Characterization of natural product inhibitors of quorum sensing in Pseudomonas aeruginosa reveals competitive inhibition of RhlR by ortho-vanillin.

Quorum sensing (QS) is a cell-cell signaling system that enables bacteria to coordinate population density-dependent changes in behavior. This chemical communication pathway is mediated by diffusible N-acyl L-homoserine lactone signals and cytoplasmic signal-responsive LuxR-type receptors in Gram-negative bacteria. As many common pathogenic bacteria use QS to regulate virulence, there is significant interest in disrupting QS as a potential therapeutic strategy. Prior studies have implicated the natural products salicylic acid, cinnamaldehyde and other related benzaldehyde derivatives as inhibitors of QS in the opportunistic pathogen Pseudomonas aeruginosa, yet we lack an understanding of the mechanisms by which these compounds function. Herein, we evaluate the activity of a set of benzaldehyde derivatives using heterologous reporters of the P. aeruginosa LasR and RhlR QS signal receptors. We find that most tested benzaldehyde derivatives can antagonize LasR or RhlR reporter activation at micromolar concentrations, although certain molecules also caused mild growth defects and nonspecific reporter antagonism. Notably, several compounds showed promising RhlR or LasR specific inhibitory activities over a range of concentrations below that causing toxicity. Ortho-Vanillin, a previously untested compound, was the most promising within this set. Competition experiments against the native ligands for LasR and RhlR revealed that ortho-vanillin can interact competitively with RhlR but not with LasR. Overall, these studies expand our understanding of benzaldehyde activities in the LasR and RhlR receptors and reveal potentially promising effects of ortho-vanillin as a small molecule QS modulator against RhlR.

Digital twinning of the human ventricular activation sequence to Clinical 12-lead ECGs and magnetic resonance imaging using realistic Purkinje networks for in silico clinical trials.

Cardiac in silico clinical trials can virtually assess the safety and efficacy of therapies using human-based modelling and simulation. These technologies can provide mechanistic explanations for clinically observed pathological behaviour. Designing virtual cohorts for in silico trials requires exploiting clinical data to capture the physiological variability in the human population. The clinical characterisation of ventricular activation and the Purkinje network is challenging, especially non-invasively. Our study aims to present a novel digital twinning pipeline that can efficiently generate and integrate Purkinje networks into human multiscale biventricular models based on subject-specific clinical 12-lead electrocardiogram and magnetic resonance recordings. Essential novel features of the pipeline are the human-based Purkinje network generation method, personalisation considering ECG R wave progression as well as QRS morphology, and translation from reduced-order Eikonal models to equivalent biophysically-detailed monodomain ones. We demonstrate ECG simulations in line with clinical data with clinical image-based multiscale models with Purkinje in four control subjects and two hypertrophic cardiomyopathy patients (simulated and clinical QRS complexes with Pearson's correlation coefficients > 0.7). Our methods also considered possible differences in the density of Purkinje myocardial junctions in the Eikonal-based inference as regional conduction velocities. These differences translated into regional coupling effects between Purkinje and myocardial models in the monodomain formulation. In summary, we demonstrate a digital twin pipeline enabling simulations yielding clinically consistent ECGs with clinical CMR image-based biventricular multiscale models, including personalised Purkinje in healthy and cardiac disease conditions.

Towards Enabling Cardiac Digital Twins of Myocardial Infarction Using Deep Computational Models for Inverse Inference.

Cardiac digital twins (CDTs) have the potential to offer individualized evaluation of cardiac function in a non-invasive manner, making them a promising approach for personalized diagnosis and treatment planning of myocardial infarction (MI). The inference of accurate myocardial tissue properties is crucial in creating a reliable CDT of MI. In this work, we investigate the feasibility of inferring myocardial tissue properties from the electrocardiogram (ECG) within a CDT platform. The platform integrates multi-modal data, such as cardiac MRI and ECG, to enhance the accuracy and reliability of the inferred tissue properties. We perform a sensitivity analysis based on computer simulations, systematically exploring the effects of infarct location, size, degree of transmurality, and electrical activity alteration on the simulated QRS complex of ECG, to establish the limits of the approach. We subsequently present a novel deep computational model, comprising a dual-branch variational autoencoder and an inference model, to infer infarct location and distribution from the simulated QRS. The proposed model achieves mean Dice scores of 0.457 ± 0.317 and 0.302 ± 0.273 for the inference of left ventricle scars and border zone, respectively. The sensitivity analysis enhances our understanding of the complex relationship between infarct characteristics and electrophysiological features. The in silico experimental results show that the model can effectively capture the relationship for the inverse inference, with promising potential for clinical application in the future. The code is available at https: //github.com/lileitech/MI_inverse_inference.

