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Cytidine triphosphate synthase 1 (CTPS1) is necessary for an effective immune response, as revealed by severe immunodeficiency in CTPS1-deficient individuals [E. Martin et al], [Nature] [510], [288-292] ([2014]). CTPS1 expression is up-regulated in activated lymphocytes to expand CTP pools [E. Martin et al], [Nature] [510], [288-292] ([2014]), satisfying increased demand for nucleic acid and lipid synthesis [L. D. Fairbanks, M. Bofill, K. Ruckemann, H. A. Simmonds], [J. Biol. Chem. ] [270], [29682-29689] ([1995]). Demand for CTP in other tissues is met by the CTPS2 isoform and nucleoside salvage pathways [E. Martin et al], [Nature] [510], [288-292] ([2014]). Selective inhibition of the proliferative CTPS1 isoform is therefore desirable in the treatment of immune disorders and lymphocyte cancers, but little is known about differences in regulation of the isoforms or mechanisms of known inhibitors. We show that CTP regulates both isoforms by binding in two sites that clash with substrates. CTPS1 is less sensitive to CTP feedback inhibition, consistent with its role in increasing CTP levels in proliferation. We also characterize recently reported small-molecule inhibitors, both CTPS1 selective and nonselective. Cryo-electron microscopy (cryo-EM) structures reveal these inhibitors mimic CTP binding in one inhibitory site, where a single amino acid substitution explains selectivity for CTPS1. The inhibitors bind to CTPS assembled into large-scale filaments, which for CTPS1 normally represents a hyperactive form of the enzyme [E. M. Lynch et al], [Nat. Struct. Mol. Biol.] [24], [507-514] ([2017]). This highlights the utility of cryo-EM in drug discovery, particularly for cases in which targets form large multimeric assemblies not amenable to structure determination by other techniques. Both inhibitors also inhibit the proliferation of human primary T cells. The mechanisms of selective inhibition of CTPS1 lay the foundation for the design of immunosuppressive therapies.
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Ligasas de Carbono-Nitrógeno/metabolismo , Isoformas de Proteínas/metabolismo , Proliferación Celular/fisiología , Humanos , Síndromes de Inmunodeficiencia/metabolismo , Linfocitos T/metabolismoRESUMEN
BACKGROUND: The study of psychological well-being and related resilient outcomes is of increasing focus in cardiovascular research. Despite the critical importance of psychological well-being and related resilient outcomes in promoting optimal cardiac health, there have been very few psychological interventions directed towards children with heart disease. This paper describes the development and theoretical framework of the WE BEAT Wellbeing Education Program, a group-based psychoeducation and coping skills training intervention designed to improve psychological well-being and resilience in adolescents with paediatric heart disease. METHODS: Program development was informed by patient and family needs and input gathered via large, international survey methods as well as qualitative investigation, a theoretical framework, and related resilience intervention research. RESULTS: An overview of the WE BEAT intervention components and structure of the programme is provided. CONCLUSIONS: The WE BEAT Wellbeing Education Program was developed as one of the first resiliency-focused interventions in paediatric heart disease with an overall objective to foster positive psychological well-being and resilient outcomes through a health promotion and prevention lens in an accessible format while providing access to safe, peer-to-peer community building. Feasibility pilot results are forthcoming. Future directions include mobile app-based delivery and larger-scale efficacy and implementation trials.
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Trans-acting siRNA form through a refined RNAi mechanism in plants. miRNA-guided cleavage triggers entry of precursor transcripts into an RNA-DEPENDENT RNA POLYMERASE6 pathway, and sets the register for phased tasiRNA formation by DICER-LIKE4. Here, we show that miR390-ARGONAUTE7 complexes function in distinct cleavage or noncleavage modes at two target sites in TAS3a transcripts. The AGO7 cleavage, but not the noncleavage, function could be provided by AGO1, the dominant miRNA-associated AGO, but only when AGO1 was guided to a modified target site through an alternate miRNA. AGO7 was highly selective for interaction with miR390, and miR390 in turn was excluded from association with AGO1 due entirely to an incompatible 5' adenosine. Analysis of AGO1, AGO2, and AGO7 revealed a potent 5' nucleotide discrimination function for some, although not all, ARGONAUTEs. miR390 and AGO7, therefore, evolved as a highly specific miRNA guide/effector protein pair to function at two distinct tasiRNA biogenesis steps.
