RESUMO

Chronic kidney disease is one of the major health issues worldwide. However, diagnosis is now highly centralized in large laboratories, resulting in low access to patient monitoring and poor personalized treatments. This work reports the development of a graphene-based lab-on-a-chip (G-LOC) for the digital testing of renal function biomarkers in serum and saliva samples. G-LOC integrates multiple bioelectronic sensors with a microfluidic system that enables multiplex self-testing of urea, potassium, sodium, and chloride. The linearity, limit of detection (LOD), accuracy, and coefficient of variability (CV) were studied. Accuracy values higher than 95.5% and CV lower than 9% were obtained for all of the biomarkers. The analytical performance was compared against three reference lab benchtop analyzers by measuring healthy- and renal-failure-level samples of serum. From receiver operating characteristic (ROC) plots, sensitivities (%) of 99.7, 97.6, 99.1, and 89.0 were obtained for urea, potassium, sodium, and chloride, respectively. Then, the test was evaluated in noninvasive saliva samples and compared against reference methods. Correlation and Bland-Altman plots showed good correlation and agreement of the G-LOC with the reference methods. It is noteworthy that the precision of G-LOC was similar to better than benchtop lab analyzers, with the advantage of being highly portable. Finally, a user testing study was conducted. The analytical performance obtained with untrained volunteers was similar to that obtained with trained chemists. Additionally, based on a user experience survey, G-LOC was found to have very simple usability and would be suitable for at-home diagnostics.

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Introducción El 20% a 30% de la población presenta episodios sincopales a lo largo de la vida y el mecanismo reflejo representa la causa más común. Su diagnóstico diferencial se basa en el interrogatorio de las características del episodio y en la reproducibilidad de los síntomas con el tilt test. Sin embargo, este último tiene limitaciones importantes, lo que nos ha llevado a explorar en sucesivas etapas de investigación un nuevo parámetro, al que denominamos ôretraso de la onda de pulso carotídeoö. Objetivos Presentar los resultados de la investigación sobre el descubrimiento, el desarrollo y la aplicación clínica del parámetro ôretraso de la onda de pulso carotídeoö, capaz de identificar a pacientes con síncope reflejo. Material y métodos Se describen el nacimiento de la idea, los resultados del análisis de la correlación entre el parámetro con el tilt test mediante un estudio piloto en 43 pacientes con síncope, la confirmación de su correlación en 100 pacientes con síncope y grupo control, el estudio del mecanismo fisiopatológico del parámetro, el diseño y la validación de un equipo de adquisición automática en un estudio multicéntrico sobre 100 pacientes con historia de síncope mediante tilt test sensibilizado y la búsqueda de un nuevo patrón oro del síncope reflejo. Resultados El análisis estadístico mediante modelos univariados y multivariados y la construcción de curvas ROC sobre 243 pacientes sometidos a tilt test mostró que, a pesar de diferentes edades o métodos empleados, el parámetro clasificó correctamente a más del 80% de los pacientes con historia de síncope y tilt test positivos y al 100% de los voluntarios (2/30) sin historia de síncope que presentaron tilt test positivo. La medición del parámetro prescindiendo de la camilla basculante identificó al 100% de los voluntarios que refirieron historia de síncope (7/30). Conclusiones Desarrollamos un parámetro de medición s imple y no invasiva capaz de predecir en 5 minutos el resultado del tilt test en pacientes con síncope e identificar a personas con historia de síncope reflejo prescindiendo de la camilla basculante. El parámetro podría ayudar a la rápida toma de decisión diagnóstica en pacientes con síncope, a comprender aspectos fisiopatológicos y a evaluar intervenciones terapéuticas.(AU)

Introduction Between 20% and 30% of persons present syncope throughout their lives and reflex syncope represents the most common cause. The differential diagnosis of syncope is based on the characteristics of the episode and on the reproducibility of symptoms with the head-up tilt test. Yet, as tilt test has important limitations, we began exploring a new parameter in successive stages of investigation, which we called ôdelay of the carotid pulse waveö. Objectives To present the results of the investigation about the discovery, development and clinical applicability of the parameter: ôdelay of the carotid pulse waveö, capable of identifying patients with reflex syncope. Methods The development of the idea and the results of the analysis of the correlation between the parameter and the tilt test evaluated in a pilot study of 43 patients with syncope are described. The correlation is confirmed in 100 patients with syncope and in controls; the pathophysiological mechanism of the parameter is evaluated; the design of an automated device is described and its validation is confirmed in a multicenter study of 100 patients with history of syncope using drug-stimulated head-up tilt test. The search of a new gold standard for reflex syncope is described. Results The statistical analysis performing univariate and multivariate models and the construction of ROC curves on 243 patients undergoing head-up tilt test showed that, despite the different ages or methods used, the parameter classified in a correct fashion more than 80% of patients with history of syncope and positive head-up tilt test and 100% of volunteers without history of syncope who presented positive head-up tilt test. The measurement of the parameter without using a tilt table identified 100% of volunteers with history of syncope (7/30). Conclusions We developed a simple and noninvasive measurement parameter, capable of predicting a positive head-up tilt test within 5 minutes in patients with syncope and of identifying people with history of syncope without using the tilt table. The parameter could help to make rapid diagnostic decisions in patients with syncope, to understand the pathophysiological aspects and to evaluate the therapeutic interventions.(AU)

