional two-dimensional histology studies that only sample the brain sparsely. To address this limitation, ex vivo MRI and dense serial histological imaging in 18 human medial temporal lobe specimens (age 75.3 ± 11.4 years, range 45 to 93) were used to construct three-dimensional quantitative maps of neurofibrillary tangle burden in the medial temporal lobe at individual and group levels. Group-level maps were obtained in the space of an in vivo brain template, and neurofibrillary tangles were measured in specific anatomical regions defined in this template. Three-dimensional maps of neurofibrillary tangle burden revealed significant variation along the anterior-posterior axis. While early neurofibrillary tangle pathology is thought to be confined to the transentorhinal region, we found similar levels of burden in this region and other medial temporal lobe subregions, including amygdala, temporopolar cortex, and subiculum/cornu ammonis 1 hippocampal subfields. Overall, the three-dimensional maps of neurofibrillary tangle burden presented here provide more complete information about the distribution of this neurodegenerative pathology in the region of the cortex where it first emerges in Alzheimer's disease, and may help inform the field about the patterns of pathology spread, as well as support development and validation of neuroimaging biomarkers.

Neuronal volume of the hippocampal regions in ageing.

The hippocampal formation (HF) has an important role in different human capacities, such as memory processing and emotional expression. Both extensive changes and limited variations of its components can cause clinically expressed dysfunctions. Although there remains no effective treatment for diseases caused by pathological changes in this brain region, detection of these changes, even minimally, could allow us to develop early interventions and establish corrective measures. This study analysed the neuronal islands of layer II of the entorhinal cortex (EC), the neuronal clumps of the external principal layer of the presubiculum (PrS) and the dentate granule cells of the dentate gyrus (DG), which represent the prominent structural regions within the HF circuit. Subjects from two age groups (younger or older than 65 years) were studied and their neuronal size assessed by the point-sampled intercepts stereological method. The quantitative v¯v(soma) estimate was a volume of roughly 8,500 µm3 for EC layer II neurons, and DG granule neurons and presubicular neurons were five and 10 times smaller, respectively. The older age group showed a v¯v(soma) increase of 2%, 18% and 28% with respect to the younger group in the PrS, DG and EC regions, respectively. None of these regions showed interhemispheric differences. This quantitative estimation is relevant because the observed variance in the v¯v(soma) estimates suggests that biological variation is the main contributory factor, with intercepts and measurements having a smaller impact. Therefore, we suggest that age has a limited influence on neuronal volume variation in these HF regions, which needs to be compared with similar measurements in neurodegenerative disorders such as Alzheimer's.

Severe manifestations of SARS-CoV-2 in children and adolescents: from COVID-19 pneumonia to multisystem inflammatory syndrome: a multicentre study in pediatric intensive care units in Spain.

BACKGROUND: Multisystem inflammatory syndrome temporally associated with COVID-19 (MIS-C) has been described as a novel and often severe presentation of SARS-CoV-2 infection in children. We aimed to describe the characteristics of children admitted to Pediatric Intensive Care Units (PICUs) presenting with MIS-C in comparison with those admitted with SARS-CoV-2 infection with other features such as COVID-19 pneumonia. METHODS: A multicentric prospective national registry including 47 PICUs was carried out. Data from children admitted with confirmed SARS-CoV-2 infection or fulfilling MIS-C criteria (with or without SARS-CoV-2 PCR confirmation) were collected. Clinical, laboratory and therapeutic features between MIS-C and non-MIS-C patients were compared. RESULTS: Seventy-four children were recruited. Sixty-one percent met MIS-C definition. MIS-C patients were older than non-MIS-C patients (p = 0.002): 9.4 years (IQR 5.5-11.8) vs 3.4 years (IQR 0.4-9.4). A higher proportion of them had no previous medical history of interest (88.2% vs 51.7%, p = 0.005). Non-MIS-C patients presented more frequently with respiratory distress (60.7% vs 13.3%, p < 0.001). MIS-C patients showed higher prevalence of fever (95.6% vs 64.3%, p < 0.001), diarrhea (66.7% vs 11.5%, p < 0.001), vomits (71.1% vs 23.1%, p = 0.001), fatigue (65.9% vs 36%, p = 0.016), shock (84.4% vs 13.8%, p < 0.001) and cardiac dysfunction (53.3% vs 10.3%, p = 0.001). MIS-C group had a lower lymphocyte count (p < 0.001) and LDH (p = 0.001) but higher neutrophil count (p = 0.045), neutrophil/lymphocyte ratio (p < 0.001), C-reactive protein (p < 0.001) and procalcitonin (p < 0.001). Patients in the MIS-C group were less likely to receive invasive ventilation (13.3% vs 41.4%, p = 0.005) but were more often treated with vasoactive drugs (66.7% vs 24.1%, p < 0.001), corticosteroids (80% vs 44.8%, p = 0.003) and immunoglobulins (51.1% vs 6.9%, p < 0.001). Most patients were discharged from PICU by the end of data collection with a median length of stay of 5 days (IQR 2.5-8 days) in the MIS-C group. Three patients died, none of them belonged to the MIS-C group. CONCLUSIONS: MIS-C seems to be the most frequent presentation among critically ill children with SARS-CoV-2 infection. MIS-C patients are older and usually healthy. They show a higher prevalence of gastrointestinal symptoms and shock and are more likely to receive vasoactive drugs and immunomodulators and less likely to need mechanical ventilation than non-MIS-C patients.