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Proteínas de Arabidopsis/metabolismo , Arabidopsis/metabolismo , MicroARNs/metabolismo , ARN Interferente Pequeño/metabolismo , Arabidopsis/genética , Secuencia de Bases , Oxidorreductasas/genética , Plantas Modificadas Genéticamente , Interferencia de ARN , ARN de Planta , ARN Polimerasa Dependiente del ARN/metabolismo , Ribonucleasa III , Ribonucleasas/metabolismo , Plantones/genética , Plantones/metabolismo , Transducción de SeñalRESUMEN
The ability to precisely design large proteins with diverse shapes would enable applications ranging from the design of protein binders that wrap around their target to the positioning of multiple functional sites in specified orientations. We describe a protein backbone design method for generating a wide range of rigid fusions between helix-containing proteins and use it to design 75,000 structurally unique junctions between monomeric and homo-oligomeric de novo designed and ankyrin repeat proteins (RPs). Of the junction designs that were experimentally characterized, 82% have circular dichroism and solution small-angle X-ray scattering profiles consistent with the design models and are stable at 95 °C. Crystal structures of four designed junctions were in close agreement with the design models with rmsds ranging from 0.9 to 1.6 Å. Electron microscopic images of extended tetrameric structures and â¼10-nm-diameter "L" and "V" shapes generated using the junctions are close to the design models, demonstrating the control the rigid junctions provide for protein shape sculpting over multiple nanometer length scales.
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Modelos Moleculares , Ingeniería de Proteínas/métodos , Proteínas/ultraestructura , Secuencias Repetitivas de Aminoácido/genética , Dicroismo Circular , Microscopía Electrónica , Biblioteca de Péptidos , Conformación Proteica en Hélice alfa/genética , Pliegue de Proteína , Proteínas/química , Proteínas/genética , Dispersión del Ángulo Pequeño , Difracción de Rayos XRESUMEN
In this survey study of institutions across the US, marked variability in evaluation, treatment, and follow-up of adolescents 12 through 18 years of age with mRNA coronavirus disease 2019 (COVID-19) vaccine-associated myopericarditis was noted. Only one adolescent with life-threatening complications was reported, with no deaths at any of the participating institutions.
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COVID-19 , Miocarditis , Adolescente , COVID-19/prevención & control , Vacunas contra la COVID-19/efectos adversos , Humanos , Miocarditis/epidemiología , Miocarditis/etiología , ARN MensajeroRESUMEN
COVID-19 associated myocarditis following mild infections is rare while incidental findings may be more common. A young athlete fully recovered from a mild COVID-19 infection presented with inferolateral T-wave inversions and left ventricular hypertrophy on imaging. Exercise testing aided in correctly diagnosing the patient with masked systolic hypertension.
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COVID-19 , Hipertensión Enmascarada , Miocarditis , Humanos , Adolescente , Miocarditis/diagnóstico por imagen , Miocarditis/etiología , Hipertrofia Ventricular Izquierda/complicaciones , Arritmias Cardíacas/complicaciones , Atletas , ElectrocardiografíaRESUMEN
Bacterial actins are an evolutionarily diverse family of ATP-dependent filaments built from protomers with a conserved structural fold. Actin-based segregation systems are encoded on many bacterial plasmids and function to partition plasmids into daughter cells. The bacterial actin AlfA segregates plasmids by a mechanism distinct from other partition systems, dependent on its unique dynamic properties. Here, we report the near-atomic resolution electron cryo-microscopy structure of the AlfA filament, which reveals a strikingly divergent filament architecture resulting from the loss of a subdomain conserved in all other actins and a mode of ATP binding. Its unusual assembly interfaces and nucleotide interactions provide insight into AlfA dynamics, and expand the range of evolutionary variation accessible to actin quaternary structure.