Penumbral Rescue by normobaric O = O administration in patients with ischemic stroke and target mismatch proFile (PROOF): Study protocol of a phase IIb trial.

RATIONALE: Oxygen is essential for cellular energy metabolism. Neurons are particularly vulnerable to hypoxia. Increasing oxygen supply shortly after stroke onset could preserve the ischemic penumbra until revascularization occurs. AIMS: PROOF investigates the use of normobaric oxygen (NBO) therapy within 6 h of symptom onset/notice for brain-protective bridging until endovascular revascularization of acute intracranial anterior-circulation occlusion. METHODS AND DESIGN: Randomized (1:1), standard treatment-controlled, open-label, blinded endpoint, multicenter adaptive phase IIb trial. STUDY OUTCOMES: Primary outcome is ischemic core growth (mL) from baseline to 24 h (intention-to-treat analysis). Secondary efficacy outcomes include change in NIHSS from baseline to 24 h, mRS at 90 days, cognitive and emotional function, and quality of life. Safety outcomes include mortality, intracranial hemorrhage, and respiratory failure. Exploratory analyses of imaging and blood biomarkers will be conducted. SAMPLE SIZE: Using an adaptive design with interim analysis at 80 patients per arm, up to 456 participants (228 per arm) would be needed for 80% power (one-sided alpha 0.05) to detect a mean reduction of ischemic core growth by 6.68 mL, assuming 21.4 mL standard deviation. DISCUSSION: By enrolling endovascular thrombectomy candidates in an early time window, the trial replicates insights from preclinical studies in which NBO showed beneficial effects, namely early initiation of near 100% inspired oxygen during short temporary ischemia. Primary outcome assessment at 24 h on follow-up imaging reduces variability due to withdrawal of care and early clinical confounders such as delayed extubation and aspiration pneumonia. TRIAL REGISTRATIONS: ClinicalTrials.gov: NCT03500939; EudraCT: 2017-001355-31.

Communication and empathy of nursing students in patient care through telenursing: A comparative cross-sectional study.

BACKGROUND: Phone calls and videoconferences are the most widely used systems to interact with patients in real time. Patient care through phone calls or videoconferences is different from an in-person meeting. Interpersonal communication skills, self-confidence communication skills and empathy with the patient may be affected during phone calls or videoconferences. AIM: The objective of this study was to describe the interpersonal communication skills, self-confidence communication skills and empathy of nursing students during patient care through phone calls or videoconferences. DESIGN: A cross-sectional study. PARTICIPANTS: A total of 170 nursing students participated from the University of Almeria. The subjects were randomly assigned to the phone call group or videoconference group. METHODS: The students contacted standardised patients through phone calls or videoconferences. Questionnaires were used to assess interpersonal communication skills with patient, empathy, and self-confidence in communication skills. Data collection was carried out between March and May 2022. RESULTS: No statistically significant differences were found between self-confidence in communication skills with the patient and the type of consultation, nor were statistically significant differences found between the empathy of the nursing students and the type of consultation. The students who used videoconference reported higher patient interpersonal communication skills than the students who made phone calls. Finally, the participants who made videoconferences obtained a higher score in dimension therapeutic use of self than those who made phone calls. CONCLUSIONS: Nursing students have shown a high level of empathy and interpersonal communication skills with patients and a moderate level of self-confidence in communication skills, both when interacting with patients through phone calls and videoconferences. Finally, differences were found in interpersonal communication skills with patient and type of consultation. In particular, interpersonal communication skills with the patient are greater when the nursing students make a videoconference.

An ex vivo model of interactions between extracellular vesicles and peripheral mononuclear blood cells in whole blood.

Extracellular vesicles (EVs) can be loaded with therapeutic cargo and engineered for retention by specific body sites; therefore, they have great potential for targeted delivery of biomolecules to treat diseases. However, the pharmacokinetics and biodistribution of EVs in large animals remain relatively unknown, especially in primates. We recently reported that when cell culture-derived EVs are administered intravenously to Macaca nemestrina (pig-tailed macaques), they differentially associate with specific subsets of peripheral blood mononuclear cells (PBMCs). More than 60% of CD20+ B cells were observed to associate with EVs for up to 1 h post-intravenous administration. To investigate these associations further, we developed an ex vivo model of whole blood collected from healthy pig-tailed macaques. Using this ex vivo system, we found that labelled EVs preferentially associate with B cells in whole blood at levels similar to those detected in vivo. This study demonstrates that ex vivo blood can be used to study EV-blood cell interactions.