An Automated Planning Model for HRI: Use Cases on Social Assistive Robotics.

Using Automated Planning for the high level control of robotic architectures is becoming very popular thanks mainly to its capability to define the tasks to perform in a declarative way. However, classical planning tasks, even in its basic standard Planning Domain Definition Language (PDDL) format, are still very hard to formalize for non expert engineers when the use case to model is complex. Human Robot Interaction (HRI) is one of those complex environments. This manuscript describes the rationale followed to design a planning model able to control social autonomous robots interacting with humans. It is the result of the authors' experience in modeling use cases for Social Assistive Robotics (SAR) in two areas related to healthcare: Comprehensive Geriatric Assessment (CGA) and non-contact rehabilitation therapies for patients with physical impairments. In this work a general definition of these two use cases in a unique planning domain is proposed, which favors the management and integration with the software robotic architecture, as well as the addition of new use cases. Results show that the model is able to capture all the relevant aspects of the Human-Robot interaction in those scenarios, allowing the robot to autonomously perform the tasks by using a standard planning-execution architecture.

Constitutive and Synaptic Activation of GIRK Channels Differentiates Mature and Newborn Dentate Granule Cells.

Sparse neural activity in the dentate gyrus is enforced by powerful networks of inhibitory GABAergic interneurons in combination with low intrinsic excitability of the principal neurons, the dentate granule cells (GCs). Although the cellular and circuit properties that dictate synaptic inhibition are well studied, less is known about mechanisms that confer low GC intrinsic excitability. Here we demonstrate that intact G protein-mediated signaling contributes to the characteristic low resting membrane potential that differentiates mature dentate GCs from CA1 pyramidal cells and developing adult-born GCs. In mature GCs from male and female mice, intact G protein signaling robustly reduces intrinsic excitability, whereas deletion of G protein-activated inwardly rectifying potassium channel 2 (GIRK2) increases excitability and blocks the effects of G protein signaling on intrinsic properties. Similarly, pharmacological manipulation of GABAB receptors (GABABRs) or GIRK channels alters intrinsic excitability and GC spiking behavior. However, adult-born new GCs lack functional GIRK activity, with phasic and constitutive GABABR-mediated GIRK signaling appearing after several weeks of maturation. Phasic activation is interneuron specific, arising primarily from nNOS-expressing interneurons rather than parvalbumin- or somatostatin-expressing interneurons. Together, these results demonstrate that G protein signaling contributes to the intrinsic excitability that differentiates mature and developing dentate GCs and further suggest that late maturation of GIRK channel activity is poised to convert early developmental functions of GABAB receptor signaling into GABABR-mediated inhibition.SIGNIFICANCE STATEMENT The dentate gyrus exhibits sparse neural activity that is essential for the computational function of pattern separation. Sparse activity is ascribed to strong local inhibitory circuits in combination with low intrinsic excitability of the principal neurons, the granule cells. Here we show that constitutive activity of G protein-coupled inwardly rectifying potassium channels (GIRKs) underlies to the hallmark low resting membrane potential and input resistance of mature dentate neurons. Adult-born neurons initially lack functional GIRK channels, with constitutive and phasic GABAB receptor-mediated GIRK inhibition developing in tandem after several weeks of maturation. Our results reveal that GABAB/GIRK activity is an important determinant of low excitability of mature dentate granule cells that may contribute to sparse DG activity in vivo.

