Direct Inhibition of BK Channels by Cannabidiol, One of the Principal Therapeutic Cannabinoids Derived from Cannabis sativa.

Cannabidiol (CBD), one of the main Cannabis sativa bioactive compounds, is utilized in the treatment of major epileptic syndromes. Its efficacy can be attributed to a multimodal mechanism of action that includes, as potential targets, several types of ion channels. In the brain, CBD reduces the firing frequency in rat hippocampal neurons, partly prolonging the duration of action potentials, suggesting a potential blockade of voltage-operated K+ channels. We postulate that this effect might involve the inhibition of the large-conductance voltage- and Ca2+-operated K+ channel (BK channel), which plays a role in the neuronal action potential's repolarization. Thus, we assessed the impact of CBD on the BK channel activity, heterologously expressed in HEK293 cells. Our findings, using the patch-clamp technique, revealed that CBD inhibits BK channel currents in a concentration-dependent manner with an IC50 of 280 nM. The inhibition is through a direct interaction, reducing both the unitary conductance and voltage-dependent activation of the channel. Additionally, the cannabinoid significantly delays channel activation kinetics, indicating stabilization of the closed state. These effects could explain the changes induced by CBD in action potential shape and duration, and they may contribute to the observed anticonvulsant activity of this cannabinoid.

LANDMARK comparison of early outcomes of newer-generation Myval transcatheter heart valve series with contemporary valves (Sapien and Evolut) in real-world individuals with severe symptomatic native aortic stenosis: a randomised non-inferiority trial.

BACKGROUND: Transcatheter aortic valve implantation is an established, guideline-endorsed treatment for severe aortic stenosis. Precise sizing of the balloon-expandable Myval transcatheter heart valve (THV) series with the aortic annulus is facilitated by increasing its diameter in 1·5 mm increments, compared with the usual 3 mm increments in valve size. The LANDMARK trial aimed to show non-inferiority of the Myval THV series compared with the contemporary THVs Sapien Series (Edwards Lifesciences, Irvine, CA, USA) or Evolut Series (Medtronic, Minneapolis, MN, USA). METHODS: In this prospective, multinational, randomised, open-label, non-inferiority trial across 31 hospitals in 16 countries (Germany, France, Sweden, the Netherlands, Italy, Spain, New Zealand, Portugal, Greece, Hungary, Poland, Slovakia, Slovenia, Croatia, Estonia, and Brazil), 768 participants with severe symptomatic native aortic stenosis were randomly assigned (1:1) to the Myval THV or a contemporary THV. Eligibility was primarily decided by the heart team in accordance with 2021 European Society of Cardiology guidelines. As per the criteria of the third Valve Academic Research Consortium, the primary endpoint at 30 days was a composite of all-cause mortality, all stroke, bleeding (types 3 and 4), acute kidney injury (stages 2-4), major vascular complications, moderate or severe prosthetic valve regurgitation, and conduction system disturbances resulting in a permanent pacemaker implantation. Non-inferiority of the study device was tested in the intention-to-treat population using a non-inferiority margin of 10·44% and assuming an event rate of 26·10%. This trial is registered with ClinicalTrials.gov, NCT04275726, and EudraCT, 2020-000137-40, and is closed to new participants. FINDINGS: Between Jan 6, 2021, and Dec 5, 2023, 768 participants with severe symptomatic native aortic stenosis were randomly assigned, 384 to the Myval THV and 384 to a contemporary THV. 369 (48%) participants had their sex recorded as female, and 399 (52%) as male. The mean age of participants was 80·0 years (SD 5·7) for those treated with the Myval THV and 80·4 years (5·4) for those treated with a contemporary THV. Median Society of Thoracic Surgeons scores were the same in both groups (Myval 2·6% [IQR 1·7-4·0] vs contemporary 2·6% [1·7-4·0]). The primary endpoint showed non-inferiority of the Myval (25%) compared with contemporary THV (27%), with a risk difference of -2·3% (one-sided upper 95% CI 3·8, pnon-inferiority<0·0001). No significant difference was seen in individual components of the primary composite endpoint. INTERPRETATION: In individuals with severe symptomatic native aortic stenosis, the Myval THV met its primary endpoint at 30 days. FUNDING: Meril Life Sciences.

