Uric acid and acute kidney injury in high-risk patients for developing acute kidney injury undergoing cardiac surgery: A prospective multicenter study.

PURPOSE: It is unclear whether preoperative serum uric acid (SUA) elevation may play a role in the development of acute kidney injury (AKI) associated with cardiac surgery (CSA-AKI). We conducted a cohort study to evaluate the influence of preoperative hyperuricemia on AKI in patients at high risk for developing SC-AKI. DESIGN: Multicenter prospective international cohort study. SETTING: Fourteen university hospitals in Spain and the United Kingdom. PARTICIPANTS: We studied 261 consecutive patients at high risk of developing CSA-AKI, according to a Cleveland score ≥ 4 points, from July to December 2017. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: AKIN criteria were used for the definition of AKI. Multivariable logistic regression models and propensity score-matched pairwise analysis were used to determine the adjusted association between preoperative hyperuricemia (≥7 mg/dL) and AKI. Elevated preoperative AUS (≥7 mg/dL) was present in 190 patients (72.8%), whereas CSA-AKI occurred in 145 patients (55.5%). In multivariable logistic regression models, hyperuricemia was not associated with a significantly increased risk of AKI (adjusted Odds Ratio [OR]: 1.58; 95% confidence interval [CI]: 0.81-3; P = .17). In propensity score-matched analysis of 140 patients, the hyperuricemia group experienced similar adjusted odds of AKI (OR 1.05, 95%CI 0.93-1.19, P = .37). CONCLUSIONS: Hyperuricemia was not associated with an increased risk of AKI in this cohort of patients undergoing cardiac surgery at high risk of developing CSA-AKI.

A computational model predicts sex-specific responses to calcium channel blockers in mammalian mesenteric vascular smooth muscle.

The function of the smooth muscle cells lining the walls of mammalian systemic arteries and arterioles is to regulate the diameter of the vessels to control blood flow and blood pressure. Here, we describe an in silico model, which we call the 'Hernandez-Hernandez model', of electrical and Ca2+ signaling in arterial myocytes based on new experimental data indicating sex-specific differences in male and female arterial myocytes from murine resistance arteries. The model suggests the fundamental ionic mechanisms underlying membrane potential and intracellular Ca2+ signaling during the development of myogenic tone in arterial blood vessels. Although experimental data suggest that KV1.5 channel currents have similar amplitudes, kinetics, and voltage dependencies in male and female myocytes, simulations suggest that the KV1.5 current is the dominant current regulating membrane potential in male myocytes. In female cells, which have larger KV2.1 channel expression and longer time constants for activation than male myocytes, predictions from simulated female myocytes suggest that KV2.1 plays a primary role in the control of membrane potential. Over the physiological range of membrane potentials, the gating of a small number of voltage-gated K+ channels and L-type Ca2+ channels are predicted to drive sex-specific differences in intracellular Ca2+ and excitability. We also show that in an idealized computational model of a vessel, female arterial smooth muscle exhibits heightened sensitivity to commonly used Ca2+ channel blockers compared to male. In summary, we present a new model framework to investigate the potential sex-specific impact of antihypertensive drugs.

High blood pressure is a major risk factor for heart disease, which is one of the leading causes of death worldwide. While drugs are available to control blood pressure, male and female patients can respond differently to treatment. However, the biological mechanisms behind this sex difference are not fully understood. Blood pressure is controlled by cells lining the artery walls called smooth muscle cells which alter the width of blood vessels. On the surface of smooth muscle cells are potassium and calcium channels which control the cell's electrical activity. When calcium ions enter the cell via calcium channels, this generates an electrical signal that causes the smooth muscle to contract and narrow the blood vessel. Potassium ions then flood out of the cell via potassium channels to dampen the rise in electrical activity, causing the muscle to relax and widen the artery. There are various sub-types of potassium and calcium channels in smooth muscle cells. Here, Hernandez-Hernandez et al. set out to find how these channels differ between male and female mice, and whether these sex differences could alter the response to blood pressure medication. The team developed a computational model of a smooth muscle cell, incorporating data from laboratory experiments measuring differences in cells isolated from the arteries of male and female mice. The model predicted that the sub-types of potassium and calcium channels in smooth muscle cells varied between males and females, and how the channels impacted electrical activity also differed. For instance, the potassium channel Kv2.1 was found to have a greater role in controlling electrical activity in female mice, and this sex difference impacted blood vessel contraction. The model also predicted that female mice were more sensitive than males to calcium channel blockers, a drug commonly prescribed to treat high blood pressure. The findings by Hernandez-Hernandez et al. provide new insights into the biological mechanisms underlying sex differences in response to blood pressure medication. They also demonstrate how computational models can be used to predict the effects of drugs on different individuals. In the future, these predictions may help researchers to identify better, more personalized treatments for blood pressure.