The firing frequency of spontaneous action potentials and their corresponding evoked exocytosis are increased in chromaffin cells of CCl4 -induced cirrhotic rats with respect to control rats.

High catecolamine plasma levels because of sympathetic nervous system over-activity contribute to cirrhosis progression. The aim of this study was to investigate whether chromaffin cells of the adrenal gland might potentiate the deleterious effect exerted by this over-activity. Electrophysiological patch-clamp and amperometric experiments with carbon-fibre electrodes were conducted in single chromaffin cells of control and CCl4 -induced cirrhotic rats. The spontaneous action potential firing frequency was increased in chromaffin cells of cirrhotic rats with respect to control rats. The exocytosis evoked by that firing was also increased. However, exocytosis elicited by ACh did not vary between control and cirrhotic rats. Exocytosis triggered by depolarizing pulses was also unchanged. Amperometric recordings confirmed the lack of increased catecholamine charge released in cirrhosis after ACh or depolarization stimuli. However, the amperometric spikes exhibited faster kinetics of release. The overall Ca2+ entry through voltage-dependent Ca2+ channels (VDCC), or in particular through Cav1 channels, did not vary between chromaffin cells of control and cirrhotic rats. The inhibition of VDCC by methionine-enkephaline or ATP was not either altered, but it was increased by adrenaline in cells of cirrhotic rats. When a cocktail composed by the three neurotransmitters was tested in order to approach a situation closer to the physiological condition, the inhibition of VDCC was similar between both types of cells. In summary, chromaffin cells of the adrenal gland might contribute to exacerbate the sympathetic nervous system over-activity in cirrhosis because of an increased exocytosis elicited by an enhanced spontaneous electrical activity.

Prevention of postoperative bleeding in hip fractures treated with prosthetic replacement: efficacy and safety of fibrin sealant and tranexamic acid. A randomised controlled clinical trial (TRANEXFER study).

INTRODUCTION: We assessed the efficacy of fibrin sealant (FS) and tranexamic acid (TXA) administered topically in patients with a hip fracture treated with prosthetic replacement. MATERIALS AND METHODS: Parallel, multicentre, open label, randomised, clinical trial. We compared three interventions to reduce blood loss: (1) 10 ml of FS, (2) 1 g of topical TXA, both administered at the end of the surgery, and (3) usual haemostasis (control group). The main outcome was blood loss collected in drains. Other secondary variables were total blood loss, hidden blood loss, transfusion rate, average hospital stay, complications, adverse events, and mortality. RESULTS: A total of 158 patients were included, 56 in the FS group, 52 in the TXA group, and 50 in the control group. The total amount of blood collected in drains was lower in the TXA group (148.6 ml, SD 122.7 in TXA; 168.2 ml, SD 137.4 in FS; and 201.5 ml, SD 166.5 in control group) without achieving statistical significance (p = 0.178). The transfusion rate was lower in the TXA group (32.7%), compared with FS group (42.9%) and control group (44.0%), without statistical significance (p = 0.341). There were no complications or adverse effects related to the evaluated interventions. CONCLUSIONS: The use of TXA and FS administered topically prior to surgical closure in patients with a sub-capital femoral fracture undergoing arthroplasty did not significantly reduce either postoperative blood loss or transfusion rate, compared with a group that only received usual haemostasis.

Substrate Specificity and Leaving Group Effect in Ester Cleavage by Metal Complexes of an Oximate Nucleophile.

