ABSTRACT
Chronic heart failure is one of the most common reasons for hospitalization. Current risk stratification is based on ejection fraction, whereas many arrhythmic events occur in patients with relatively preserved ejection fraction. We aim to investigate the mechanistic link between proarrhythmic abnormalities, reduced contractility and diastolic dysfunction in heart failure, using electromechanical modelling and simulations of human failing cardiomyocytes. We constructed, calibrated and validated populations of human electromechanical models of failing cardiomyocytes, that were able to reproduce the prolonged action potential, reduced contractility and diastolic dysfunction as observed in human data, as well as increased propensity to proarrhythmic incidents such as early afterdepolarization and beat-to-beat alternans. Our simulation data reveal that proarrhythmic incidents tend to occur in failing myocytes with lower diastolic tension, rather than with lower contractility, due to the relative preserved SERCA and sodium calcium exchanger current. These results support the inclusion of end-diastolic volume to be potentially beneficial in the risk stratifications of heart failure patients.
Subject(s)
Action Potentials , Arrhythmias, Cardiac , Heart Failure , Myocytes, Cardiac , Humans , Myocytes, Cardiac/metabolism , Heart Failure/physiopathology , Arrhythmias, Cardiac/physiopathology , Arrhythmias, Cardiac/etiology , Diastole/physiology , Models, Cardiovascular , Myocardial Contraction/physiology , Computer Simulation , Sarcoplasmic Reticulum Calcium-Transporting ATPases/metabolismABSTRACT
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 cause 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. IMPORTANCE: Quorum sensing (QS) regulates many aspects of bacterial pathogenesis and has attracted much interest as a target for anti-virulence therapies over the past 30 years, for example, antagonists of the LasR and RhlR QS receptors in Pseudomonas aeruginosa. Potent and selective QS inhibitors remain relatively scarce. However, natural products have provided a bounty of chemical scaffolds with anti-QS activities, but their molecular mechanisms are poorly characterized. The current study serves to fill this void by examining the activity of an important and wide-spread class of natural product QS modulators, benzaldehydes, and related derivatives, in LasR and RhlR. We demonstrate that ortho-vanillin can act as a competitive inhibitor of RhlR, a receptor that has emerged and may supplant LasR in certain settings as a target for P. aeruginosa QS control. The results and insights provided herein will advance the design of chemical tools to study QS with improved activities and selectivities.
ABSTRACT
AIMS: Patients with persistent atrial fibrillation (AF) experience 50% recurrence despite pulmonary vein isolation (PVI), and no consensus is established for secondary treatments. The aim of our i-STRATIFICATION study is to provide evidence for stratifying patients with AF recurrence after PVI to optimal pharmacological and ablation therapies, through in silico trials. METHODS AND RESULTS: A cohort of 800 virtual patients, with variability in atrial anatomy, electrophysiology, and tissue structure (low-voltage areas, LVAs), was developed and validated against clinical data from ionic currents to electrocardiogram. Virtual patients presenting AF post-PVI underwent 12 secondary treatments. Sustained AF developed in 522 virtual patients after PVI. Second ablation procedures involving left atrial ablation alone showed 55% efficacy, only succeeding in the small right atria (<60â mL). When additional cavo-tricuspid isthmus ablation was considered, Marshall-PLAN sufficed (66% efficacy) for the small left atria (<90â mL). For the bigger left atria, a more aggressive ablation approach was required, such as anterior mitral line (75% efficacy) or posterior wall isolation plus mitral isthmus ablation (77% efficacy). Virtual patients with LVAs greatly benefited from LVA ablation in the left and right atria (100% efficacy). Conversely, in the absence of LVAs, synergistic ablation and pharmacotherapy could terminate AF. In the absence of ablation, the patient's ionic current substrate modulated the response to antiarrhythmic drugs, being the inward currents critical for optimal stratification to amiodarone or vernakalant. CONCLUSION: In silico trials identify optimal strategies for AF treatment based on virtual patient characteristics, evidencing the power of human modelling and simulation as a clinical assisting tool.