LANDMARK comparison of early outcomes of newer-generation Myval transcatheter heart valve series with contemporary valves (Sapien and Evolut) in real-world individuals with severe symptomatic native aortic stenosis: a randomised non-inferiority trial

BACKGROUND Transcatheter aortic valve implantation is an established, guideline-endorsed treatment for severe aortic stenosis. Precise sizing of the balloon-expandable Myval transcatheter heart valve (THV) series with the aortic annulus is facilitated by increasing its diameter in 1•5 mm increments, compared with the usual 3 mm increments in valve size. The LANDMARK trial aimed to show non-inferiority of the Myval THV series compared with the contemporary THVs Sapien Series (Edwards Lifesciences, Irvine, CA, USA) or Evolut Series (Medtronic, Minneapolis, MN, USA). METHODS In this prospective, multinational, randomised, open-label, non-inferiority trial across 31 hospitals in 16 countries (Germany, France, Sweden, the Netherlands, Italy, Spain, New Zealand, Portugal, Greece, Hungary, Poland, Slovakia, Slovenia, Croatia, Estonia, and Brazil), 768 participants with severe symptomatic native aortic stenosis were randomly assigned (1:1) to the Myval THV or a contemporary THV. Eligibility was primarily decided by the heart team in accordance with 2021 European Society of Cardiology guidelines. As per the criteria of the third Valve Academic Research Consortium, the primary endpoint at 30 days was a composite of all-cause mortality, all stroke, bleeding (types 3 and 4), acute kidney injury (stages 2­4), major vascular complications, moderate or severe prosthetic valve regurgitation, and conduction system disturbances resulting in a permanent pacemaker implantation. Non-inferiority of the study device was tested in the intention-to-treat population using a non-inferiority margin of 10•44% and assuming an event rate of 26•10%. This trial is registered with ClinicalTrials.gov, NCT04275726, and EudraCT, 2020-000137-40, and is closed to new participants. FINDINGS Between Jan 6, 2021, and Dec 5, 2023, 768 participants with severe symptomatic native aortic stenosis were randomly assigned, 384 to the Myval THV and 384 to a contemporary THV. 369 (48%) participants had their sex recorded as female, and 399 (52%) as male. The mean age of participants was 80•0 years (SD 5•7) for those treated with the Myval THV and 80•4 years (5•4) for those treated with a contemporary THV. Median Society of Thoracic Surgeons scores were the same in both groups (Myval 2•6% [IQR 1•7­4•0] vs contemporary 2•6% [1•7­4•0]). The primary endpoint showed non-inferiority of the Myval (25%) compared with contemporary THV (27%), with a risk difference of ­2•3% (one-sided upper 95% CI 3•8, pnon-inferiority<0•0001). No significant difference was seen in individual components of the primary composite endpoint. INTERPRETATION In individuals with severe symptomatic native aortic stenosis, the Myval THV met its primary endpoint at 30 days.

Miastenia gravis y enfermedad de Alzheimer: una asociación a estudio / Association between myasthenia gravis and Alzheimer’s disease

Introducción La miastenia gravis (MG) y la enfermedad de Alzheimer (EA) son dos de las enfermedades neurológicas en cuya fisiopatología interviene la acetilcolina en distintos niveles. En la primera, la alteración de este neurotransmisor se produce en la unión neuromuscular, y en la segunda, en el sistema nervioso central. Objetivo Analizar la posible relación entre dichas patologías estudiando la prevalencia y la odds ratio de la EA dentro de los pacientes diagnosticados de MG con respecto a la prevalencia de EA en la población general. Pacientes y métodos Se han examinado datos de las historias clínicas electrónicas del sistema de salud de Castilla-La Mancha utilizando el procesamiento de lenguaje natural a través de la plataforma clínica de inteligencia artificial Savana Manager?. Resultados Se ha identificado a 970.503 pacientes mayores de 60 años, de los que 1.028 tenían diagnóstico de MG. La proporción de pacientes con diagnóstico de EA dentro de este grupo (4,28%) es mayor que en el resto de la población (2,82%; p = 0,0047), con una odds ratio de 1,54 (intervalo de confianza al 95%: 1,13-2,08; p = 0,0051), sin que se encuentren diferencias significativas en el análisis bivariante del resto de los factores de riesgo para EA más importantes conocidos hasta ahora. Conclusiones Nuestros resultados sugieren que podría existir un aumento de la prevalencia de EA en pacientes con MG. (AU)