Deprotonated zinc(II) and cadmium(II) complexes of a tridentate oxime nucleophile (1, OxH) show a very high reactivity, breaking by 2-3 orders of magnitude the previously established limiting reactivity of oximate nucleophiles in the cleavage of substituted phenyl acetates and phosphate triesters, but are unreactive with p-nitrophenyl phosphate di- and monoesters. With reactive substrates, these complexes operate as true catalysts through an acylation-deacylation mechanism. Detailed speciation and kinetic studies in a wide pH interval allowed us to establish as catalytically active forms [Cd(Ox)]+, [Zn(Ox)(OH)], and [Zn(Ox)(OH)2]- complexes. The formation of an unusual and most reactive zinc(II) oximatodihydroxo complex was confirmed by electrospray ionization mass spectrometry data and supported by density functional theory calculations, which also supported the previously noticed fact that the coordinated water in [Zn(OxH)(H2O)2]2+ deprotonates before the oxime. Analysis of the leaving group effect on the cleavage of phenyl acetates shows that the rate-determining step in the reaction with the free oximate anion is the nucleophilic attack, while with both zinc(II) and cadmium(II) oximate complexes, it changes to the expulsion of the leaving phenolate anion. The major new features of these complexes are (1) a very high esterolytic activity surpassing that of enzyme hydrolysis of aryl acetate esters and (2) an increased reactivity of coordinated oxime compared to free oxime in phosphate triester cleavage, contrary to the previously observed inhibitory effect of oxime coordination with these substrates.

Trends in nosocomial infections and multidrug-resistant microorganisms in Spanish pediatric intensive care units.

INTRODUCTION: Nosocomial infections (NI) are a major healthcare problem. National surveillance systems enable data to be compared and to implement new measures to improve our practice. METHODS: A multicentre, prospective, descriptive and observational study was conducted using the data from surveillance system for nosocomial infections created in 2007 for Spanish pediatric intensive care units. Data were collected for one month, between 01 and 31 March, for every study year (2008-2012). The objective was to report 5-years of NI surveillance data, as well as trends in infections by multidrug resistant organisms in Spanish pediatric intensive care units. RESULTS: A total of 3667 patients were admitted to the units during the study period. There were 90 (2.45%) patients with nosocomial infections. The mean rates during the 5 years study were: central line-associated bloodstream infection, 3.8/1000 central venous catheter-days, Ventilator-associated pneumonia 7.5/1000 endotracheal tube-days, and catheter-associated urinary tract infections 4.1/1000 urinary catheter-days. The comparison between the 2008 and 2009 rates for nosocomial infections did not show statistically significant differences. All rates homogeneously decreased from 2009 to 2012: central line-associated bloodstream infection 5.83 (95% CI 2.67-11.07) to 0.49 (95% CI 0.0125-2.76), P=0.0029; ventilator-associated pneumonia 10.44 (95% CI 5.21-18.67) to 4.04 (95% CI 1.48-8.80), P=0.0525; and Catheter-associated urinary tract infections 7.10 (95% CI 3.067-13.999) to 2.56 (95% CI 0.697-6.553), P=0.0817; respectively. The microorganism analysis: 63 of the 99 isolated bacteria (63.6%) were Gram-negative bacteria (36.5% were resistant), 19 (19.2%) Gram-positive bacteria, and 17 (17.2%) were Candida spp. infections. CONCLUSIONS: The local surveillance systems provide information for dealing with nosocomial infections rates.

Does nebulized epinephrine improve the efficacy of hypertonic saline solution in the treatment of hospitalized moderate acute bronchiolitis? A double blind, randomized clinical trial.

BACKGROUND: Nebulized 3% hypertonic saline solution (HSS 3%) has proven to reduce hospital stay in infants with acute bronchiolitis, as compared with nebulized physiological saline solutions. There are no studies assessing the effectiveness of nebulized epinephrine in patients treated with HSS 3%. The aim of this study was to compare the length of stay (LOS) in hospitalized patients treated with HSS 3% with placebo vs. HSS 3% with epinephrine. Secondarily we aimed to assess the effectiveness and safety of both treatments. METHODS: We performed a prospective, randomized, double-blind, parallel-group study, including infants hospitalized for moderate acute bronchiolitis. Both groups received standard life support and were randomly treated with nebulized HSS 3% (7 mL) with either placebo 3 mL or epinephrine 3 mL. Nebulizations were initially administered every four hours and this interval was modified according to the patient's response. RESULTS: Sixty-four infants were included, 32 patients in each group. No statistically significant differences were found between the two groups (P=0.948) in length of stay, disease severity, SatO2, respiratory rate or heart rate. On the third day of hospitalization, severity and respiratory rate in the HSS 3%+E presented a non statistically significant trend to an earlier improvement, (P=0.063 and P=0.096 repectively). No adverse events occurred. Four patients (two from each group) required transfer to the pediatric intensive care unit. CONCLUSIONS: With a third of the final estimated sample, we find a trend to an earlier clinical recovery in the epinephrine group, even though no statistical significant differences in LOS were found. The study needs to be continued until the total sample is recruited.