Optimisation of the Manufacturing Process of Organic-Solvent-Free Omeprazole Enteric Pellets for the Paediatric Population: Full Factorial Design.

Liquid formulations are mostly used in the paediatric population. However, with certain active pharmaceutical ingredients (APIs), it is very difficult to guarantee quality and stability; this is the case, for example, with omeprazole. Omeprazole is used as a model drug due to the lack of a paediatric formulation meeting gastro-resistance requirements, which remains a challenge today. In this experimental study, the development of enteric polymer-coated pellets is proposed. It is proposed to use aqueous coating dispersions without the use of organic solvents, which are commonly used in fluidised bed coatings. To do this, the design of experiments method is used as a statistical tool for experiment creation and the subsequent analysis of the responses. In particular, this study uses a randomised full factorial design. The mean weight increases of the protective layer and the enteric coating are chosen as factors. Each factor is assigned two levels. Therefore, the design of the used experiments is a 22 + 1 central point. Overall, the obtained pellets can be an alternative to the compounding formulas of omeprazole that are currently used in the paediatric population, which do not meet the gastro-resistance specifications necessary to guarantee the therapeutic efficacy of this active ingredient.

Effective communication between nursing professionals and patients after the implementation of mask-wearing requirements in the clinical setting: A cross-sectional study.

This study aimed to evaluate staff nurses' perspectives on the use of face masks in effective communication and relationship management skills with patients in the hospital setting. The study surveyed registered nurses (RNs) who work with adult patients in different hospital units. An online survey was completed by RNs who were selected by convenience sampling. RNs' communication with patients was perceived as moderately affected by the use of face masks. Statistically significant differences were found when comparing communication with years of professional experience. Participants who had over 10 years of experience reported having greater difficulty in their communication with patients when using face masks. The effect of provider-patient relationship on effective nurse-patient face-mask communication was statistically significant and negative. This study shows that some participants found face masks used in the clinical setting may affect nurse-patient communication, as well as the nurses' ability to manage their relationships with patients. The findings of this study support the need for targeted research into effective communication strategies when face mask use is needed in the healthcare setting.

The promise of digital healthcare technologies.

Digital health technologies have been in use for many years in a wide spectrum of healthcare scenarios. This narrative review outlines the current use and the future strategies and significance of digital health technologies in modern healthcare applications. It covers the current state of the scientific field (delineating major strengths, limitations, and applications) and envisions the future impact of relevant emerging key technologies. Furthermore, we attempt to provide recommendations for innovative approaches that would accelerate and benefit the research, translation and utilization of digital health technologies.

[LDH-neutrophil-lymphocyte index as a predictor of 28-day mortality in patients with COVID-19]. / Índice DHL-neutrófilos-linfocitos como predictor de mortalidad a 28 días en pacientes con COVID-19.

Background: Coronavirus disease 2019 (COVID-19) represents the greatest health crisis of our times; it was declared by WHO a pandemic in March 2020. The risk of presenting a severe disease is inter-individual, since it varies according to age, comorbidities, and immunological status, in addition to the type of SARS-CoV-2 variant. The neutrophil/lymphocyte ratio (NLR) and lactic dehydrogenase (LDH) are widely used markers to assess the severity and predict the course of the disease in patients with COVID-19, with a direct relationship of higher value-worse prognosis. Objective: To verify if the LDH-neutrophil-lymphocyte index calculated from laboratory tests taken within the first 24 hours of admission is useful as a predictor of 28-day mortality in adult patients diagnosed with COVID-19. Material and methods: Retrospective and analytical cohort study. All consecutive patients over 16 years of any gender, admitted to a tertiary care center from March 2020 to March 2021, who had a diagnosis of COVID-19 with a positive PCR for SARS-CoV-2, were included. Results: Higher levels of the LDHNL index were associated with higher mortality in patients hospitalized for COVID-19 (Q2 vs. Q1: RR 1.52 [1.24-1.87], p < 0.05; Q3 vs. Q1: RR 1.87 [1.55-2.25], p < 0.05; and Q4 vs. Q1: RR 2.74 [2.22-3-39], p < 0.05). Conclusions: The serum LDHNL index taken in the first 24 hours of admission can help to predict early the risk of mortality in hospitalized patients with COVID-19.