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Actinas/metabolismo , Actinas/ultraestructura , Adenosina Trifosfato/metabolismo , Proteínas Bacterianas/metabolismo , Proteínas Bacterianas/ultraestructura , Secuencia de Aminoácidos , Microscopía por Crioelectrón , Cristalografía por Rayos X , Citoesqueleto/metabolismo , Modelos Moleculares , Dominios Proteicos , Homología de SecuenciaRESUMEN
Elongator is a ~850 kDa protein complex involved in multiple processes from transcription to tRNA modification. Conserved from yeast to humans, Elongator is assembled from two copies of six unique subunits (Elp1 to Elp6). Despite the wealth of structural data on the individual subunits, the overall architecture and subunit organization of the full Elongator and the molecular mechanisms of how it exerts its multiple activities remain unclear. Using single-particle electron microscopy (EM), we revealed that yeast Elongator adopts a bilobal architecture and an unexpected asymmetric subunit arrangement resulting from the hexameric Elp456 subassembly anchored to one of the two Elp123 lobes that form the structural scaffold. By integrating the EM data with available subunit crystal structures and restraints generated from cross-linking coupled to mass spectrometry, we constructed a multiscale molecular model that showed the two Elp3, the main catalytic subunit, are located in two distinct environments. This work provides the first structural insights into Elongator and a framework to understand the molecular basis of its multifunctionality.
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Proteínas Fúngicas/química , Histona Acetiltransferasas/química , Modelos Moleculares , Complejos Multiproteicos/química , Subunidades de Proteína/química , Secuencia Conservada , Evolución Molecular , Proteínas Fúngicas/genética , Proteínas Fúngicas/metabolismo , Histona Acetiltransferasas/genética , Histona Acetiltransferasas/metabolismo , Espectrometría de Masas , Complejos Multiproteicos/metabolismo , Complejos Multiproteicos/ultraestructura , Unión Proteica , Conformación Proteica , Multimerización de Proteína , Subunidades de Proteína/genética , Subunidades de Proteína/metabolismo , Proteínas de Saccharomyces cerevisiae/química , Proteínas de Saccharomyces cerevisiae/metabolismo , Eliminación de Secuencia , Relación Estructura-ActividadRESUMEN
Management of hypoplastic left heart syndrome (HLHS) is resource intensive. Heath care systems are pressured to provide value to patients by improving outcomes while decreasing costs. A single-center retrospective cohort of infants with HLHS who underwent Norwood procedure or hybrid Norwood from 2004 to 2014 and survived to first outpatient follow up were studied. The primary outcome was total cost through 12 months with a sub-analysis of patients with 60 months of data. Costs were calculated using internal cost accounting system and reported by cost center. Of the 152 HLHS patients identified, 69 met inclusion criteria. Stage I hospitalization (n = 69), with a median length of stay 34 days [interquartile range (IQR) 24-58 days], resulted in a median cost of $203,817 (IQR $136,236-272,453). Of survivors at 12 months (n = 55), the median cost was $369,393 (IQR $216,289-594,038) generated in part by a median of 67 (40-126 days) hospitalized days during that year. A subgroup analysis of patients who reached 60 months of age (n = 29) demonstrated a median total cost of $391,812 (IQR $293,801-577,443) and a median of 74 lifetime hospitalized days (IQR 58-116 days). High cost centers included intensive care (41%), non-ICU hospital (17%), operative services (11%), catheterization lab (9%), and pharmacy (9%). Using multiple regression analysis, significant drivers of cost included reoperation, length of hospitalization, low birthweight, and use of ECMO. Costs related to HLHS management are driven both by care-related complications such as surgical re-intervention and patient factors such as low birth weight.
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Costos de la Atención en Salud/estadística & datos numéricos , Hospitalización/economía , Síndrome del Corazón Izquierdo Hipoplásico/economía , Procedimientos de Norwood/economía , Cuidados Paliativos/economía , Preescolar , Estudios de Cohortes , Femenino , Humanos , Síndrome del Corazón Izquierdo Hipoplásico/cirugía , Lactante , Recién Nacido , Tiempo de Internación/economía , Estudios Longitudinales , Masculino , Procedimientos de Norwood/métodos , Cuidados Paliativos/métodos , Sistema de Registros , Estudios RetrospectivosRESUMEN
The current research examines Colorado's experience implementing evidence-based mandated treatment Standards, which use a uniform risk assessment, differentiated treatment levels, offender competencies, and a multidisciplinary treatment team (MTT) composed of a victim advocate, probation officer, and treatment provider to manage offender treatment. Using data from MTT member surveys (n = 107) and follow-up interviews (n = 14), the study investigates perceptions of implementation and treatment fidelity, MTT decision making and communication, and the process of successful treatment completion. Results demonstrate that full implementation of Colorado's standards for domestic violence treatment has not yet been achieved and that many MTT members report challenges to communication and decision making regarding offender treatment plans and successful achievement of competencies. Recommendations for further improvements in Colorado's domestic violence treatment model are made and directions for future research are discussed.