Pneumonia and purulent pericarditis caused by Streptococcus pneumoniae: an uncommon association in the antibiotic era.

Bacterial pericarditis in children has become a rare entity in the modern antibiotic era. The most common pathogen is Staphylococcus aureus, being Streptococcus pneumoniae an exceptional cause. We present 2 children, who were diagnosed of pneumonia complicated with a pleural effusion that developed a purulent pericarditis with signs of cardiac tamponade. One of them had received 4 doses of the 7-valent conjugated pneumococcal vaccine. Systemic antibiotics and pericardial and pleural drainages were used. Pneumococcal antigens were positive in pleural and pericardial fluids in both cases, and S. pneumoniae was isolated from pleural effusion in one of them. Both children fully recovered, and none of them developed constrictive pericarditis, although 1 case presented a transient secondary left ventricular dysfunction. Routine immunization with 10- and 13-valent vaccines including a wider range of serotypes should further decrease the already low incidence.

TAV-in-TAV in patients with prosthesis embolization: Impact of commissural alignment and global outcomes.

BACKGROUND: Optimal strategies to manage embolization of transcatheter aortic valve implantation (TAVI) devices are unclear; valve-in-valve (ViV) is often used. We aimed to describe through one-single center experience its rate, causes, consequences, and management as well as the rate and relevance of commissural alignment (CA) in this context. METHODS: We identified across 1038 TAVI cases, those cases requiring ViV for the management of first device embolization. CA (absence or mild misalignment) after first and second device was assessed by CT or fluoroscopy. RESULTS: A total of 23 cases (2.2%) were identified, 52.3% embolized towards the aorta and 47.7% towards the ventricle. Suboptimal implant height (38%) and embolization at the time of post-dilation (23%) were the most frequent mechanisms together with greater rate of bicuspid valve (p < 0.001) and a trend to greater annular eccentricity. Procedural and 1-year death occurred in 13% and 34%, respectively (vs. 1.1% and 7.8% in the global cohort, p < 0.001). CA was present in 76.9% of the prostheses initially implanted but was only spontaneously achieved in 30.8% of the second ViV device. Adequate CA of both prostheses was identified in only two cases (8.7%). There were no cases of coronary obstruction. CONCLUSIONS: TAVI device embolization mechanisms can often be predicted and prevented. Mortality following bail-out ViV is higher than in regular TAVI procedures but 2/3 of these patients survived beyond 1-year follow-up. In them, valve degeneration or coronary re-access might be particularly challenging since CA was rarely achieved with both devices suggesting that greater efforts should be made in this regard.

Postmortem imaging reveals patterns of medial temporal lobe vulnerability to tau pathology in Alzheimer's disease.

Our current understanding of the spread and neurodegenerative effects of tau neurofibrillary tangles (NFTs) within the medial temporal lobe (MTL) during the early stages of Alzheimer's Disease (AD) is limited by the presence of confounding non-AD pathologies and the two-dimensional (2-D) nature of conventional histology studies. Here, we combine ex vivo MRI and serial histological imaging from 25 human MTL specimens to present a detailed, 3-D characterization of quantitative NFT burden measures in the space of a high-resolution, ex vivo atlas with cytoarchitecturally-defined subregion labels, that can be used to inform future in vivo neuroimaging studies. Average maps show a clear anterior to poster gradient in NFT distribution and a precise, spatial pattern with highest levels of NFTs found not just within the transentorhinal region but also the cornu ammonis (CA1) subfield. Additionally, we identify granular MTL regions where measures of neurodegeneration are likely to be linked to NFTs specifically, and thus potentially more sensitive as early AD biomarkers.

Exocytotic dynamics in human chromaffin cells: experiments and modeling.