Toward Digital Twin Technology for Precision Pharmacology.

The authors demonstrate the feasibility of technological innovation for personalized medicine in the context of drug-induced arrhythmia. The authors use atomistic-scale structural models to predict rates of drug interaction with ion channels and make predictions of their effects in digital twins of induced pluripotent stem cell-derived cardiac myocytes. The authors construct a simplified multilayer, 1-dimensional ring model with sufficient path length to enable the prediction of arrhythmogenic dispersion of repolarization. Finally, the authors validate the computational pipeline prediction of drug effects with data and quantify drug-induced propensity to repolarization abnormalities in cardiac tissue. The technology is high throughput, computationally efficient, and low cost toward personalized pharmacologic prediction.

A computational model predicts sex-specific responses to calcium channel blockers in mammalian mesenteric vascular smooth muscle.

The function of the smooth muscle cells lining the walls of mammalian systemic arteries and arterioles is to regulate the diameter of the vessels to control blood flow and blood pressure. Here, we describe an in-silico model, which we call the "Hernandez-Hernandez model", of electrical and Ca2+ signaling in arterial myocytes based on new experimental data indicating sex-specific differences in male and female arterial myocytes from murine resistance arteries. The model suggests the fundamental ionic mechanisms underlying membrane potential and intracellular Ca2+ signaling during the development of myogenic tone in arterial blood vessels. Although experimental data suggest that KV1.5 channel currents have similar amplitudes, kinetics, and voltage dependencies in male and female myocytes, simulations suggest that the KV1.5 current is the dominant current regulating membrane potential in male myocytes. In female cells, which have larger KV2.1 channel expression and longer time constants for activation than male myocytes, predictions from simulated female myocytes suggest that KV2.1 plays a primary role in the control of membrane potential. Over the physiological range of membrane potentials, the gating of a small number of voltage-gated K+ channels and L-type Ca2+ channels are predicted to drive sex-specific differences in intracellular Ca2+ and excitability. We also show that in an idealized computational model of a vessel, female arterial smooth muscle exhibits heightened sensitivity to commonly used Ca2+ channel blockers compared to male. In summary, we present a new model framework to investigate the potential sex-specific impact of anti-hypertensive drugs.

The formation of KV2.1 macro-clusters is required for sex-specific differences in L-type CaV1.2 clustering and function in arterial myocytes.

In arterial myocytes, the canonical function of voltage-gated CaV1.2 and KV2.1 channels is to induce myocyte contraction and relaxation through their responses to membrane depolarization, respectively. Paradoxically, KV2.1 also plays a sex-specific role by promoting the clustering and activity of CaV1.2 channels. However, the impact of KV2.1 protein organization on CaV1.2 function remains poorly understood. We discovered that KV2.1 forms micro-clusters, which can transform into large macro-clusters when a critical clustering site (S590) in the channel is phosphorylated in arterial myocytes. Notably, female myocytes exhibit greater phosphorylation of S590, and macro-cluster formation compared to males. Contrary to current models, the activity of KV2.1 channels seems unrelated to density or macro-clustering in arterial myocytes. Disrupting the KV2.1 clustering site (KV2.1S590A) eliminated KV2.1 macro-clustering and sex-specific differences in CaV1.2 cluster size and activity. We propose that the degree of KV2.1 clustering tunes CaV1.2 channel function in a sex-specific manner in arterial myocytes.

