Site-resolved multiple-quantum filtered correlations and distance measurements by magic-angle spinning NMR: Theory and applications to spins with weak to vanishing quadrupolar couplings.

We discuss and analyze four magic-angle spinning solid-state NMR methods that can be used to measure internuclear distances and to obtain correlation spectra between a spin I = 1/2 and a half-integer spin S > 1/2 having a small quadrupolar coupling constant. Three of the methods are based on the heteronuclear multiple-quantum and single-quantum correlation experiments, that is, high rank tensors that involve the half spin and the quadrupolar spin are generated. Here, both zero and single-quantum coherence of the half spins are allowed and various coherence orders of the quadrupolar spin are generated, and filtered, via active recoupling of the dipolar interaction. As a result of generating coherence orders larger than one, the spectral resolution for the quadrupolar nucleus increases linearly with the coherence order. Since the formation of high rank tensors is independent of the existence of a finite quadrupolar interaction, these experiments are also suitable to materials in which there is high symmetry around the quadrupolar spin. A fourth experiment is based on the initial quadrupolar-driven excitation of symmetric high order coherences (up to p = 2S, where S is the spin number) and subsequently generating by the heteronuclear dipolar interaction higher rank (l + 1 or higher) tensors that involve also the half spins. Due to the nature of this technique, it also provides information on the relative orientations of the quadrupolar and dipolar interaction tensors. For the ideal case in which the pulses are sufficiently strong with respect to other interactions, we derive analytical expressions for all experiments as well as for the transferred echo double resonance experiment involving a quadrupolar spin. We show by comparison of the fitting of simulations and the analytical expressions to experimental data that the analytical expressions are sufficiently accurate to provide experimental (7)Li-(13)C distances in a complex of lithium, glycine, and water. Discussion of the regime for which such an approach is valid is given.

An optimal double-magic flip angle for performing the distance measurement REDOR experiment on a spin S=1.

Distance measurements between a half-spin and a quadrupolar S=1 spin having a small quadrupolar coupling constant can be performed using the rotational echo double resonance (REDOR) experiment. We derived an analytical expression for the probability of transitions between energy levels resulting from the application of an arbitrary pulse flip angle to the quadrupolar spin and consequently minimized the probability that populations of individual levels do not undergo a spin transition during the pulse. As a result we discovered that if the flip angle of the quadrupolar spin pulse is 109.47°, the maximal recoupling values are the largest possible and the signal reaches a maximum value of 8/9, larger than in the use of either a 90° pulse or a 180° pulse. In addition, the slope of the initial decay is higher than that of the 90° pulse. The recoupling signal can be modeled by an exact analytical formula in the ideal case and simulations show that the advantage of the 109.47° pulse is preserved when the quadrupolar coupling constant CQ has a finite value typical of (2)H and (6)Li spins (up to CQ~200kHz). Experimental results on two spin pairs, (2)H-(13)C and (6)Li-(13)C, demonstrate the validity and accuracy of this method.

How does the mood stabilizer lithium bind ATP, the energy currency of the cell: Insights from solid-state NMR.

BACKGROUND: Lithium, in the form of a salt, is a mood stabilizer and a leading drug for the treatment of bipolar disorder. It has a very narrow therapeutic range and a variety of side effects. Lithium can replace magnesium and other cations in enzymes and small molecules, among them ATP, thereby affecting and inhibiting many biochemical pathways. The form of binding of lithium ions to ATP is not known. METHODS: Here we extract the binding environment of lithium in solid ATP using a multi-nuclear multi-dimensional solid-state NMR approach. RESULTS: We determine that the coordination sphere of lithium includes, at a distance of 3.0(±0.4) Å, three phosphates; the two phosphates closest to the ribose ring from one ATP molecule, and the middle phosphate from another ATP molecule. A water molecule most probably completes the fourth coordination. Despite the use of excess lithium in the preparations, sodium ions still remain bound to the sample, at distances of 4.3-5.5 Šfrom Li, and coordinate the first phosphate and two terminal phosphates. CONCLUSIONS: Solid-state NMR enables to unravel the exact coordination of lithium in ATP showing binding to three phosphates from two molecules, none of which are the terminal gamma phosphate. GENERAL SIGNIFICANCE: The methods we use are applicable to study lithium bound to a variety of ATP-bound enzymes, or to other cellular targets of lithium, consequently suggesting a molecular basis for its mode of action.

Characterization of lithium coordination sites with magic-angle spinning NMR.