INTRODUCTION Myasthenia gravis (MG) and Alzheimer’s disease (AD) are two of the most important diseases where the dysregulation of acetylcholine activity plays a crucial role. In the first, this dysregulation happens at the level of the neu­romuscular junction and in the second, in the central nervous system (CNS). AIM To analyze the possible relationship between these two pathologies, analyzing the prevalence and the odds ratio of AD within patients previously diagnosed with MG. We will compare these data with respect to the prevalence of AD in the general population. PATIENTS AND METHODS We examined the data obtained by the electronic medical records of patients in the health care system of Castilla La Mancha using the Natural Language Process provided by a clinical platform of artificial intelligence known as the Savana Manager?. RESULTS We identified 970,503 patients over the age of 60 years, of which 1,028 were diagnosed with MG. The proportion of the patients diagnosed with AD within this group (4.28%) was greater than the rest of the population (2.82%) (p = 0,0047) with an odds ratio of 1.54 (confidence interval at 95% 1.13-2.08; p = 0.0051) without finding significant differences in the bivariate analysis for the rest of the most important actual known risk factors for AD. CONCLUSION. Our results suggest that there might be an increase in the prevalence of AD in patients previously diagnosed with MG. (AU)

A Combined Ligand- and Structure-Based Virtual Screening To Identify Novel NaV1.2 Blockers: In Vitro Patch Clamp Validation and In Vivo Anticonvulsant Activity.

Epilepsy is a neurological disorder characterized by recurrent seizures that arise from abnormal electrical activity in the brain. Voltage-gated sodium channels (NaVs), responsible for the initiation and propagation of action potentials in neurons, play a critical role in the pathogenesis of epilepsy. This study sought to discover potential anticonvulsant compounds that interact with NaVs, specifically, the brain subtype hNaV1.2. A ligand-based QSAR model and a docking model were constructed, validated, and applied in a parallel virtual screening over the DrugBank database. Montelukast, Novobiocin, and Cinnarizine were selected for in vitro testing, using the patch-clamp technique, and all of them proved to inhibit hNaV1.2 channels heterologously expressed in HEK293 cells. Two hits were evaluated in the GASH/Sal model of audiogenic seizures and demonstrated promising activity, reducing the severity of sound-induced seizures at the doses tested. The combination of ligand- and structure-based models presents a valuable approach for identifying potential NaV inhibitors. These findings may provide a basis for further research into the development of new antiseizure drugs for the treatment of epilepsy.

A study of microbial diversity in a biofertilizer consortium.

Biofertilizers supply living microorganisms to help plants grow and keep their health. This study examines the microbiome composition of a commercial biofertilizer known for its plant growth-promoting activity. Using ITS and 16S rRNA gene sequence analyses, we describe the microbial communities of a biofertilizer, with 163 fungal species and 485 bacterial genera found. The biofertilizer contains a variety of microorganisms previously reported to enhance nutrient uptake, phytohormone production, stress tolerance, and pathogen resistance in plants. Plant roots created a microenvironment that boosted bacterial diversity but filtered fungal communities. Notably, preserving the fungal-inoculated substrate proves critical for keeping fungal diversity in the root fraction. We described that bacteria were more diverse in the rhizosphere than in the substrate. In contrast, root-associated fungi were less diverse than the substrate ones. We propose using plant roots as bioreactors to sustain dynamic environments that promote the proliferation of microorganisms with biofertilizer potential. The study suggests that bacteria grow close to plant roots, while root-associated fungi may be a subset of the substrate fungi. These findings show that the composition of the biofertilizer may be influenced by the selection of microorganisms associated with plant roots, which could have implications for the effectiveness of the biofertilizer in promoting plant growth. In conclusion, our study sheds light on the intricate interplay between plant roots and the biofertilizer's microbial communities. Understanding this relationship can aid in optimizing biofertilizer production and application, contributing to sustainable agricultural practices and improved crop yields.

Advanced Liquid Chromatography with Tandem Mass Spectrometry Method for Quantifying Glyphosate, Glufosinate, and Aminomethylphosphonic Acid Using Pre-Column Derivatization.

Analytical limitations make it challenging to develop effective methodologies for understanding glyphosate-based herbicide levels in drinking water and groundwater. Due to their lack of chromophores and zwitterionic nature, glyphosate-based herbicides are difficult to detect using traditional methods. This paper offers a straightforward method for quantifying glyphosate, glufosinate, and aminomethylphosphonic acid (AMPA) via 9-fluorenylmethylchloroformate (FMOC-Cl) pre-column derivatization and analysis by liquid chromatography with tandem mass spectrometry (LC-MS/MS). Method development was focused on optimizing the critical variables for optimal derivatization using a 24-factorial design. We found that complete derivatization significantly depends on the inclusion of borate buffer to create the alkaline conditions necessary for aminolysis. Ethylenediaminetetraacetic acid (EDTA) addition was critical to minimize metallic chelation and ensure reproducible retention times and peaks. However, EDTA concentrations ≥5% decreased peak intensity due to ion suppression. The FMOC-Cl concentration and derivatization time exhibited a direct proportional relationship, with the complete reaction achieved with 2.5 mM FMOC-Cl after 4 h. Concentrations of FMOC-Cl greater than 2.5 mM led to the formation of oxides, which interfere with the detection sensitivity and selectivity. Desirable results were achieved with 1% EDTA, 5% borate, and 2.5 mM FMOC-Cl, which led to complete derivatization after 4 h.