Introducción: la enfermedad por coronavirus del 2019 (COVID-19) es la mayor crisis sanitaria de nuestros tiempos; fue declarada pandemia por la OMS en marzo de 2020. El riesgo de presentar enfermedad grave es interindividual y varía según la edad, las comorbilidades, el estado inmunológico y la variante del virus. La relación neutrófilos/linfocitos (RNL) y la deshidrogenasa láctica (DHL) son marcadores muy utilizados para evaluar la gravedad y predecir el curso de la enfermedad en pacientes con COVID-19, con una relación directa de mayor valor-peor pronóstico. Objetivo: comprobar si el índice DHL-neutrófilos-linfocitos calculado con estudios de laboratorio tomados en las primeras 24 horas de ingreso a hospital es útil como predictor de mortalidad a 28 días en pacientes adultos con diagnóstico de COVID-19. Material y métodos: estudio de tipo cohorte retrospectivo y analítico. Se incluyeron consecutivamente todos los pacientes mayores de 16 años de cualquier género, ingresados en un hospital de tercer nivel de marzo de 2020 a marzo de 2021, los cuales presentaron diagnóstico de COVID-19 con PCR positiva de SARS-CoV-2. Resultados: los niveles más altos del índice DHLNL se asociaron con una mayor mortalidad en pacientes hospitalizados por COVID-19 (Q2 frente a Q1: RR 1.52 [1.24-1.87], p < 0.05; Q3 frente a Q1: RR 1.87 [1.55-2.25], p < 0.05; y Q4 frente a Q1: RR 2.74 [2.22-3-39], p < 0.05). Conclusiones: el índice DHLNL en suero tomado en las primeras 24 horas del ingreso puede ayudar a identificar de manera temprana entre los pacientes hospitalizados por COVID-19 a aquellos con mayor riesgo de mortalidad.

Development of a Carvedilol Oral Liquid Formulation for Paediatric Use.

Carvedilol (CARV) is an 'off-label' ß-blocker drug to treat cardiovascular diseases in children. Since CARV is nearly insoluble in water, only CARV solid forms are commercialized. Usually, CARV tablets are manipulated to prepare an extemporaneous liquid formulation for children in hospitals. We studied CARV to improve its aqueous solubility and develop an oral solution. In this study, we assessed the solubility and preliminary stability of CARV in different pH media. Using malic acid as a solubility enhancer had satisfactory results. We studied the chemical, physical, and microbiological stability of 1 mg/mL CARV-malic acid solution. A design of experiment (DoE) was used to optimize the CARV solution's preparation parameters. A 1 mg/mL CARV solution containing malic acid was stable for up to 12 months at 25 °C and 30 °C and 6 months at 40 °C. An equation associating malic acid with CARV concentrations was obtained using DoE. Microbiological data showed that the use of methylparaben was not necessary for this period of time. We successfully developed an aqueous CARV solution suitable for paediatrics and proven to be stable over a 12-month period.

[Hipersensibility to red tattoo ink, review of a case]. / Hipersensibilidad a tinta roja de tatuaje, revisión a propósito de un caso.

Introduction: The hypersensitivity reaction associated with tattoo ink and its management represent a growing challenge, despite having precedents in diagnostic and treatment experience in other reports or case series in recent decades, no one has been found homogeneous offer that is effective and safe. Therefore, a review is presented with what has been described in pathophysiological theories, as well as therapeutic proposals and the response found in related cases that have been reported to date. Clinical case: 30-year-old male, with dermatosis located on the right upper extremity, affecting the inner side of the forearm and the outer side of the arm, unilateral, asymmetric, monomorphic in appearance, made up of an artificial macula, caused by red ink (tattoo), with development of papular-like lesions in original trace, pruritic, referred evolution time of one month. Tattoo completion time of 5 and 2 years on the outer side of the right arm and inner side of the ipsilateral forearm, respectively. Conclusions: According to antecedents in other reports and case series, including the experience of our patient, there is no proven efficacy with the use of topical immunomodulators, in turn, patients who shows complete improvement until the elimination of the allergen, either from excisional or laser.