Lithium, in the form of lithium carbonate, is one of the most common drugs for bipolar disorder. Lithium is also considered to have an effect on many other cellular processes hence it possesses additional therapeutic as well as side effects. In order to quantitatively characterize the binding mode of lithium, it is required to identify the interacting species and measure their distances from the metal center. Here we use magic-angle spinning (MAS) solid-state NMR to study the binding site of lithium in complex with glycine and water (LiGlyW). Such a compound is a good enzyme mimetic since lithium is four-coordinated to one water molecule and three carboxylic groups. Distance measurements to carbons are performed using a 2D transferred echo double resonance (TEDOR) MAS solid-state NMR experiment, and water binding is probed by heteronuclear high-resolution proton-lithium and proton-carbon correlation (wPMLG-HETCOR) experiments. Both HETCOR experiments separate the main complex from impurities and non-specifically bound lithium species, demonstrating the sensitivity of the method to probe the species in the binding site. Optimizations of the TEDOR pulse scheme in the case of a quadrupolar nucleus with a small quadrupole coupling constant show that it is most efficient when pulses are positioned on the spin-1/2 (carbon-13) nucleus. Since the intensity of the TEDOR signal is not normalized, careful data analysis that considers both intensity and dipolar oscillations has to be performed. Nevertheless we show that accurate distances can be extracted for both carbons of the bound glycine and that these distances are consistent with the X-ray data and with lithium in a tetrahedral environment. The lithium environment in the complex is very similar to the binding site in inositol monophosphatase, an enzyme associated with bipolar disorder and the putative target for lithium therapy. A 2D TEDOR experiment applied to the bacterial SuhB gene product of this enzyme was designed to probe direct correlations between lithium, the enzyme inhibitor, and the closest carboxyl carbons of the binding site. At this point, the chemical shift of the bound carboxyl groups in this 29 kDa enzyme could be determined.

Telemedicina en las Unidades de Cuidados Intensivos Pediátricos: Desarrollo de una nueva modalidad asistencial / Telemedicinein Pediatric Intensive Care Units: Development of a new care model

Los Programas telemédicos entre unidades de cuidados intensivos han demostrado ser eficaces en el mundo. En Argentina realizamos el primer programa piloto entre una Unidad de Cuidados Intensivos Pediátricos de Buenos Aires (UCIP- BA) y Santiago del Estero (UCIP-S). En el presente trabajo describimos el desarrollo y la evaluación de una nueva modalidad de asistencia para el diagnóstico, tratamiento y seguimiento a distancia de los pacientes en UCIP. Se implementó un programa de atención sincrónica para pacientes internados y seleccionados por la UCIP-S. Se utilizó un sistema de videoconferencia y se realizó un seguimiento en conjunto de los pacientes. La evaluación se realizó con una encuesta de satisfacción de los usuarios. Ingresaron al estudio 29 pacientes, 72 % del sexo masculino. La edad promedio fue de 35 meses (2-168). El diagnóstico más frecuente fue shock séptico y el acompañamiento en el diagnóstico la conducta más frecuente. Solo cinco pacientes obitaron y se registraron 3 derivaciones al Hospital Garrahan. Se realizaron 155 teleconferencias y 396 consultas, con un tiempo promedio diario de 48 minutos, La media de seguimientos por pacientes fue de 20,6 días (2-107). Tele-UCI mejoró la capacidad de comprensión de la situación clínica (96%) y modificó la relación con la familia (65%). El modelo asistencial demostró un 88.5% de satisfacción. A través de estos resultados concluimos que según los profesionales participantes, Tele-UCI respaldó al equipo que se encarga del seguimiento diario de los pacientes, generando una disminución de traslados de pacientes (AU)

Telemedicine programs between intensive care units have proven effective worldwide. In Argentina we conducted the first pilot program between a Pediatric Intensive Care Unit in Buenos Aires (PICU- BA) and another in Santiago del Estero (PICU-S). In this study, we describe the development and evaluation of a new care modality for the diagnosis, treatment, and remote monitoring of patients in the PICU. A synchronous care program for inpatients selected by PICU-S was implemented. A videoconferencing system was used and patients were monitored together. The program was evaluated with a user satisfaction survey. Twenty-nine patients, 72% of the male sex, were included in the study. Mean age was 35 months (2-168). The most common diagnosis was septic shock and in the majority of cases the diagnosis was confirmed. Only five patients died and three were referred to Garrahan Hospital. Overall, 155 teleconferences and 396 consultations were conducted, with a mean daily time of 48 minutes. Mean monitoring time per patient was 20.6 days (2-107). Tele-ICU improved the ability to understand the clinical situation (96%) and changed the relationship with the family (65%). The care model showed an 88.5% satisfaction rate. Based on these results, we conclude that according to the participating professionals, TeleICU supported the team that is in charge of the daily monitoring of patients, leading to a decrease in patient transfers (AU)