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Maltrato a los Niños/prevención & control , Adhesión a Directriz , Implementación de Plan de Salud/organización & administración , Servicios Preventivos de Salud/organización & administración , Maltrato Conyugal/prevención & control , Violencia/prevención & control , Adulto , Niño , Colorado , Intervención en la Crisis (Psiquiatría) , Femenino , Regulación Gubernamental , Humanos , Comunicación Interdisciplinaria , Relaciones Interinstitucionales , Masculino , Persona de Mediana EdadRESUMEN
Youth with sexually problematic behaviors are impacted by the reciprocal interplay between individual characteristics and the key social and ecological systems in which they are embedded. The paucity of research on protective factors mitigating risks within various socioecological systems is of concern, as the school is one such system that has been overlooked. This study retroactively investigated probation files among youth who were adjudicated of a sexual crime (N = 85) to determine how school-level variables are associated with treatment completion. A sequential logistical regression model revealed reduced odds for school-based risk factors and a greater proportion of variance explained when school-based protective factors were included. Implications and research considerations are discussed.
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Conducta del Adolescente/psicología , Delincuencia Juvenil/estadística & datos numéricos , Instituciones Académicas/estadística & datos numéricos , Delitos Sexuales/estadística & datos numéricos , Adolescente , Femenino , Humanos , Masculino , Factores Protectores , Factores de RiesgoRESUMEN
Mycobacteria produce an unusual, glycolylated form of muramyl dipeptide (MDP) that is more potent and efficacious at inducing NOD2-mediated host responses. We tested the importance of this modified form of MDP in Mycobacterium tuberculosis by disrupting the gene, namH, responsible for this modification. In vitro, the namH mutant did not produce N-glycolylated muropeptides, but there was no alteration in colony morphology, growth kinetics, cellular morphology, or mycolic acid profile. Ex vivo, the namH mutant survived and replicated normally in murine and human macrophages, yet induced diminished production of tumor necrosis factor α. In vivo, namH disruption did not affect the bacterial burden during infection of C57BL/6 mice or cellular recruitment to the lungs but modestly prolonged survival after infection in Rag1(-/-) mice. These results indicate that the modified MDP is an important contributor to the unusual immunogenicity of mycobacteria but has a limited role in the pathogenesis of M. tuberculosis infection.
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Acetilmuramil-Alanil-Isoglutamina/inmunología , Mycobacterium tuberculosis/inmunología , Mycobacterium tuberculosis/patogenicidad , Peptidoglicano/inmunología , Acetilmuramil-Alanil-Isoglutamina/metabolismo , Animales , Carga Bacteriana , Células Cultivadas , Modelos Animales de Enfermedad , Eliminación de Gen , Humanos , Macrófagos/microbiología , Ratones , Ratones Endogámicos C57BL , Oxigenasas de Función Mixta/genética , Oxigenasas de Función Mixta/metabolismo , Mycobacterium tuberculosis/química , Mycobacterium tuberculosis/enzimología , Peptidoglicano/química , Procesamiento Proteico-Postraduccional , Análisis de Supervivencia , Tuberculosis Pulmonar/inmunología , Tuberculosis Pulmonar/microbiología , VirulenciaRESUMEN
The extracellular matrix (ECM) serves as a scaffold for cells and plays an essential role in regulating numerous cellular processes, including cell migration and proliferation. Due to limitations in specimen preparation for conventional room-temperature electron microscopy, we lack structural knowledge on how ECM components are secreted, remodeled, and interact with surrounding cells. We have developed a 3D-ECM platform compatible with sample thinning by cryo-focused ion beam milling, the lift-out extraction procedure, and cryo-electron tomography. Our workflow implements cell-derived matrices (CDMs) grown on EM grids, resulting in a versatile tool closely mimicking ECM environments. This allows us to visualize ECM for the first time in its hydrated, native context. Our data reveal an intricate network of extracellular fibers, their positioning relative to matrix-secreting cells, and previously unresolved structural entities. Our workflow and results add to the structural atlas of the ECM, providing novel insights into its secretion and assembly.