Chromaffin cells have been widely used to study neurosecretion since they exhibit similar calcium dependence of several exocytotic steps as synaptic terminals do, but having the enormous advantage of being neither as small or fast as neurons, nor as slow as endocrine cells. In the present study, secretion associated to experimental measurements of the exocytotic dynamics in human chromaffin cells of the adrenal gland was simulated by using a model that combines stochastic and deterministic approaches for short and longer depolarizing pulses, respectively. Experimental data were recorded from human chromaffin cells, obtained from healthy organ donors, using the perforated patch configuration of the patch-clamp technique. We have found that in human chromaffin cells, secretion would be mainly managed by small pools of non-equally fusion competent vesicles, slowly refilled over time. Fast secretion evoked by brief pulses can be predicted only when 75% of one of these pools (the "ready releasable pool" of vesicles, abbreviated as RRP) are co-localized to Ca²âº channels, indicating an immediately releasable pool in the range reported for isolated cells of bovine and rat (Álvarez and Marengo, J Neurochem 116:155-163, 2011). The need for spatial correlation and close proximity of vesicles to Ca²âº channels suggests that in human chromaffin cells there is a tight control of those releasable vesicles available for fast secretion.

Response of water yield to silvicultural treatments in a temperate forest in northern Mexico.

Forest management modifies tree cover, directly influencing various ecosystem services, such as water regulation. Evapotranspiration, water interception, surface runoff, stemflow, and throughfall are among those processes that depend on tree cover. The objective of this study was to evaluate the changes in water yield, defined as the difference between precipitation and evapotranspiration, after the application of silvicultural treatments in a temperate forest ecosystem in northern Mexico. Fifteen experimental plots were established in which the following treatments were applied: intensive management (clearcutting), semi-intensive management (selection, tree cutting of 59-61% of basal area), conservative management (selection, tree cutting of 29-31% of basal area), and no treatment (control group). Incident precipitation, throughfall, stemflow, net precipitation, interception, and surface runoff were analyzed. Results show that conservative management treatments increase water yield between 2 to 3.6 mm per m-2 ha-1 of tree basal area removed. Water flow distribution, in relation to the incident precipitation, ranged from 72.3 to 91.8% for throughfall, 0.2 to 0.4% for stemflow, 72.7 to 91.8% for net precipitation, 8.19 to 27.42% for interception or evaporation, and 0.54 to 1.93% for surface runoff. The conservative management treatment was the most viable alternative for increasing water yield without compromising timber harvesting and loss of soil due to hydric erosion.

Circadian regulation of dentate gyrus excitability mediated by G-protein signaling.

The central circadian regulator within the suprachiasmatic nucleus transmits time of day information by a diurnal spiking rhythm driven by molecular clock genes controlling membrane excitability. Most brain regions, including the hippocampus, harbor similar intrinsic circadian transcriptional machinery, but whether these molecular programs generate oscillations of membrane properties is unclear. Here, we show that intrinsic excitability of mouse dentate granule neurons exhibits a 24-h oscillation that controls spiking probability. Diurnal changes in excitability are mediated by antiphase G-protein regulation of potassium and sodium currents that reduce excitability during the Light phase. Disruption of the circadian transcriptional machinery by conditional deletion of Bmal1 enhances excitability selectively during the Light phase by removing G-protein regulation. These results reveal that circadian transcriptional machinery regulates intrinsic excitability by coordinated regulation of ion channels by G-protein signaling, highlighting a potential novel mechanism of cell-autonomous oscillations.

Percutaneous paravalvular leak closure after transcatheter aortic valve implantation: the international PLUGinTAVI Registry.

BACKGROUND: Data regarding the safety and long-term effectiveness of percutaneous closure of paravalvular leak (PVL) after transcatheter aortic valve implantation (TAVI) are scarce. AIMS: This study aims to present a large multicentre international experience of percutaneous post-TAVI PVL closure. METHODS: All patients who underwent percutaneous post-TAVI PVL closure in 14 hospitals across Europe and North America between January 2018 and October 2022 were included. RESULTS: Overall, 45 patients (64% male) were enrolled. The median age was 80 years (75-84). Among them, 67% and 33% had self-expanding and balloon-expandable valve implantations, respectively. Baseline post-TAVI PVL was severe in 67% of cases and moderate in the rest. The time from index TAVI to PVL closure procedure was 16.1 (8.7-34.8) months. Most patients were in NYHA Class III and IV (73%) before the procedure, and 40% had referred hospitalisations for heart failure between TAVI and the PVL closure procedure. Successful PVL closure was achieved in 94%, reducing regurgitation to ≤mild in 91% and moderate in the rest. The Amplatzer Valvular Plug III was the most frequently used device (27 cases), followed by the Amplatzer Valvular Plug 4. The incidence of severe adverse events was 11%. None of the patients died during the index hospitalisation. During long-term follow-up (21.7±16.2 months), the all-cause mortality rate was 14%, and patients presented improvement in functional status and a significant reduction in the rate of hospitalisation for heart failure (from 40% to 6%). CONCLUSIONS: Percutaneous PVL closure is a feasible and safe option for treating post-TAVI leaks. Successful PVL reduction to mild or less could be associated with acute and long-lasting improvements in clinical outcomes.