Clinical outcomes of TAVI with the Myval balloon-expandable valve for non-calcified aortic regurgitation.

BACKGROUND: Transcatheter aortic valve replacement (TAVR) in non-calcified aortic regurgitation (NCAR) is an off-label procedure. The balloon-expandable Myval includes extra-large sizes (30.5 mm and 32 mm) of interest in this setting. AIMS: We aimed to evaluate the safety and feasibility of Myval in NCAR. METHODS: This was an international, multicentre, observational study that enrolled all consecutive patients with symptomatic severe NCAR undergoing TAVR with the Myval device. The images were centrally analysed. RESULTS: A total of 113 patients were recruited, 64.6% were men, the mean age was 78.4±7.5 years, and the Society of Thoracic Surgeons score was 2.7±1.7%. Aortic root dilatation was present in 59.3% of patients, 7.1% were bicuspid, and the mean annular area was 638.6±106.0 mm2. The annular area was beyond the recommended range for extra-large sizes in 2.6% of cases, and additional volume was added in 92% (median 4 cc, up to 9 cc). The extra-large sizes were used in 95 patients (84.1%), and the mean oversizing was 17.9±11.0%. The technical success rate was 94.7%; the rate of residual ≥moderate aortic regurgitation was 8.9%, and the pacemaker rate was 22.2%. There were no cases of annular rupture, cardiac tamponade, or aortic dissection, but in 4 patients (3.5%) valve embolisation occurred (1 antegrade and 3 ventricular), all in cases with a tapered left ventricle outflow tract (p=0.007). Thirty-day and 1-year mortality were 5.3% and 9.7%, respectively. Technical success was associated with better survival (97.1% vs 72.7%; p=0.012), and valve embolisation was the main determinant of mortality (p=0.047). CONCLUSIONS: Myval is a feasible and safe option for selected non-operable patients with NCAR and demonstrated good midterm outcomes and lack of impact of oversizing on device durability.

Upper gastrointestinal bleeding and Rigler triad.

Gallstone ileus is a rare complication of cholelithiasis, characterized by mechanical bowel obstruction due to a biliary calculus originating from a bilioenteric fistula. The Rigler triad, consisting of aerobilia, ectopic gallstone, and intestinal obstruction, is rarely observed in its complete form. We present the case of a 92-year-old male with a history of acute lithiasic cholecystitis who presented to the Emergency department with acute epigastric pain. Initial evaluation revealed gallbladder dilatation, gallstones, and gallbladder wall thickening suggestive of acute cholecystitis. During hospitalization, the patient experienced an episode of hematemesis, leading to the diagnosis of a cholecystoduodenal fistula and a large blood clot in the duodenal bulb. Further imaging showed an ectopic gallstone causing small bowel obstruction. The patient underwent urgent surgery for stone extraction, followed by endoscopic intervention for the bleeding vessel identified at a subsequent gastroscopy. Unfortunately, the patient had a poor postoperative course and passed away seven days later. This case report highlights the exceptional occurrence of both the Rigler triad and upper gastrointestinal bleeding in a patient with gallstone ileus. Surgical intervention is crucial for the initial resolution of intestinal obstruction, followed by cholecystectomy and repair of the bilioenteric fistula. Awareness of these rare presentations is important for timely diagnosis and appropriate management of this uncommon complication of cholelithiasis.

Sympathetic nervous activation, mitochondrial dysfunction and outcome in acutely decompensated cirrhosis: the metabolomic prognostic models (CLIF-C MET).