Introducción: la reacción de hipersensibilidad asociada a tinta de tatuaje y su manejo representan un reto diagnóstico y terapéutico, ya que no se ha realizado una guía de manejo homogénea, eficaz y segura. Por lo que se presenta una revisión con lo que se ha descrito en teorías fisiopatológicas, así como las propuestas terapéuticas y la respuesta encontrada en los casos relacionados que se han reportado. Caso clínico: paciente hombre de 30 años que inicia con dermatosis localizada en extremidad superior derecha, unilateral, asimétrica, de aspecto monomorfo, constituida por mácula artificial, provocada por tinta roja (tatuaje), con desarrollo de lesiones de aspecto papular en trazo original, pruriginosa, tiempo de evolución referido de un mes. El hallazgo histopatológico corresponde a reacción de cuerpo extraño con respuesta parcial a esteroide tópico de baja potencia. Conclusiones: según antecedentes en otros reportes y series de casos, incluyendo la experiencia con nuestro paciente, no existe una eficacia aplicable para la mayoría de los pacientes con el uso de inmunomodulares tópicos, ya que muestran mejoría completa hasta la eliminación del hapteno, ya sea de forma escicional o con láser.

Enhanced optimization-based method for the generation of patient-specific models of Purkinje networks.

Cardiac Purkinje networks are a fundamental part of the conduction system and are known to initiate a variety of cardiac arrhythmias. However, patient-specific modeling of Purkinje networks remains a challenge due to their high morphological complexity. This work presents a novel method based on optimization principles for the generation of Purkinje networks that combines geometric and activation accuracy in branch size, bifurcation angles, and Purkinje-ventricular-junction activation times. Three biventricular meshes with increasing levels of complexity are used to evaluate the performance of our approach. Purkinje-tissue coupled monodomain simulations are executed to evaluate the generated networks in a realistic scenario using the most recent Purkinje/ventricular human cellular models and physiological values for the Purkinje-ventricular-junction characteristic delay. The results demonstrate that the new method can generate patient-specific Purkinje networks with controlled morphological metrics and specified local activation times at the Purkinje-ventricular junctions.

What determines the optimal pharmacological treatment of atrial fibrillation? Insights from in silico trials in 800 virtual atria.

The best pharmacological treatment for each atrial fibrillation (AF) patient is unclear. We aim to exploit AF simulations in 800 virtual atria to identify key patient characteristics that guide the optimal selection of anti-arrhythmic drugs. The virtual cohort considered variability in electrophysiology and low voltage areas (LVA) and was developed and validated against experimental and clinical data from ionic currents to ECG. AF sustained in 494 (62%) atria, with large inward rectifier K+ current (IK1 ) and Na+ /K+ pump (INaK ) densities (IK1 0.11 ± 0.03 vs. 0.07 ± 0.03 S mF-1 ; INaK 0.68 ± 0.15 vs. 0.38 ± 26 S mF-1 ; sustained vs. un-sustained AF). In severely remodelled left atrium, with LVA extensions of more than 40% in the posterior wall, higher IK1 (median density 0.12 ± 0.02 S mF-1 ) was required for AF maintenance, and rotors localized in healthy right atrium. For lower LVA extensions, rotors could also anchor to LVA, in atria presenting short refractoriness (median L-type Ca2+ current, ICaL , density 0.08 ± 0.03 S mF-1 ). This atrial refractoriness, modulated by ICaL and fast Na+ current (INa ), determined pharmacological treatment success for both small and large LVA. Vernakalant was effective in atria presenting long refractoriness (median ICaL density 0.13 ± 0.05 S mF-1 ). For short refractoriness, atria with high INa (median density 8.92 ± 2.59 S mF-1 ) responded more favourably to amiodarone than flecainide, and the opposite was found in atria with low INa (median density 5.33 ± 1.41 S mF-1 ). In silico drug trials in 800 human atria identify inward currents as critical for optimal stratification of AF patient to pharmacological treatment and, together with the left atrial LVA extension, for accurately phenotyping AF dynamics. KEY POINTS: Atrial fibrillation (AF) maintenance is facilitated by small L-type Ca2+ current (ICaL ) and large inward rectifier K+ current (IK1 ) and Na+ /K+ pump. In severely remodelled left atrium, with low voltage areas (LVA) covering more than 40% of the posterior wall, sustained AF requires higher IK1 and rotors localize in healthy right atrium. For lower LVA extensions, rotors can also anchor to LVA, if the atria present short refractoriness (low ICaL ) Vernakalant is effective in atria presenting long refractoriness (high ICaL ). For short refractoriness, atria with fast Na+ current (INa ) up-regulation respond more favourably to amiodarone than flecainide, and the opposite is found in atria with low INa . The inward currents (ICaL and INa ) are critical for optimal stratification of AF patient to pharmacological treatment and, together with the left atrial LVA extension, for accurately phenotyping AF dynamics.