Interstitial cells of Cajal - pacemakers of the gastrointestinal tract.

Gastrointestinal (GI) organs display spontaneous, non-neurogenic electrical, and mechanical rhythmicity that underlies fundamental motility patterns, such as peristalsis and segmentation. Electrical rhythmicity (aka slow waves) results from pacemaker activity generated by interstitial cells of Cajal (ICC). ICC express a unique set of ionic conductances and Ca2+ handling mechanisms that generate and actively propagate slow waves. GI smooth muscle cells lack these conductances. Slow waves propagate actively within ICC networks and conduct electrotonically to smooth muscle cells via gap junctions. Slow waves depolarize smooth muscle cells and activate voltage-dependent Ca2+ channels (predominantly CaV1.2), causing Ca2+ influx and excitation-contraction coupling. The main conductances responsible for pacemaker activity in ICC are ANO1, a Ca2+ -activated Cl- conductance, and CaV3.2. The pacemaker cycle, as currently understood, begins with spontaneous, localized Ca2+ release events in ICC that activate spontaneous transient inward currents due to activation of ANO1 channels. Depolarization activates CaV 3.2 channels, causing the upstroke depolarization phase of slow waves. The upstroke is transient and followed by a long-duration plateau phase that can last for several seconds. The plateau phase results from Ca2+ -induced Ca2+ release and a temporal cluster of localized Ca2+ transients in ICC that sustains activation of ANO1 channels and clamps membrane potential near the equilibrium potential for Cl- ions. The plateau phase ends, and repolarization occurs, when Ca2+ stores are depleted, Ca2+ release ceases and ANO1 channels deactivate. This review summarizes key mechanisms responsible for electrical rhythmicity in gastrointestinal organs.

A multiscale predictive digital twin for neurocardiac modulation.

Cardiac function is tightly regulated by the autonomic nervous system (ANS). Activation of the sympathetic nervous system increases cardiac output by increasing heart rate and stroke volume, while parasympathetic nerve stimulation instantly slows heart rate. Importantly, imbalance in autonomic control of the heart has been implicated in the development of arrhythmias and heart failure. Understanding of the mechanisms and effects of autonomic stimulation is a major challenge because synapses in different regions of the heart result in multiple changes to heart function. For example, nerve synapses on the sinoatrial node (SAN) impact pacemaking, while synapses on contractile cells alter contraction and arrhythmia vulnerability. Here, we present a multiscale neurocardiac modelling and simulator tool that predicts the effect of efferent stimulation of the sympathetic and parasympathetic branches of the ANS on the cardiac SAN and ventricular myocardium. The model includes a layered representation of the ANS and reproduces firing properties measured experimentally. Model parameters are derived from experiments and atomistic simulations. The model is a first prototype of a digital twin that is applied to make predictions across all system scales, from subcellular signalling to pacemaker frequency to tissue level responses. We predict conditions under which autonomic imbalance induces proarrhythmia and can be modified to prevent or inhibit arrhythmia. In summary, the multiscale model constitutes a predictive digital twin framework to test and guide high-throughput prediction of novel neuromodulatory therapy. KEY POINTS: A multi-layered model representation of the autonomic nervous system that includes sympathetic and parasympathetic branches, each with sparse random intralayer connectivity, synaptic dynamics and conductance based integrate-and-fire neurons generates firing patterns in close agreement with experiment. A key feature of the neurocardiac computational model is the connection between the autonomic nervous system and both pacemaker and contractile cells, where modification to pacemaker frequency drives initiation of electrical signals in the contractile cells. We utilized atomic-scale molecular dynamics simulations to predict the association and dissociation rates of noradrenaline with the ß-adrenergic receptor. Multiscale predictions demonstrate how autonomic imbalance may increase proclivity to arrhythmias or be used to terminate arrhythmias. The model serves as a first step towards a digital twin for predicting neuromodulation to prevent or reduce disease.

The formation of KV2.1 macro-clusters is required for sex-specific differences in L-type CaV1.2 clustering and function in arterial myocytes.