BACKGROUND AND AIMS: Current prognostic scores of patients with acutely decompensated cirrhosis (AD), particularly those with acute-on-chronic liver failure (ACLF), underestimate the risk of mortality. This is probably because systemic inflammation (SI), the major driver of AD/ACLF, is not reflected in the scores. SI induces metabolic changes, which impair delivery of the necessary energy for the immune reaction. This investigation aimed to identify metabolites associated with short-term (28-day) death and to design metabolomic prognostic models. METHODS: Two prospective multicentre large cohorts from Europe for investigating ACLF and development of ACLF, CANONIC (discovery, n=831) and PREDICT (validation, n=851), were explored by untargeted serum metabolomics to identify and validate metabolites which could allow improved prognostic modelling. RESULTS: Three prognostic metabolites strongly associated with death were selected to build the models. 4-Hydroxy-3-methoxyphenylglycol sulfate is a norepinephrine derivative, which may be derived from the brainstem response to SI. Additionally, galacturonic acid and hexanoylcarnitine are associated with mitochondrial dysfunction. Model 1 included only these three prognostic metabolites and age. Model 2 was built around 4-hydroxy-3-methoxyphenylglycol sulfate, hexanoylcarnitine, bilirubin, international normalised ratio (INR) and age. In the discovery cohort, both models were more accurate in predicting death within 7, 14 and 28 days after admission compared with MELDNa score (C-index: 0.9267, 0.9002 and 0.8424, and 0.9369, 0.9206 and 0.8529, with model 1 and model 2, respectively). Similar results were found in the validation cohort (C-index: 0.940, 0.834 and 0.791, and 0.947, 0.857 and 0.810, with model 1 and model 2, respectively). Also, in ACLF, model 1 and model 2 outperformed MELDNa 7, 14 and 28 days after admission for prediction of mortality. CONCLUSIONS: Models including metabolites (CLIF-C MET) reflecting SI, mitochondrial dysfunction and sympathetic system activation are better predictors of short-term mortality than scores based only on organ dysfunction (eg, MELDNa), especially in patients with ACLF.

Transcatheter valve-in-valve or valve-in-ring implantation with a novel balloon-expandable device in patients with bioprosthetic left side heart valves failure: 1-year follow-up from a multicenter experience.

BACKGROUND: Transcatheter aortic and mitral valve-in-valve (ViV) or valve-in-ring (ViR) implantation into failed bioprosthetic heart valves (BHVs) or rings represents an appealing, less invasive, treatment option for patients at high surgical risk. Nowadays, few data have been reported on the use of balloon-expandable Myval (Meril Life Science, Vapi, India) transcatheter heart valve (THV) for the treatment of degenerated BHVs or rings. We aimed at evaluating the early and mid-term clinical outcomes of patients with left side heart bioprosthesis deterioration treated with transcatheter ViV/ViR implantation using Myval THV. METHODS: 97 consecutive patients with symptomatic, severe aortic(n=33) and mitral(n=64) BHVs/ring dysfunction underwent transcatheter aortic ViV and mitral ViV/ViR implantation with Myval THV. RESULTS: Technical success was achieved in 95 (98%) of the patients. Two cases of acute structural trans-catheter mitral ViV/ViR dysfunction requiring a second THV implantation were reported. At 30-day, a significant reduction in prosthetic trans-valvular pressure gradients and increase in valve areas were seen following both aortic and mitral ViV/ViR implantation. Overall survival at 15 months (IQR 8-21) was 92%. Patients undergoing mitral ViV/ViR had a relatively worse survival compared with those undergoing aortic ViV implantation (89% vs. 97% respectively; HR:2.7,CI:0.33-22.7;p=0.34). At longest follow-up available a significant improvement in NYHA functional class I and II was observed in patients with aortic and mitral ViV/ViR implantation(93.8% and 92.1%). CONCLUSIONS: Despite high surgical risk, transcatheter ViV/ViR implantation for failed left side heart bioprosthesis can be performed safely using Myval THV with a high success rate and low early and mid-term mortality and morbidity.

Vagus Nerve Stimulation in the Carotid Triangle: An Effective Method for Monitoring the Recurrent Laryngeal Nerve in Thyroid and Parathyroid Surgery.

OBJECTIVE: Our objective is the description of the technique of vagus nerve stimulation in carotid triangle in order to monitor the recurrent laryngeal nerve (RLN) during thyroid and parathyroid surgery. METHODS: We stimulated the vagus nerve in the carotid triangle during 150 thyroid or parathyroid surgeries using a monopolar electromyography electrode inserted under the mastoid process towards the jugular foramen as a cathode, and using another subdermal electrode in the mastoid as an anode. Another complementary method of vagus stimulation was achieved with a pair of subdermal electrodes, placing the cathode at the mandibular angle and the anode at the mastoid. RESULTS: In all patients, compound muscle action potential (CMAP) was recorded in the vocal cords with both stimulation techniques, allowing semi-continuous monitoring to be carried out. Intraoperative lesions were detected in 16 of the cases; 9 of them were transient with CMAP recovery achieved when modifying surgical maneuvers. CONCLUSIONS: Vagus nerve stimulation in the carotid triangle is a reliable technique for monitoring the RLN in thyroid surgery. Vagus nerve stimulation in the carotid triangle is effective and safe for RLN monitoring, and it is a clear alternative to direct continuous stimulation of the nerve that by contrast requires its dissection in the carotid sheath.