Isolation and Identification of Mesenchymal Stem Cells Derived from Adipose Tissue of Sprague Dawley Rats.

Adult mesenchymal cells have revolutionized molecular and cell biology in recent decades. They can differentiate into different specialized cell types, in addition to their great capacity for self-renewal, migration, and proliferation. Adipose tissue is one of the least invasive and most accessible sources of mesenchymal cells. It has also been reported to have higher yields compared to other sources, as well as superior immunomodulatory properties. Recently, different procedures for obtaining adult mesenchymal cells from different tissue sources and animal species have been published. After evaluating the criteria of some authors, we standardized a methodology applicable to different purposes and easily reproducible. A pool of stromal vascular fraction (SVF) from perirenal and epididymal adipose tissue allowed us to develop primary cultures with optimal morphology and functionality. The cells were observed adhered to the plastic surface for 24 h, and exhibited a fibroblast-like morphology, with prolongations and a tendency to form colonies. Flow cytometry (FC) and immunofluorescence (IF) techniques were used to assess the expression of the membrane markers CD105, CD9, CD63, CD31, and CD34. The ability of adipose-derived stem cells (ASCs) to differentiate into the adipogenic lineage was also assessed using a cocktail of factors (4 µM insulin, 0.5 mM 3-methyl-iso-butyl-xanthine, and 1 µM dexamethasone). After 48 h, a gradual loss of fibroblastoid morphology was observed, and at 12 days, the presence of lipid droplets positive to oil red staining was confirmed. In summary, a procedure is proposed to obtain optimal and functional ASC cultures for application in regenerative medicine.

Testing the nonclinical Comprehensive In Vitro Proarrhythmia Assay (CiPA) paradigm with an established anti-seizure medication: Levetiracetam case study.

Levetiracetam (LEV), a well-established anti-seizure medication (ASM), was launched before the original ICH S7B nonclinical guidance assessing QT prolongation potential and the introduction of the Comprehensive In Vitro Proarrhythmia Assay (CiPA) paradigm. No information was available on its effects on cardiac channels. The goal of this work was to "pressure test" the CiPA approach with LEV and check the concordance of nonclinical core and follow-up S7B assays with clinical and post-marketing data. The following experiments were conducted with LEV (0.25-7.5 mM): patch clamp assays on hERG (acute or trafficking effects), NaV 1.5, CaV 1.2, Kir 2.1, KV 7.1/mink, KV 1.5, KV 4.3, and HCN4; in silico electrophysiology modeling (Virtual Assay® software) in control, large-variability, and high-risk human ventricular cell populations; electrophysiology measurements in human induced pluripotent stem cell (hiPSC)-derived cardiomyocytes and dog Purkinje fibers; ECG measurements in conscious telemetered dogs after single oral administration (150, 300, and 600 mg/kg). Except a slight inhibition (<10%) of hERG and KV 7.1/mink at 7.5 mM, that is, 30-fold the free therapeutic plasma concentration (FTPC) at 1500 mg, LEV did not affect any other cardiac channels or hERG trafficking. In both virtual and real human cardiomyocytes, and in dog Purkinje fibers, LEV induced no relevant changes in electrophysiological parameters or arrhythmia. No QTc prolongation was noted up to 2.7 mM unbound plasma levels in conscious dogs, corresponding to 10-fold the FTPC. Nonclinical assessment integrating CiPA assays shows the absence of QT prolongation and proarrhythmic risk of LEV up to at least 10-fold the FTPC and the good concordance with clinical and postmarketing data, although this does not exclude very rare occurrence of QT prolongation cases in patients with underlying risk factors.

[Zero Emissions. A shared responsibility. Gas capture and recycling project at the Cruces University Hospital (Spain).] / Emisiones Zero. Una responsabilidad compartida. Proyecto captura de gases y reciclado en el Hospital Universitario de Cruces.