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Tomografía con Microscopio Electrónico , Matriz Extracelular , Transporte Biológico , Movimiento Celular , Citosol , Tomografía con Microscopio Electrónico/métodos , Matriz Extracelular/ultraestructuraRESUMEN
Poxviruses are among the largest double-stranded DNA viruses, with members such as variola virus, monkeypox virus and the vaccination strain vaccinia virus (VACV). Knowledge about the structural proteins that form the viral core has remained sparse. While major core proteins have been annotated via indirect experimental evidence, their structures have remained elusive and they could not be assigned to individual core features. Hence, which proteins constitute which layers of the core, such as the palisade layer and the inner core wall, has remained enigmatic. Here we show, using a multi-modal cryo-electron microscopy (cryo-EM) approach in combination with AlphaFold molecular modeling, that trimers formed by the cleavage product of VACV protein A10 are the key component of the palisade layer. This allows us to place previously obtained descriptions of protein interactions within the core wall into perspective and to provide a detailed model of poxvirus core architecture. Importantly, we show that interactions within A10 trimers are likely generalizable over members of orthopox- and parapoxviruses.
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Microscopía por Crioelectrón , Modelos Moleculares , Multimerización de Proteína , Virus Vaccinia/ultraestructura , Virus Vaccinia/química , Virus Vaccinia/metabolismo , Poxviridae/ultraestructura , Poxviridae/metabolismo , Poxviridae/química , Proteínas del Núcleo Viral/química , Proteínas del Núcleo Viral/ultraestructura , Proteínas del Núcleo Viral/metabolismo , HumanosRESUMEN
The Fontan Udenafil Exercise Longitudinal (FUEL) trial showed that treatment with udenafil was associated with improved exercise performance at the ventilatory anaerobic threshold in children with Fontan physiology. However, it is not known how the initiation of phosphodiesterase 5 inhibitor therapy affects heart rate and blood pressure in this population. These data may help inform patient selection and monitoring after the initiation of udenafil therapy. The purpose of this study is to evaluate the effects of udenafil on vital signs in the cohort of patients enrolled in the FUEL trial. This international, multicenter, randomized, double-blind, placebo-controlled trial of udenafil included adolescents with single ventricle congenital heart disease who had undergone Fontan palliation. Changes in vital signs (heart rate [HR], systolic [SBP] and diastolic blood pressure [DBP]) were compared both to subject baseline and between the treatment and the placebo groups. Additional exploratory analyses were performed to evaluate changes in vital signs for prespecified subpopulations believed to be most sensitive to udenafil initiation. Baseline characteristics were similar between the treatment and placebo cohorts (n = 200 for each). The groups demonstrated a decrease in HR, SBP, and DBP 2 hours after drug/placebo administration, except SBP in the placebo group. There was an increase in SBP from baseline to after 6-min walk test in the treatment and placebo groups, and the treatment group showed an increase in HR (87.4 ± 15.0 to 93.1 ± 19.4 beats/min, p <0.01) after exercise. When comparing changes from baseline to the 26-week study visit, small decreases in both SBP (-1.9 ± 12.3 mm Hg, p = 0.03) and DBP (-3.0 ± 9.6 mm Hg, p <0.01) were seen in the treatment group. There were no clinically significant differences between treatment and placebo group in change in HR or blood pressure in the youngest age quartile, lightest weight quartile, or those on afterload-reducing agents. In conclusion, initiation of treatment with udenafil in patients with Fontan circulation was not associated with clinically significant changes in vital signs, implying that for patients similar to those enrolled in the FUEL trial, udenafil can be started without the requirement for additional monitoring after initial administration.