Checking Different Video Game Mechanics to Assess Cognitive Abilities in Groups with and without Emotional Problems.

This study assesses cognitive abilities through video games for entertainment (Blek, Edge, and Unpossible) that were programmed from scratch to record players' behavior and the levels achieved in a sample without emotional problems and in one with emotional problems. The non-emotional-problem sample was recruited from three universities and two bachelor's degree programs. The emotional-problem sample was recruited from two outpatient centers. The participants in the emotional-problem sample completed reduced versions of the ability tests and video games, as required by their emotional problems. Three subtests of the Differential Aptitude Test that assessed abstract reasoning, visuospatial reasoning, and perceptual speed were selected as ability tests. All participants were required to complete a mental health questionnaire (PROMIS) and a brief questionnaire on their gaming habits and previous experience with the video games used. The results that were obtained showed good convergent validity of the video games as measures of cognitive abilities, and they showed that the behavior of players in the sample without emotional problems while playing predicted the level achieved in the Blek and Unpossible game fragments, but this was only true for Unpossible in the emotional-problem sample; finally, shorter versions of the Blek and Edge game fragments can be used because they maintain their good psychometric properties.

Experiences of first year undergraduate nursing students using Instagram in their clinical practicum during COVID-19 pandemic: A qualitative study.

BACKGROUND: Social media provides us with easy access to information. For students, it is an additional learning resource used in different types of theoretical and practical teaching methodologies. OBJECTIVES: The aim of this paper was to describe the perspective of undergraduate nursing students on the use of Instagram during their clinical practicums in the midst of the COVID-19 pandemic. DESIGN: A qualitative descriptive and exploratory study based on an interpretative framework. SETTINGS AND PARTICIPANTS: First-year undergraduate nursing students at the Universidad Europea de Madrid were included. METHODS: In-depth interviews and researchers' field notes were used to collect the data. Purposive sampling and inductive thematic analysis were applied. During the interviews, themes such as accompaniment during practicums or training opportunities were identified. RESULTS: The use of Instagram helped students to feel closer to professors, identifying it as an opportunity to remedy the possible lack of connection between theory and practice. Moreover, Instagram helped them build an image of nursing in clinical practicum environments. By using Instagram, undergraduate nursing students were able to better integrate and apply the knowledge acquired at university during their clinical practicums in hospitals. CONCLUSIONS: Our results can be applied to future studies on the use of social media platforms as teaching tools in clinical practicum settings and to observe the evolution of the image and role of nursing and its relationship with social media.

Structure-Based Virtual Screening Identifies Novobiocin, Montelukast, and Cinnarizine as TRPV1 Modulators with Anticonvulsant Activity In Vivo.

The transient receptor potential vanilloid 1 (TRPV1) receptor is a nonselective cation channel, known to be involved in the regulation of many important physiological and pathological processes. In the last few years, it has been proposed as a promising target to develop novel anticonvulsant compounds. However, thermoregulatory effects associated with the channel inhibition have hampered the path for TRPV1 antagonists to become marketed drugs. In this regard, we conducted a structure-based virtual screening campaign to find potential TRPV1 modulators among approved drugs, which are known to be safe and thermally neutral. To this end, different docking models were developed and validated by assessing their pose and score prediction powers. Novobiocin, montelukast, and cinnarizine were selected from the screening as promising candidates for experimental testing and all of them exhibited nanomolar inhibitory activity. Moreover, the in vivo profiles showed promising results in at least one of the three models of seizures tested.

Ability of lactate, procalcitonin, and criteria defining sepsis to predict 30-day mortality, bacteremia, and microbiologically confirmed infection in patients with infection suspicion treated in emergency departments. / Capacidad del lactato, procalcitonina y de los criterios definitorios de sepsis para predecir mortalidad a 30 días, bacteriemia o infección confirmada microbiológicamente en los pacientes atendidos por sospecha de infección en urgencias.