OBJECTIVE: The use of volatile anesthetics plays an important role in the production of greenhouse gases and other environmental pollutants that negatively affect global health. Programs to reduce anesthesia contaminants have been shown to be effective and reduce costs. For this reason, we conducted a study to implementing a Zero Emissions Program for zero carbon dioxide emissions derived from anesthetic gases used in the operating room, as recommended by the Green Deal of the European Union by 2030 and be climate neutral in 2050, maintaining satisfaction and current clinical results. METHODS: A Zero Emissions Program was implemented within the Zero safety programs of the Cruces University Hospital in order to produce zero emissions of carbon dioxide derived from the anesthetic gases used in the operating rooms. The contribution of anesthetic gases to carbon dioxide production before and after implementation of program was determined. Data analysis was conducted descriptively to analyze program effectiveness. RESULTS: The implementation of a Zero Emissions Program allowed us to achieve a reduction in emissions to zero. CONCLUSIONS: Anesthesiologists must understand that minimizing our harmful impact on environmental health sustainability is not only desirable, but ethically necessary. A way to contribute to this ethical responsibility is Zero Emissions Programs which are effective in reducing emissions to zero, probably improving our impact on planet health.

OBJETIVO: El uso de anestésicos volátiles juega un papel importante en la producción de gases de efecto invernadero y otros contaminantes ambientales que afectan negativamente a la salud mundial. Se ha demostrado que los programas para reducir los contaminantes de la anestesia en el medio ambiente son eficaces y también reducen los costes. Por este motivo nos planteamos como objetivo implementar un Programa de Emisiones Zero para producir cero emisiones de dióxido de carbono derivados de los gases anestésicos utilizados en el quirófano, como recomienda el Pacto Verde de la Unión Europea, para 2030 y ser climáticamente neutros en 2050, manteniendo la satisfacción y los resultados clínicos actuales. METODOS: Se implementó un Programa de Emisiones Zero dentro de los programas Zero de seguridad del Hospital Universitario de Cruces (Barakaldo) con la finalidad de producir cero emisiones de dióxido de carbono derivado de los gases anestésicos utilizados en los quirófanos. Se determinó la contribución de los gases anestésicos a la producción de dióxido de carbono previo y posterior a la implementación del programa. El análisis de los datos se llevó a cabo de forma descriptiva para analizar la efectividad del programa. RESULTADOS: La implementación de un Programa de Emisiones de Zero nos permitió conseguir una disminución de las emisiones a cero. CONCLUSIONES: Los anestesiólogos debemos comprender que minimizar nuestro impacto nocivo en la sostenibilidad de la salud ambiental no es solo deseable, sino éticamente necesario. Una de las formas de contribuir con esta responsabilidad ética es con la implementación de Programas de Emisiones Zero que son eficaces en la reducción a cero de estas emisiones con lo que mejoraremos nuestro impacto en la salud del planeta.

Emisiones Zero. Una responsabilidad compartida. Proyecto captura de gases y reciclado en el Hospital Universitario de Cruces / Zero Emissions. A shared responsibility. Gas capture and recycling project at the Cruces University Hospital (Spain)

FUNDAMENTOS: El uso de anestésicos volátiles juega un papel importante en la producción de gases de efecto invernadero y otros contaminantes ambientales que afectan negativamente a la salud mundial. Se ha demostrado que los programas para reducir los contaminantes de la anestesia en el medio ambiente son eficaces y también reducen los costes. Por este motivo nos planteamos como objetivo implementar un Programa de Emisiones Zero para producir cero emisiones de dióxido de carbono derivados de los gases anestésicos utilizados en el quirófano, como recomienda el Pacto Verde de la Unión Europea, para 2030 y ser climáticamente neutros en 2050, manteniendo la satisfacción y los resultados clínicos actuales. MÉTODOS: Se implementó un Programa de Emisiones Zero dentro de los programas Zero de seguridad del Hospital Universitario de Cruces (Barakaldo) con la finalidad de producir cero emisiones de dióxido de carbono derivado de los gases anestésicos utilizados en los quirófanos. Se determinó la contribución de los gases anestésicos a la producción de dióxido de carbono previo y posterior a la implementación del programa. El análisis de los datos se llevó a cabo de forma descriptiva para analizar la efectividad del programa. RESULTADOS: La implementación de un Programa de Emisiones de Zero nos permitió conseguir una disminución de las emisiones a cero. CONCLUSIONES: Los anestesiólogos debemos comprender que minimizar nuestro impacto nocivo en la sostenibilidad de la salud ambiental no es solo deseable, sino éticamente necesario. Una de las formas de contribuir con esta responsabilidad ética es con la implementación de Programas de Emisiones Zero que son eficaces en la reducción a cero de estas emisiones con lo que mejoraremos nuestro impacto en la salud del planeta.(AU)