Latest-iteration balloon- and self-expandable transcatheter valves for severe bicuspid aortic stenosis: the TRITON study.

INTRODUCTION AND OBJECTIVES: No comparisons have been published yet regarding the newest iteration of balloon- and self-expandable transcatheter heart valves for the treatment of bicuspid aortic valve (BAV) stenosis. METHODS: Multicenter registry of consecutive patients with severe BAV stenosis treated with balloon-expandable transcatheter heart valves (Myval and SAPIEN 3 Ultra, S3U) or self-expanding Evolut PRO+(EP+). TriMatch analysis was carried out to minimize the impact of baseline differences. The primary endpoint of the study was 30-day device success, and the secondary endpoints were the composite and individual components of early safety at 30 days. RESULTS: A total of 360 patients (age 76.6±7.6 years, 71.9% males) were included: 122 Myval (33.9%), 129 S3U (35.8%), and 109 EP+(30.3%). The mean STS score was 3.6±1.9%. There were no cases of coronary artery occlusion, annulus rupture, aortic dissection, or procedural death. The primary endpoint of device success at 30 days was significantly higher in the Myval group (Myval: 100%; S3U: 87.5%; and EP+: 81.3%), mainly due to higher residual aortic gradients with S3U and greater≥moderate aortic regurgitation (AR) with EP+. No significant differences were found in the unadjusted rate of pacemaker implantation. CONCLUSIONS: In patients with BAV stenosis deemed unsuitable for surgery, Myval, S3U and EP+showed similar safety but balloon-expandable Myval had better gradients than S3U, and both balloon-expandable devices had lower residual AR than EP+, suggesting that, taking into consideration the patient-specific risks, any of these devices can be selected with optimal outcomes.

Validation of Quantitative Flow Ratio-Derived Virtual Angioplasty with Post-Angioplasty Fractional Flow Reserve-The QIMERA-I Study.

Background: Quantitative flow ratio (QFR) virtual angioplasty with pre-PCI residual QFR showed better results compared with an angiographic approach to assess post-PCI functional results. However, correlation with pre-PCI residual QFR and post-PCI fractional flow reserve (FFR) is lacking. Methods: A multicenter prospective study including consecutive patients with angiographically 50-90% coronary lesions and positive QFR results. All patients were evaluated with QFR, hyperemic and non-hyperemic pressure ratios (NHPR) before and after the index PCI. Pre-PCI residual QFR (virtual angioplasty) was calculated and compared with post-PCI fractional flow reserve (FFR), QFR and NHPR. Results: A total of 84 patients with 92 treated coronary lesions were included, with a mean age of 65.5 ± 10.9 years and 59% of single vessel lesions being the left anterior descending artery in 69%. The mean vessel diameter was 2.82 ± 0.41 mm. Procedural success was achieved in all cases, with a mean number of implanted stents of 1.17 ± 0.46. The baseline QFR value was 0.69 ± 0.12 and baseline FFR and NHPR were 0.73 ± 0.08 and 0.82 ± 0.11, respectively. Mean post-PCI FFR increased to 0.87 ± 0.05 whereas residual QFR had been estimated as 0.95 ± 0.05, showing poor correlation with post-PCI FFR (0.163; 95% CI:0.078-0.386) and low diagnostic accuracy (30.9%, 95% CI:20-43%). Conclusions: In this analysis, the results of QFR-based virtual angioplasty did not seem to accurately correlate with post-PCI FFR.