Impacto de la cateterización venosa central percutánea bajo guía ecográfica en una terapia intensiva pediátrica polivalente / Impact of ultrasound-guided percutaneous central venous catheterization at a general pediatric intensive care unit

Introducción: La cateterización venosa central es un procedimiento usual en Unidades de Cuidados Intensivos (UCI). El ultrasonido (US) para guiar la cateterización, ofrece ventajas, permitiendo tener una imagen topográfica precisa del vaso, reduciendo las complicaciones, el tiempo y el número de punciones. Objetivo: determinar, si la US en la colocación de catéteres venosos centrales (CVC), podría disminuir el número de punciones y lograr la cateterización exitosa. Población y métodos: Estudio descriptivo, prospectivo de los CVC colocados mediante punción guiada por US, en una UCI polivalente del Hospital de Pediatría Juan P. Garrahan, entre el año 2018 al 2019. Población: pacientes de 1 mes a 18 años que requirieron colocación de un CVS por US. Se consideró significativo un valor de p< 0.05. Resultados: VYI en 66 pacientes (43,5%), VF fue en 86 pacientes (56,5%). 86 (56,5%) CVC, fueron insertados en el primer intento y 66 (43,5%), requirieron más de un intento. Las inserciones en VYI fueron exitosas en el primer intento en 46 pac. (53,5%) 20 pac. requirieron más de un intento (30,3%) p 0,004 OR 0,37 (IC 95% 0,18-0,78. En <6 meses los CVC colocados en VYI tuvieron menos riesgo de requerir más de un intento, con respecto a aquellos en los cuales se eligió la VF, p 0,0026 OR 0,31 (IC 95% 0,12 -0,75). 5,2% presentaron complicaciones, no hubo mortalidad relacionada al procedimiento. Conclusiones: La inserción de CVC guiados por US fue segura y significativamente exitosa en el primer intento cuando el vaso de elección fue la VYI, especialmente en < 6 meses (AU)

IIntroduction: Central venous catheterization is a common procedure in intensive care units (ICU). The use of ultrasound (US) to guide catheterization offers advantages, allowing for an accurate topographic image of the vessel, reducing complications as well as time and number of punctures. Objective: To determine whether the use of US for the placement of central venous catheters (CVCs) may decrease the number of punctures and achieve successful catheterization. Patients and methods: A descriptive, prospective study was conducted of CVCs placed by US-guided puncture at a general ICU of Hospital de Pediatría Juan P. Garrahan between 2018 and 2019. Patients from 1 month to 18 years of age who required US-guided placement of a CVC were included. A p< 0.05 was considered significant. Results: The internal jugular vein (IJV) was used in 66 (43.5%) and the femoral vein (FV) in 86 patients (56.5%). Overall, in 86 (56.5%) CVC were inserted on the first attempt and 66 (43.5%) required more than one attempt. Insertions into the VYI were successful on the first attempt in 46 (53.5%) patients and 20 (30.3%) patients required more than one attempt, p 0.004; OR 0.37 (95% CI 0.18-0.78). In patients <6 months CVCs placed in the IJV had a lower risk of requiring more than one attempt compared to those in which the FV was chosen, p 0.0026 OR 0.31 (95% CI 0.12 -0.75). Complications occurred in 5.2%; no procedure-related mortality was observed. Conclusions: US-guided insertion of CVC was safe and significantly successful on the first attempt when the vessel of choice was the IJV, especially in patients < 6 months (AU)

Programa de prevención de las bacteriemias asociadas a catéteres venosos centrales / Program for prevention of central venous catheter-related bacteremia

Introducción: Las infecciones son las complicaciones más importantes asociadas al uso de los Catéteres Venosos Centrales (CVC), representan un riesgo 20 veces mayor de bacteriemias que los catéteres venosos periféricos. El objetivo de este estudio fue evaluar el efecto de la implementación de un paquete de medidas o "bundle" en las infecciones asociadas a catéteres venosos centrales (BACT- CVC) en la Unidad de Cuidados Intensivos del Hospital Garrahan (UCI). Métodos: El Programa de Intervención para disminuir las bacteriemias asociadas a catéteres venosos centrales requirió de la aplicación de cuatro paquetes de medidas y un subprograma para aumentar la adherencia a la higiene de manos. Se aplicó en todas las UCI, pero en el presente estudio se presenta como modelo de referencia el que se llevó a cabo en una de ellas. Período del estudio: se compararon 2 períodos: basal (1º Agosto de 2008 - 31 de Diciembre de 2009) y intervención (1º de Enero 2010 al 31 de Diciembre de 2011). La tasa de BACT - CVC se calculó en concordancia con los protocolos utilizados por el sistema NHSN - CDC de los Estados Unidos y el sistema nacional VIHDA. La base de datos utilizada para el estudio fue el software provisto por el programa VIHDA. Se compararon las tasas de BACT - CVC en el período previo y posterior a las intervenciones realizadas. Para el análisis estadístico se utilizó el programa EPIINFO. Se consideró estadísticamente significativo un valor de p < 0.05. Resultados: en el primer período (Agosto 2008 - Diciembre 2009) se produjeron un total de 44 BACT - CVC, con una tasa promedio de 9.64 BACT-CVC por 1000 días-catéter versus 17 BACT - CVC, tasa promedio de 4.41 BACT-CVC por 1000 días-catéter en el período en que se desarrolla el programa de intervención. Esta disminución resulta estadísticamente significativa (Chi cuadrado; valor P= 0,0048; RR 0,46; IC 95%: 0,26 - 0,80). Conclusiones: La aplicación de los combos y el subprograma para mejorar la adherencia a la higiene de manos según orientación de la OMS y aplicando Estrategias Multimodales, resultaron en una mejora significativa en la tasa de BACT- CVC (AU)