OBJECTIVES: To evaluate lactate, procalcitonin, criteria defining systemic inflammatory response syndrome (SIRS), and the Quick Sepsis-Related Organ Failure Assessment (qSOFA) and compare their ability to predict 30-day mortality, infection with microbiologic confirmation, and true bacteremia in patients treated for infection in hospital emergency departments. MATERIAL AND METHODS: Prospective multicenter observational cohort study. We enrolled a convenience sample of patients aged 18 years or older attended in 71 Spanish emergency departments from October 1, 2019, to March 31, 2020. Each model's predictive power was analyzed with the area under the receiver operating characteristic curve (AUC), and predetermined decision points were assessed. RESULTS: A total of 4439 patients with a mean (SD) age of 18 years were studied; 2648 (59.7%) were men and 459 (10.3%) died within 30 days. True bacteremia was detected in 899 (20.25%), and microbiologic confirmation was on record for 2057 (46.3%). The model that included the qSOFA score (2) and lactate concentration (0.738 mmol/L; 95% CI, 0.711-0.765 mmol/L) proved to be the best predictor of 30-day mortality, with an AUC of 0.890 (95% CI, 0.880-0.901). The model that included the SIRS score (2) and procalcitonin concentration (0.51 ng/mL) proved to be the best predictor of true bacteremia and microbiologic confirmation, with an AUC of 0.713 (95% CI, 0.698-0.728). CONCLUSION: A qSOFA score of 2 or more plus lactate concentration (0.738 mmol/L) predict 30-day mortality better than the combination of a SIRS score of 2 or more and procalcitonin concentration. A SIRS score of 2 or more plus procalcitonin concentration (0.51 ng/mL) predict true bacteremia and microbiologic confirmation.

OBJETIVO: Evaluar y comparar la capacidad del lactato, la procalcitonina (PCT) y de los criterios definitorios de sepsis (síndrome de respuesta inflamatoria sistémica ­SRIS­ y del quick Sepsis-related Organ Failure Assessment ­qSOFA­) para predecir mortalidad a 30 días, o infección ­con confirmación microbiológica o bacteriemia verdadera (BV)­ en los pacientes que acuden al servicio de urgencias hospitalario (SUH) por un episodio de sospecha de infección. METODO: Estudio observacional de cohortes, multicéntrico, prospectivo. Se incluyó por oportunidad a pacientes 18 años atendidos por sospecha de infección en 71 SUH españoles desde el 01/10/2019 al 31/03/2020. Se analizó la capacidad predictiva con el área bajo la curva (ABC) de la característica operativa del receptor (COR) y puntos de decisión predeterminados. RESULTADOS: Se incluyeron 4.439 pacientes con edad media de 67 (18) años, 2.648 (59,7%) fueron hombres, fallecieron a los 30 días 459 (10,3%), se consideraron BV 899 (20,2%) y se consiguió confirmación microbiológica en 2.057 (46,3%). Para la mortalidad a 30 días la mejor ABC-COR fue la obtenida con el modelo qSOFA 2 más lactato 2 mmol/l con un ABC-COR de 0,738 (0,711-0,765). Para predecir BV y confirmación microbiológica el mejor rendimiento se obtuvo con el modelo de SRIS 2 más PCT 0,51 ng/ml, con un ABC-COR de 0,890 (0,880-0,901) y 0,713 (0,698-0,728), respectivamente. CONCLUSIONES: Para la predicción de mortalidad a 30 días, el qSOFA 2 es superior al SRIS 2 y el mejor rendimiento lo consigue el modelo qSOFA 2 más lactato 2 mmol/l. Para predecir BV y confirmación microbiológica, la PCT es superior al lactato y el mejor rendimiento lo obtiene el modelo SRIS 2 más PCT 0,51 ng/ml.

Novel Dimeric hHv1 Model and Structural Bioinformatic Analysis Reveal an ATP-Binding Site Resulting in a Channel Activating Effect.

The human voltage-gated proton channel (hHv1) is a highly selective ion channel codified by the HVCN1 gene. It plays a fundamental role in several physiological processes such as innate and adaptive immunity, insulin secretion, and sperm capacitation. Moreover, in humans, a higher hHv1 expression/function has been reported in several types of cancer cells. Here we report a multitemplate homology model of the hHv1 channel, built and refined as a dimer in Rosetta. The model was then subjected to extensive Gaussian accelerated molecular dynamics (GaMD) for enhanced conformational sampling, and representative snapshots were extracted by clustering analysis. Combining different structure- and sequence-based methodologies, we predicted a putative ATP-binding site located on the intracellular portion of the channel. Furthermore, GaMD simulations of the ATP-bound dimeric hHv1 model showed that ATP interacts with a cluster of positively charged residues from the cytoplasmic N and C terminal segments. According to the in silico predictions, we found that 3 mM intracellular ATP significantly increases the H+ current mediated by the hHv1 channel expressed in HEK293 cells and measured by the patch-clamp technique in an inside-out configuration (2.86 ± 0.63 fold over control at +40 mV). When ATP was added on the extracellular side, it was not able to activate the channel supporting the idea that the ATP-binding site resides in the intracellular face of the hHV1 channel. In a physiological and pathophysiological context, this ATP-mediated modulation could integrate the cell metabolic state with the H+ efflux, especially in cells where hHv1 channels are relevant for pH regulation, such as pancreatic ß-cells, immune cells, and cancer cells.