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Procedimiento de Fontan , Niño , Humanos , Adolescente , Presión Sanguínea , Frecuencia Cardíaca , Sulfonamidas/efectos adversos , Método Doble CiegoRESUMEN
Many children and adolescents with congenital and acquired heart disease (CHD) are physically inactive and participate in an insufficient amount of moderate-to-vigorous intensity exercise. Although physical activity (PA) and exercise interventions are effective at improving short- and long-term physiological and psychosocial outcomes in youth with CHD, several barriers including resource limitations, financial costs, and knowledge inhibit widespread implementation and dissemination of these beneficial programs. New and developing eHealth, mHealth, and remote monitoring technologies offer a potentially transformative and cost-effective solution to increase access to PA and exercise programs for youth with CHD, yet little has been written on this topic. In this review, a cardiac exercise therapeutics (CET) model is presented as a systematic approach to PA and exercise, with assessment and testing guiding three sequential PA and exercise intervention approaches of progressive intensity and resource requirements: (1) PA and exercise promotion within a clinical setting; (2) unsupervised exercise prescription; and (3) medically supervised fitness training intervention (i.e., cardiac rehabilitation). Using the CET model, the goal of this review is to summarize the current evidence describing the application of novel technologies within CET in populations of children and adolescents with CHD and introduce potential future applications of these technologies with an emphasis on improving equity and access to patients in low-resource settings and underserved communities.
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Many metabolic enzymes self-assemble into micron-scale filaments to organize and regulate metabolism. The appearance of these assemblies often coincides with large metabolic changes as in development, cancer, and stress. Yeast undergo cytoplasmic acidification upon starvation, triggering the assembly of many metabolic enzymes into filaments. However, it is unclear how these filaments assemble at the molecular level and what their role is in the yeast starvation response. CTP Synthase (CTPS) assembles into metabolic filaments across many species. Here, we characterize in vitro polymerization and investigate in vivo consequences of CTPS assembly in yeast. Cryo-EM structures reveal a pH-sensitive assembly mechanism and highly ordered filament bundles that stabilize an inactive state of the enzyme, features unique to yeast CTPS. Disruption of filaments in cells with non-assembly or pH-insensitive mutations decreases growth rate, reflecting the importance of regulated CTPS filament assembly in homeotstasis.
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Ligasas de Carbono-Nitrógeno/química , Saccharomyces cerevisiae/enzimología , Microscopía por Crioelectrón , Concentración de Iones de Hidrógeno , Conformación Proteica , Saccharomyces cerevisiae/genética , Saccharomyces cerevisiae/crecimiento & desarrollo , Proteínas de Saccharomyces cerevisiae/químicaRESUMEN
Mutations in the E3 ubiquitin ligase RING domains of BRCA1/BARD1 predispose carriers to breast and ovarian cancers. We present the structure of the BRCA1/BARD1 RING heterodimer with the E2 enzyme UbcH5c bound to its cellular target, the nucleosome, along with biochemical data that explain how the complex selectively ubiquitylates lysines 125, 127 and 129 in the flexible C-terminal tail of H2A in a fully human system. The structure reveals that a novel BARD1-histone interface couples to a repositioning of UbcH5c compared to the structurally similar PRC1 E3 ligase Ring1b/Bmi1 that ubiquitylates H2A Lys119 in nucleosomes. This interface is sensitive to both H3 Lys79 methylation status and mutations found in individuals with cancer. Furthermore, NMR reveals an unexpected mode of E3-mediated substrate regulation through modulation of dynamics in the C-terminal tail of H2A. Our findings provide insight into how E3 ligases preferentially target nearby lysine residues in nucleosomes by a steric occlusion and distancing mechanism.