Introduction: Infections are the main complication associated with the use of central venous catheters (CVC), accounting for an infection risk about 20 times that of peripheral venous catheters. The aim of this study was to assess the effect of the implementation of sets of measures or "bundle" for the prevention of CVC-associated bacteremia (CVC-BACT) in the ICU. Methods: The intervention program for the reduction of CVC-BACT consisted of four sets of measures and a sub-program to increase adherence to hand hygiene. Bundle use was started in all PICUs, however, in this study implementation of the program in one of them was used as a reference model. Study period: Two periods were compared: Baseline (August 1, 2008 ­ December 31, 2009) and intervention (January 1, 2010 ­ December 31, 2011). The CVC-BACT rate was calculated according to the NHSN-CDC protocols of the United States and the Argentine VIHDA system. For the data base of the study software provided by the VIHDA program was used. CVC-BACT rates before and after the intervention period were calculated. For statistical analysis the EPIINFO program was used. A p < 0.05 was considered significant. Results: In the first period (August 2008 - December 2009) 44 CVC-BACT occurred, with a mean CVC-BACT rate of 9.64 per 1000 catheter days versus 17 CVC-BACT, mean CVC-BACT rate of 4.41 per 1000 catheter days, in the intervention period. This decrease was statistically significant (Chi square 7.94; p = 0.0048; RR 0.46; 95% CI: 0.26 ­ 0.80). Conclusions: Bundle use and the subprogram for better adherence to hand hygiene, according to WHO guidelines and applying multimodal strategies, resulted in a significantly lower CVC-BACT rate (AU)

Evaluación de la atención hospitalaria de los pacientes fallecidos en el Hospital de Pediatría Juan.P Garrahan entre marzo y septiembre de 2001. Informe de la Comisión de Mortalidad / Evaluation of in-patient care of patients dying at the Hospital de Pediatría J. P Garrahan between March and September 2001

Objetivo:En el marco de un programa de evaluacíon de calidad de atención médica,se crea la comisión de Mortalidad con el objetivo de analizar,con una nueva propuesta metodológica,la atención de los pacientes fallecidos en el hospital.Este informe reporta los resultados de trabajo de dicha comisión.Pacientes y métodos:se realizó un análisis retrospectivo de todos los pacientes fallecidos en el hospital entre el 15 de marzo y el 30 de septiembre de 2001.Cada historia clínica tuvo dos instancias independientes de revisión:el grupo tratante y un miembro de la comisión.Se registraron;edad,lugar/res de internación,diagnostico de base,lugar de óbito,solicitud de necropsia,y concordancia entre el grupo tratante y la comisióm.La muerte se clasifico en inevitable,potencialmente evitable o evitable.Resultados:se registraron 7759 admisiones y 149 fallecimientos(1.9 por ciento)siete historias clínicas no pudieron ser evaluadas.La mediana de edad fue de 18.5 meses(r=1d-19a)El 17,6 por ciento eran menores de 1 mes y 43,4 por ciento menor de 1 año.la mediana del tiempo de internación de 9.5 días(r=3-215)Los diagnósticos más frecuentes de enfermedad de base fueron:enfermedad oncológica 36,cardiopatía congénita 15 e infección respiratoria 12.La principal causa de muerte de aquellas consideradas potencialemente evitables(n=10)fue la infección intrahospitalaria.Conclusiones:La mortalidad hospitalaria durante el período de estudio fue de 1.9 por ciento,El 80 por ciento de la muertes ocurrieron en el área de terapia intensiva(ucip,ucin y quemados)Se consideraron inevitables 97/107 muertes(90 por ciento)potencialmente evitables 10(9.3 por ciento)y una evitables(0.9 por ciento)Solo se realizó necropsia en el 14.7 por ciento de la población estudiada