BACKGROUND: The use of volatile anesthetics plays an important role in the production of greenhouse gases and other environmental pollutants that negatively affect global health. Programs to reduce anesthesia contaminants have been shown to be effective and reduce costs. For this reason, we conducted a study to implementing a Zero Emissions Program for zero carbon dioxide emissions derived from anesthetic gases used in the operating room, as recommended by the Green Deal of the European Union by 2030 and be climate neutral in 2050, maintaining satisfaction and current clinical results. METHODS: A Zero Emissions Program was implemented within the Zero safety programs of the Cruces University Hospital in order to produce zero emissions of carbon dioxide derived from the anesthetic gases used in the operating rooms. The contribution of anesthetic gases to carbon dioxide production before and after implementation of program was determined. Data analysis was conducted descriptively to analyze program effectiveness. RESULTS: The implementation of a Zero Emissions Program allowed us to achieve a reduction in emissions to zero. CONCLUSIONS: Anesthesiologists must understand that minimizing our harmful impact on environmental health sustainability is not only desirable, but ethically necessary. A way to contribute to this ethical responsibility is Zero Emissions Programs which are effective in reducing emissions to zero, probably improving our impact on planet health.(AU)

Palatability and Stability Studies to Optimize a Carvedilol Oral Liquid Formulation for Pediatric Use.

Carvedilol (CARV) is a blocker of α- and ß- adrenergic receptors, used as an "off-label" treatment for cardiovascular diseases in pediatrics. Currently, there is no marketed pediatric-appropriate CARV liquid formulation, so its development is necessary. Palatability (appreciation of smell, taste, and aftertaste) is a key aspect to be considered during the development of pediatric formulations since only formulations with good palatability also have adequate acceptability in this population. Consequently, the aim of this research was to assess the palatability and acceptability of different CARV formulations using an in vivo taste assessment (ID Number PR103/22) in order to select the highest palatability-rated CARV formulation. The preparation of CARV formulations was based on a reference 1 mg/mL CARV solution, which contains malic acid as a solubilizing agent. Subsequently, sucralose and flavoring agents were added and mixed until complete dissolution to the corresponding formulations. Adult volunteers participated in this study and evaluated the taste and odor of various CARV formulations through a questionnaire and a sensory test. The mean palatability score, measured on a 10-point scale, increased from 1.60 for the unflavored control to 7.65 for the highest-rated flavored formulation. Moreover, the bitterness of the optimized CARV formulation was reduced from 66.67% to 17.86%, and the taste pleasantness was increased from 25/100 to 73/100. This optimized CARV formulation contains a sweetening agent, sucralose, in addition to two flavoring agents at appropriate concentrations for pediatrics. Furthermore, the physicochemical and microbiological stability of the optimized CARV formulation were evaluated for 6 months at 25, 30, and 40 °C, in addition to in-use stability for 15 days at 25 °C, whose results were confirmed. Thus, we successfully developed a palatable CARV liquid solution that contains excipients appropriate for pediatrics and is stable under the studied conditions.

Mechanism based therapies enable personalised treatment of hypertrophic cardiomyopathy.

Cardiomyopathies have unresolved genotype-phenotype relationships and lack disease-specific treatments. Here we provide a framework to identify genotype-specific pathomechanisms and therapeutic targets to accelerate the development of precision medicine. We use human cardiac electromechanical in-silico modelling and simulation which we validate with experimental hiPSC-CM data and modelling in combination with clinical biomarkers. We select hypertrophic cardiomyopathy as a challenge for this approach and study genetic variations that mutate proteins of the thick (MYH7R403Q/+) and thin filaments (TNNT2R92Q/+, TNNI3R21C/+) of the cardiac sarcomere. Using in-silico techniques we show that the destabilisation of myosin super relaxation observed in hiPSC-CMs drives disease in virtual cells and ventricles carrying the MYH7R403Q/+ variant, and that secondary effects on thin filament activation are necessary to precipitate slowed relaxation of the cell and diastolic insufficiency in the chamber. In-silico modelling shows that Mavacamten corrects the MYH7R403Q/+ phenotype in agreement with hiPSC-CM experiments. Our in-silico model predicts that the thin filament variants TNNT2R92Q/+ and TNNI3R21C/+ display altered calcium regulation as central pathomechanism, for which Mavacamten provides incomplete salvage, which we have corroborated in TNNT2R92Q/+ and TNNI3R21C/+ hiPSC-CMs. We define the ideal characteristics of a novel thin filament-targeting compound and show its efficacy in-silico. We demonstrate that hybrid human-based hiPSC-CM and in-silico studies accelerate pathomechanism discovery and classification testing, improving clinical interpretation of genetic variants, and directing rational therapeutic targeting and design.