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Proteína BRCA1/química , Proteína BRCA1/metabolismo , Histonas/metabolismo , Nucleosomas/química , Nucleosomas/metabolismo , Proteínas Supresoras de Tumor/química , Proteínas Supresoras de Tumor/metabolismo , Ubiquitina-Proteína Ligasas/química , Ubiquitina-Proteína Ligasas/metabolismo , Ubiquitinación , Proteína BRCA1/ultraestructura , Sitios de Unión , Dominio Catalítico , Microscopía por Crioelectrón , Histonas/química , Histonas/ultraestructura , Humanos , Lisina/química , Lisina/metabolismo , Modelos Moleculares , Unión Proteica , Reproducibilidad de los Resultados , Proteínas Supresoras de Tumor/ultraestructura , Enzimas Ubiquitina-Conjugadoras/química , Enzimas Ubiquitina-Conjugadoras/metabolismo , Enzimas Ubiquitina-Conjugadoras/ultraestructura , Ubiquitina-Proteína Ligasas/ultraestructuraRESUMEN
Background The routine use of angiotensin-converting enzyme inhibitors (ACEI) during palliation of hypoplastic left heart syndrome is controversial. We sought to describe ACEI prescription in the interstage between stage 1 palliation (stage I Norwood procedure) discharge and stage 2 palliation (stage II superior cavopulmonary anastomosis procedure) admission using the NPC-QIC (National Pediatric Cardiology Quality Improvement Collaborative) registry. Methods and Results Analysis of all patients (n=2180) enrolled in NPC-QIC from 2008 to 2016 included preoperative anatomy, risk factors, and echocardiographic data. ACEI were prescribed at stage I Norwood procedure discharge in 38% of patients. ACEI prescription declined from 2011 to 2016 compared with pre-2010 (36.8% versus 45%; P=0.005) with significant variation across centers (range 7-100%; P<0.001) and decreased prescribing rates associated with increased center volume (P=0.004). There was no difference in interstage mortality (P=0.662), change in atrioventricular valve regurgitation (P=0.101), or change in ventricular dysfunction (P=0.134) between groups. In multivariable analysis of all patients, atrioventricular septal defect (odds ratio [OR], 1.84; 95% CI, 1.28-2.65) or double outlet right ventricle (OR, 1.47; CI, 1.02-2.11), and preoperative mechanical ventilation (OR, 1.37; 95% CI, 1.12-1.68) were associated with increased ACEI prescription. In multivariable analysis of patients with complete echocardiographic data (n=812), ACEI prescription was more common with at least moderate atrioventricular valve regurgitation (OR, 1.88; 95% CI, 1.22-2.31). Conclusions ACEI prescription remains common in the interstage despite limited evidence of benefit. ACEI prescription is associated with preoperative mechanical ventilation, double outlet right ventricle, and atrioventricular valve regurgitation with marked inter-center variation. ACEI prescription is not associated with reduction in mortality, ventricular dysfunction, or atrioventricular valve regurgitation during the interstage.
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Inhibidores de la Enzima Convertidora de Angiotensina/uso terapéutico , Síndrome del Corazón Izquierdo Hipoplásico/tratamiento farmacológico , Pautas de la Práctica en Medicina , Inhibidores de la Enzima Convertidora de Angiotensina/efectos adversos , Prescripciones de Medicamentos , Utilización de Medicamentos , Femenino , Puente Cardíaco Derecho , Humanos , Síndrome del Corazón Izquierdo Hipoplásico/diagnóstico , Síndrome del Corazón Izquierdo Hipoplásico/mortalidad , Síndrome del Corazón Izquierdo Hipoplásico/fisiopatología , Lactante , Recién Nacido , Masculino , Procedimientos de Norwood , Cuidados Paliativos , Sistema de Registros , Estudios Retrospectivos , Resultado del Tratamiento , Estados UnidosRESUMEN
INTRODUCTION: Interdisciplinary communication failures contribute to medical mistakes and adverse events. At our institution, provider communication previously occurred through unidirectional pager systems. We utilized quality improvement methodology to (1) implement a secure text messaging system for providers on a pediatric ward and (2) evaluate its impact on communication failures. We aimed to reduce potential communication failures between providers by > 25% within 1 month. METHODS: Implementation of secure text messaging occurred via Plan-Do-Study-Act cycles focused on education, feedback, and electronic health record interventions. We collected pager data before implementation and both pager and secure text messaging data after intervention. Potential communication failures were identified a priori through manual review of the messaging data to capture lack of closed-loop communication. A run chart was used to track daily potential communication failures and total communication volumes. RESULTS: Before implementation of secure text messaging, the median daily potential communication failure rate was 5.5%. Usage of secure text messaging increased after implementation, representing 3.5 of 7.2 communications per patient-day. Paging communications decreased from 4.2 to 3.7 per patient-day. Potential communication failures decreased to a median daily rate of 2.2%, representing a 59% reduction in communication failures. CONCLUSION: Implementation of secure text messaging using quality improvement methods resulted in a significant reduction in potential communication failures between residents and nurses. Future interventions will be aimed at maintaining and augmenting providers' use of secure text messaging to ensure the potential for communication failure remains low.