In arterial myocytes, the canonical function of voltage-gated CaV1.2 and KV2.1 channels is to induce myocyte contraction and relaxation through their responses to membrane depolarization, respectively. Paradoxically, KV2.1 also plays a sex-specific role by promoting the clustering and activity of CaV1.2 channels. However, the impact of KV2.1 protein organization on CaV1.2 function remains poorly understood. We discovered that KV2.1 forms micro-clusters, which can transform into large macro-clusters when a critical clustering site (S590) in the channel is phosphorylated in arterial myocytes. Notably, female myocytes exhibit greater phosphorylation of S590, and macro-cluster formation compared to males. Contrary to current models, the activity of KV2.1 channels seems unrelated to density or macro-clustering in arterial myocytes. Disrupting the KV2.1 clustering site (KV2.1S590A) eliminated KV2.1 macro-clustering and sex-specific differences in CaV1.2 cluster size and activity. We propose that the degree of KV2.1 clustering tunes CaV1.2 channel function in a sex-specific manner in arterial myocytes.

The formation of K V 2.1 macro-clusters is required for sex-specific differences in L-type Ca V 1.2 clustering and function in arterial myocytes.

In arterial myocytes, the canonical function of voltage-gated Ca V 1.2 and K V 2.1 channels is to induce myocyte contraction and relaxation through their responses to membrane depolarization, respectively. Paradoxically, K V 2.1 also plays a sex-specific role by promoting the clustering and activity of Ca V 1.2 channels. However, the impact of K V 2.1 protein organization on Ca V 1.2 function remains poorly understood. We discovered that K V 2.1 forms micro-clusters, which can transform into large macro-clusters when a critical clustering site (S590) in the channel is phosphorylated in arterial myocytes. Notably, female myocytes exhibit greater phosphorylation of S590, and macro-cluster formation compared to males. Contrary to current models, the activity of K V 2.1 channels seems unrelated to density or macro-clustering in arterial myocytes. Disrupting the K V 2.1 clustering site (K V 2.1 S590A ) eliminated K V 2.1 macro-clustering and sex-specific differences in Ca V 1.2 cluster size and activity. We propose that the degree of K V 2.1 clustering tunes Ca V 1.2 channel function in a sex-specific manner in arterial myocytes.

Blockade of Kv7 channels reverses the inhibitory effects of exchange protein directly activated by cAMP activation on purinergic contractions of the murine detrusor.

Purinergic contractions of the detrusor are reduced by cAMP, but the underlying mechanisms are unclear. We examined the effects of BK and Kv7 channel modulators on purinergic contractions of the detrusor and tested if the inhibitory effects of activators of the cAMP effectors, PKA and EPAC, were reduced by blockade of BK or Kv7 channels. Purinergic contractions of the murine detrusor were induced by electric field stimulation (EFS) or application of the P2X receptor agonist α,ß-MeATP. EFS responses were inhibited by the L-type Ca2+ channel blocker nifedipine, but not by the SERCA inhibitor CPA or the SOCE blocker GSK7975A. The Kv7 channel opener retigabine and BK channel activator compound X inhibited purinergic responses, while blockade of Kv7 or BK channels with XE991 or iberiotoxin, respectively, augmented these responses. Application of the EPAC activator 007-AM or PKA activator 6-MB-cAMP inhibited EFS responses. These effects were unaffected by iberiotoxin; however, XE991 reduced the effects of 007-AM, but not 6-MB-cAMP. Kv7.5 was the only Kv7 transcript detected in isolated detrusor myocytes. These data suggest that purinergic contractions of the detrusor are regulated by BK and Kv7 channels and the latter may also play a role in EPAC-dependent inhibition of this activity.