Subject(s)
Anti-Arrhythmia Agents , Atrial Fibrillation , Catheter Ablation , Pulmonary Veins , Recurrence , Atrial Fibrillation/surgery , Atrial Fibrillation/drug therapy , Atrial Fibrillation/physiopathology , Atrial Fibrillation/diagnosis , Humans , Catheter Ablation/methods , Pulmonary Veins/surgery , Pulmonary Veins/physiopathology , Anti-Arrhythmia Agents/therapeutic use , Treatment Outcome , Models, Cardiovascular , Computer Simulation , Action Potentials , Risk Assessment , Heart Atria/physiopathology , Heart Atria/surgery , Male , Anisoles/therapeutic use , Patient Selection , Female , Patient-Specific Modeling , Middle Aged , Pyrrolidines/therapeutic use , Electrocardiography , Clinical Decision-MakingABSTRACT
BACKGROUND AND OBJECTIVES: Whether the outcome of patients with spontaneous intracerebral hemorrhage (ICH) differs depending on the type of hospital where they are admitted is uncertain. The objective of this study was to determine influence of hospital type at admission (telestroke center [TSC], primary stroke center [PSC], or comprehensive stroke center [CSC]) on outcome for patients with ICH. We hypothesized that outcomes may be better for patients admitted to a CSC. METHODS: This is a multicenter prospective observational and population-based study of a cohort of consecutively recruited patients with ICH (March 2020-March 2022). We included all patients with spontaneous ICH in Catalonia (Spain) who had a pre-ICH modified Rankin scale (mRS) score of 0-3 and who were admitted to the hospital within 24 hours of onset. We compared patients admitted to a TSC/PSC (n = 641) or a CSC (n = 1,320) and also analyzed the subgroup of patients transferred (n = 331) or not transferred (n = 310) from a TSC/PSC to a CSC. The main outcome was the 3-month mRS score obtained by blinded investigators. Outcomes were compared using adjusted ordinal logistic regression to estimate the common odds ratio (OR) and 95% CI for a shift in mRS scores. A propensity score matching (PSM) analysis was performed for the subgroup of transferred patients. RESULTS: Relevant data were obtained from 1961 of a total of 2,230 patients, with the mean (SD) age of 70 (14.1) years, and 713 (38%) patients were women. After adjusting for confounders (age, NIH Stroke Scale score, intraventricular hemorrhage, hematoma volume, and pre-ICH mRS score), type of hospital of initial admission (CSC vs TSC/PSC) was not associated with outcome (adjusted common OR 1.13, 95% CI 0.93-1.38). A PSM analysis indicated that transfer to a CSC was not associated with more favorable outcomes (OR 0.77, 95% CI 0.55-1.10; p = 0.16). DISCUSSION: In this population-based study, we found that, after adjusting for confounders, hospital types were not associated with functional outcomes. In addition, for patients who were transferred from a TSC/PSC to a CSC, PSM indicated that outcomes were similar to nontransferred patients. Our findings suggest that patient characteristics are more important than hospital characteristics in determining outcome after ICH. TRIAL REGISTRATION INFORMATION: ClinicalTrials.gov Identifier: NCT03956485.
Subject(s)
Cerebral Hemorrhage , Humans , Female , Male , Aged , Cerebral Hemorrhage/epidemiology , Middle Aged , Prospective Studies , Spain/epidemiology , Aged, 80 and over , Treatment Outcome , Hospitals/statistics & numerical data , Hospitalization/statistics & numerical dataABSTRACT
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.
ABSTRACT
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.
Subject(s)
Magnetic Resonance Imaging , Purkinje Fibers , Humans , Purkinje Fibers/diagnostic imaging , Purkinje Fibers/anatomy & histology , Purkinje Fibers/physiology , Myocardium , Computer Simulation , Electrocardiography/methodsABSTRACT
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.
Subject(s)
Electrocardiography , Magnetic Resonance Imaging , Myocardial Infarction , Myocardial Infarction/diagnostic imaging , Myocardial Infarction/physiopathology , Humans , Electrocardiography/methods , Magnetic Resonance Imaging/methods , Computer Simulation , Heart/diagnostic imaging , Deep Learning , AlgorithmsABSTRACT
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.
Subject(s)
Students, Nursing , Telenursing , Humans , Cross-Sectional Studies , Empathy , Communication , Patient CareABSTRACT
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.
Subject(s)
Brain Ischemia , Endovascular Procedures , Ischemic Stroke , Humans , Brain Ischemia/complications , Endovascular Procedures/methods , Ischemic Stroke/complications , Ischemic Stroke/diagnosis , Multicenter Studies as Topic , Oxygen/therapeutic use , Quality of Life , Thrombectomy/methods , Treatment Outcome , Clinical Trials, Phase II as TopicABSTRACT
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.
Subject(s)
Extracellular Vesicles , Animals , Extracellular Vesicles/metabolism , Leukocytes, Mononuclear , Tissue Distribution , Macaca nemestrina , Cell CommunicationABSTRACT
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.
Subject(s)
Communication , Nurse-Patient Relations , Adult , Humans , Cross-Sectional Studies , Patients , HospitalsABSTRACT
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.
ABSTRACT
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.
Subject(s)
Biomedical Technology , Delivery of Health CareABSTRACT
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.
ABSTRACT
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.
Subject(s)
COVID-19 , Adult , Humans , COVID-19/diagnosis , SARS-CoV-2 , Neutrophils , Retrospective Studies , Cohort Studies , Lymphocytes , PrognosisABSTRACT
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.
Subject(s)
Hypersensitivity , Tattooing , Male , Humans , Adult , Tattooing/adverse effects , Ink , Hypersensitivity/etiologyABSTRACT
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.
Subject(s)
Amiodarone , Atrial Fibrillation , Humans , Atrial Fibrillation/drug therapy , Flecainide/pharmacology , Flecainide/therapeutic use , Heart Atria , Amiodarone/pharmacology , Amiodarone/therapeutic use , Action Potentials/physiologyABSTRACT
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.
Subject(s)
Benchmarking , Heart , Humans , Cardiac Conduction System Disease , Heart Conduction System , Heart VentriclesABSTRACT
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.
Subject(s)
Adipose Tissue , Mesenchymal Stem Cells , Rats , Animals , Rats, Sprague-Dawley , Cell Differentiation , Adipocytes , Cells, CulturedABSTRACT
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.