RESUMO

Introducción El 20% a 30% de la población presenta episodios sincopales a lo largo de la vida y el mecanismo reflejo representa la causa más común. Su diagnóstico diferencial se basa en el interrogatorio de las características del episodio y en la reproducibilidad de los síntomas con el tilt test. Sin embargo, este último tiene limitaciones importantes, lo que nos ha llevado a explorar en sucesivas etapas de investigación un nuevo parámetro, al que denominamos “retraso de la onda de pulso carotídeo”. Objetivos Presentar los resultados de la investigación sobre el descubrimiento, el desarrollo y la aplicación clínica del parámetro “retraso de la onda de pulso carotídeo”, capaz de identificar a pacientes con síncope reflejo. Material y métodos Se describen el nacimiento de la idea, los resultados del análisis de la correlación entre el parámetro con el tilt test mediante un estudio piloto en 43 pacientes con síncope, la confirmación de su correlación en 100 pacientes con síncope y grupo control, el estudio del mecanismo fisiopatológico del parámetro, el diseño y la validación de un equipo de adquisición automática en un estudio multicéntrico sobre 100 pacientes con historia de síncope mediante tilt test sensibilizado y la búsqueda de un nuevo patrón oro del síncope reflejo. Resultados El análisis estadístico mediante modelos univariados y multivariados y la construcción de curvas ROC sobre 243 pacientes sometidos a tilt test mostró que, a pesar de diferentes edades o métodos empleados, el parámetro clasificó correctamente a más del 80% de los pacientes con historia de síncope y tilt test positivos y al 100% de los voluntarios (2/30) sin historia de síncope que presentaron tilt test positivo. La medición del parámetro prescindiendo de la camilla basculante identificó al 100% de los voluntarios que refirieron historia de síncope (7/30). Conclusiones Desarrollamos un parámetro de medición s imple y no invasiva capaz de predecir en 5 minutos el resultado del tilt test en pacientes con síncope e identificar a personas con historia de síncope reflejo prescindiendo de la camilla basculante. El parámetro podría ayudar a la rápida toma de decisión diagnóstica en pacientes con síncope, a comprender aspectos fisiopatológicos y a evaluar intervenciones terapéuticas.

Introduction Between 20% and 30% of persons present syncope throughout their lives and reflex syncope represents the most common cause. The differential diagnosis of syncope is based on the characteristics of the episode and on the reproducibility of symptoms with the head-up tilt test. Yet, as tilt test has important limitations, we began exploring a new parameter in successive stages of investigation, which we called “delay of the carotid pulse wave”. Objectives To present the results of the investigation about the discovery, development and clinical applicability of the parameter: “delay of the carotid pulse wave”, capable of identifying patients with reflex syncope. Methods The development of the idea and the results of the analysis of the correlation between the parameter and the tilt test evaluated in a pilot study of 43 patients with syncope are described. The correlation is confirmed in 100 patients with syncope and in controls; the pathophysiological mechanism of the parameter is evaluated; the design of an automated device is described and its validation is confirmed in a multicenter study of 100 patients with history of syncope using drug-stimulated head-up tilt test. The search of a new gold standard for reflex syncope is described. Results The statistical analysis performing univariate and multivariate models and the construction of ROC curves on 243 patients undergoing head-up tilt test showed that, despite the different ages or methods used, the parameter classified in a correct fashion more than 80% of patients with history of syncope and positive head-up tilt test and 100% of volunteers without history of syncope who presented positive head-up tilt test. The measurement of the parameter without using a tilt table identified 100% of volunteers with history of syncope (7/30). Conclusions We developed a simple and noninvasive measurement parameter, capable of predicting a positive head-up tilt test within 5 minutes in patients with syncope and of identifying people with history of syncope without using the tilt table. The parameter could help to make rapid diagnostic decisions in patients with syncope, to understand the pathophysiological aspects and to evaluate the therapeutic interventions.