Estado del arte de inteligencia artificial en ortodoncia. Revisión narrativa / State of the art on artificial intelligence in orthodontics. A narrative review

Introducción: Inteligencia artificial (IA) es la automatización de actividades vinculadas con procesos de pensamiento humano. En ortodoncia se han desarrollado sistemas que asistidos por IA pueden tomar decisiones terapéuticas y realizar análisis. No existe un compendio actualizado sobre el uso de IA en ortodoncia. Objetivos: Describir los usos de IA en ortodoncia de acuerdo con la literatura actual. Metodología: Se realizó una revisión narrativa en las bases Medline y SciELO mediante la búsqueda: (orthodont*) AND (“machine learning” OR “deep learning” OR “artificial intelligence” OR “neural network”). Resultados: Se obtuvieron 19 artículos que mostraron que IA se ha desarrollado en cinco áreas: 1) Cefalometría asistida por IA, donde la localización de puntos y análisis cefalométricos mostraron una precisión igual a ortodoncistas. 2) Localización de dientes no erupcionados en CBCT, con resultados similares entre IA y ortodoncistas. 3) Determinación de edad y maduración ósea de forma más eficiente apoyada por IA, que por métodos convencionales, 4) Análisis facial, donde la IA permite una evaluación objetiva del atractivo facial, con aplicaciones en diagnóstico y planificación quirúrgica. 5) Decisiones terapéuticas con IA, para determinar la necesidad de exodoncias y dientes que serán extraídos. Discusión: La IA se está incorporando aceleradamente en ortodoncia, por lo que debe conocerse conceptos y posibilidades que brinda. (AU)Conclusiones:Un número creciente de artículos sobre usos de IA en ortodoncia muestran resultados similares con IA a los obtenidos por especialistas. Sin embargo, la evidencia aún es poca y principalmente experimental, por lo que la IA debiera usarse cautelosamente en ortodoncia.

Introduction: Artificial Intelligence (AI) is the automation of activities related to human thought processes. In orthodontics, systems have been developed which, assisted by AI, can make therapeutic decisions and perform analyses. There is no updated compendium on the use of AI in orthodontics. Objectives: To describe the uses of AI in orthodontics according to the current literature. Methodology: A narrative review was performed in the Medline and SciELO bases by means of the following search: (orthodont*) AND (“machine learning” OR “deep learning” OR “artificial intelligence” OR “neural network”). Results: 19 articles were obtained, showing that AI has been developed in four areas: 1) IA assisted cephalometry, where localization of cephalometric points and cephalometric analysis showed equal accuracy than orthodontists. 2) Unerupted tooth localization with CBCT, with similar results between AI and orthodontists. 3) Determination of skeletal age, which is more efficient with AI than with conventional methods. 4) Facial analysis, where AI allows an objective evaluation of facial attractiveness with applications in diagnosis and surgical planning. 5) Therapeutic decisions with AI, to determine the need for exodontia and teeth to be extracted. Discussion: AI is being incorporated rapidly in orthodontics, so we must know concepts and possibilities that it gives us in orthodontics. Conclusions: An increasing number of articles refer to the uses of AI in orthodontics, with similar results to those obtained by specialists. However, the evidence is still scarce and mainly experimental, so AI should still be used with caution in orthodontics. (AU)

Mechanisms and physiological implications of cooperative gating of clustered ion channels.

Ion channels play a central role in the regulation of nearly every cellular process. Dating back to the classic 1952 Hodgkin-Huxley model of the generation of the action potential, ion channels have always been thought of as independent agents. A myriad of recent experimental findings exploiting advances in electrophysiology, structural biology, and imaging techniques, however, have posed a serious challenge to this long-held axiom, as several classes of ion channels appear to open and close in a coordinated, cooperative manner. Ion channel cooperativity ranges from variable-sized oligomeric cooperative gating in voltage-gated, dihydropyridine-sensitive CaV1.2 and CaV1.3 channels to obligatory dimeric assembly and gating of voltage-gated NaV1.5 channels. Potassium channels, transient receptor potential channels, hyperpolarization cyclic nucleotide-activated channels, ryanodine receptors (RyRs), and inositol trisphosphate receptors (IP3Rs) have also been shown to gate cooperatively. The implications of cooperative gating of these ion channels range from fine-tuning excitation-contraction coupling in muscle cells to regulating cardiac function and vascular tone, to modulation of action potential and conduction velocity in neurons and cardiac cells, and to control of pacemaking activity in the heart. In this review, we discuss the mechanisms leading to cooperative gating of ion channels, their physiological consequences, and how alterations in cooperative gating of ion channels may induce a range of clinically significant pathologies.