Capacidad del lactato, procalcitonina y de los criterios definitorios de sepsis para predecir mortalidad a 30 días, bacteriemia o infección confirmada microbiológicamente en los pacientes atendidos por sospecha de infección en urgencias / Ability of lactate, procalcitonin, and criteria defining sepsis to predict 30-day mortality, bacteremia, and microbiologically confirmed infection in patients with infection suspicion treated in emergency departments

Objetivo. Evaluar y comparar la capacidad del lactato, la procalcitonina (PCT) y de los criterios definitorios de sepsis (síndrome de respuesta inflamatoria sistémica –SRIS– y del quick Sepsis-related Organ Failure Assessment –qSOFA–) para predecir mortalidad a 30 días, o infección –con confirmación microbiológica o bacteriemia verdadera (BV)– en los pa- cientes que acuden al servicio de urgencias hospitalario (SUH) por un episodio de sospecha de infección. Método. Estudio observacional de cohortes, multicéntrico, prospectivo. Se incluyó por oportunidad a pacientes $ 18 años atendidos por sospecha de infección en 71 SUH españoles desde el 01/10/2019 al 31/03/2020. Se analizó la capacidad predictiva con el área bajo la curva (ABC) de la característica operativa del receptor (COR) y puntos de de- cisión predeterminados. Resultados. Se incluyeron 4.439 pacientes con edad media de 67 (18) años, 2.648 (59,7%) fueron hombres, fallecie- ron a los 30 días 459 (10,3%), se consideraron BV 899 (20,2%) y se consiguió confirmación microbiológica en 2.057 (46,3%). Para la mortalidad a 30 días la mejor ABC-COR fue la obtenida con el modelo qSOFA $ 2 más lactato $ 2 mmol/l con un ABC-COR de 0,738 (0,711-0,765). Para predecir BV y confirmación microbiológica el mejor rendi- miento se obtuvo con el modelo de SRIS $ 2 más PCT $ 0,51 ng/ml, con un ABC-COR de 0,890 (0,880-0,901) y 0,713 (0,698-0,728), respectivamente. Conclusiones. Para la predicción de mortalidad a 30 días, el qSOFA $ 2 es superior al SRIS $ 2 y el mejor rendimien- to lo consigue el modelo qSOFA $ 2 más lactato $ 2 mmol/l. Para predecir BV y confirmación microbiológica, la PCT es superior al lactato y el mejor rendimiento lo obtiene el modelo SRIS $ 2 más PCT $ 0,51 ng/ml.

Objectives. To evaluate lactate, procalcitonin, criteria defining systemic inflammatory response syndrome (SIRS), and the Quick Sepsis-Related Organ Failure Assessment (qSOFA) and compare their ability to predict 30-day mortality, infection with microbiologic confirmation, and true bacteremia in patients treated for infection in hospital emergency departments. Methods. Prospective multicenter observational cohort study. We enrolled a convenience sample of patients aged 18 years or older attended in 71 Spanish emergency departments from October 1, 2019, to March 31, 2020. Each model’s predictive power was analyzed with the area under the receiver operating characteristic curve (AUC), and predetermined decision points were assessed. Results. A total of 4439 patients with a mean (SD) age of 18 years were studied; 2648 (59.7%) were men and 459 (10.3%) died within 30 days. True bacteremia was detected in 899 (20.25%), and microbiologic confirmation was on record for 2057 (46.3%). The model that included the qSOFA score ($ 2) and lactate concentration ($ 0.738 mmol/L; 95% CI, 0.711-0.765 mmol/L) proved to be the best predictor of 30-day mortality, with an AUC of 0.890 (95% CI, 0.880-0.901). The model that included the SIRS score ($ 2) and procalcitonin concentration ($ 0.51 ng/mL) proved to be the best predictor of true bacteremia and microbiologic confirmation, with an AUC of 0.713 (95% CI, 0.698-0.728). Conclusions. A qSOFA score of 2 or more plus lactate concentration ($ 0.738 mmol/L) predict 30-day mortality better than the combination of a SIRS score of 2 or more and procalcitonin concentration. A SIRS score of 2 or more plus procalcitonin concentration ($ 0.51 ng/mL) predict true bacteremia and microbiologic confirmation.