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1.
Nature ; 627(8002): 212-220, 2024 Mar.
Artículo en Inglés | MEDLINE | ID: mdl-38355801

RESUMEN

Circular RNAs (circRNAs), which are increasingly being implicated in a variety of functions in normal and cancerous cells1-5, are formed by back-splicing of precursor mRNAs in the nucleus6-10. circRNAs are predominantly localized in the cytoplasm, indicating that they must be exported from the nucleus. Here we identify a pathway that is specific for the nuclear export of circular RNA. This pathway requires Ran-GTP, exportin-2 and IGF2BP1. Enhancing the nuclear Ran-GTP gradient by depletion or chemical inhibition of the major protein exporter CRM1 selectively increases the nuclear export of circRNAs, while reducing the nuclear Ran-GTP gradient selectively blocks circRNA export. Depletion or knockout of exportin-2 specifically inhibits nuclear export of circRNA. Analysis of nuclear circRNA-binding proteins reveals that interaction between IGF2BP1 and circRNA is enhanced by Ran-GTP. The formation of circRNA export complexes in the nucleus is promoted by Ran-GTP through its interactions with exportin-2, circRNA and IGF2BP1. Our findings demonstrate that adaptors such as IGF2BP1 that bind directly to circular RNAs recruit Ran-GTP and exportin-2 to export circRNAs in a mechanism that is analogous to protein export, rather than mRNA export.


Asunto(s)
Transporte Activo de Núcleo Celular , Núcleo Celular , Transporte de ARN , ARN Circular , Transporte Activo de Núcleo Celular/fisiología , Núcleo Celular/metabolismo , Guanosina Trifosfato/metabolismo , Carioferinas/antagonistas & inhibidores , Carioferinas/deficiencia , Carioferinas/genética , Carioferinas/metabolismo , Proteínas Nucleares/metabolismo , Proteína de Unión al GTP ran/metabolismo , ARN Circular/metabolismo , Precursores del ARN/genética , Precursores del ARN/metabolismo , Proteínas de Unión al ARN/metabolismo , Proteína Exportina 1/metabolismo , Transporte de Proteínas
3.
Eur Heart J ; 45(24): 2133-2141, 2024 Jun 28.
Artículo en Inglés | MEDLINE | ID: mdl-38678737

RESUMEN

BACKGROUND AND AIMS: Atrial fibrillation (AF) and flutter are common causes of hospitalizations but contemporary long-term outcomes following these episodes are uncertain. This study assessed outcomes up to 10 years after an acute AF or flutter hospitalization. METHODS: Patients hospitalized acutely with a primary diagnosis of AF or flutter from 2008-17 from all public and most private hospitals in Australia and New Zealand were included. Kaplan-Meier methods and flexible parametric survival modelling were used to estimate survival and loss in life expectancy, respectively. Competing risk model accounting for death was used when estimating incidence of non-fatal outcomes. RESULTS: A total of 260 492 adults (mean age 70.5 ± 14.4 years, 49.6% female) were followed up for 1 068 009 person-years (PY), during which 69 167 died (incidence rate 6.5/100 PY) with 91.2% survival at 1 year, 72.7% at 5 years, and 55.2% at 10 years. Estimated loss in life expectancy was 2.6 years, or 16.8% of expected life expectancy. Re-hospitalizations for heart failure (2.9/100 PY), stroke (1.7/100 PY), and myocardial infarction (1.1/100 PY) were common with respective cumulative incidences of 16.8%, 11.0%, and 7.1% by 10 years. Re-hospitalization for AF or flutter occurred in 21.3% by 1 year, 35.3% by 5 years, and 41.2% by 10 years (11.6/100 PY). The cumulative incidence of patients undergoing catheter ablation of AF was 6.5% at 10 years (1.2/100 PY). CONCLUSIONS: Patients hospitalized for AF or flutter had high death rates with an average 2.6-year loss in life expectancy. Moreover, re-hospitalizations for AF or flutter and related outcomes such as heart failure and stroke were common with catheter ablation used infrequently for treatment, which warrant further actions.


Asunto(s)
Fibrilación Atrial , Aleteo Atrial , Hospitalización , Humanos , Aleteo Atrial/epidemiología , Fibrilación Atrial/epidemiología , Fibrilación Atrial/mortalidad , Fibrilación Atrial/terapia , Femenino , Masculino , Anciano , Hospitalización/estadística & datos numéricos , Nueva Zelanda/epidemiología , Australia/epidemiología , Persona de Mediana Edad , Readmisión del Paciente/estadística & datos numéricos , Esperanza de Vida , Accidente Cerebrovascular/epidemiología , Accidente Cerebrovascular/etiología , Infarto del Miocardio/epidemiología , Infarto del Miocardio/mortalidad , Insuficiencia Cardíaca/epidemiología , Insuficiencia Cardíaca/mortalidad , Anciano de 80 o más Años , Incidencia
4.
Heart Lung Circ ; 32(5): 619-628, 2023 May.
Artículo en Inglés | MEDLINE | ID: mdl-37003938

RESUMEN

BACKGROUND: Prior studies have reported a high rate of unplanned readmissions following acute percutaneous coronary intervention (PCI). Data outside the USA comparing 30-day unplanned readmissions following elective PCI to those who undergo acute PCI remain limited. METHODS: Patients who underwent a PCI procedure in Australia and New Zealand between 2010 and 2015 were included. We determined the rates, causes and predictors of 30-day unplanned readmissions, as well as rates of repeat revascularisation procedures, for patients who underwent an elective or acute PCI. Predictors of readmissions were identified using logistic regression. RESULTS: A total of 199,686 PCI encounters were included, of which 74,890 (37.5%) were elective and 124,796 (62.5%) were acute procedures. Overall, 10.6% of patients had at least one unplanned readmission within 30 days of discharge with lower rates following elective PCI (7.0%) compared to acute PCI (12.7%) (p<0.01). Non-specific chest pain was the commonest cause of readmission after elective and acute PCI, accounting for 20.7% and 21.5% of readmission diagnoses, respectively. Readmissions for acute myocardial infarction (13.0% vs 4.6%, p<0.01) and heart failure (6.5% vs 3.3%, p<0.01) were higher following acute PCI compared to elective PCI. Among readmitted patients, 16.7% had a coronary catheterisation, 12.2% had a PCI and 0.7% had coronary artery bypass surgery. Multivariable predictors of 30-day unplanned readmission included female sex and comorbidities such as heart failure, metastatic disease, chronic lung disease and renal failure (p<0.0001 for all). CONCLUSIONS: Unplanned readmissions following elective or acute PCI are high. Clinical and quality-control measures are required to prevent avoidable readmissions in both settings.


Asunto(s)
Insuficiencia Cardíaca , Infarto del Miocardio , Intervención Coronaria Percutánea , Humanos , Femenino , Readmisión del Paciente , Intervención Coronaria Percutánea/efectos adversos , Infarto del Miocardio/epidemiología , Comorbilidad , Factores de Riesgo , Estudios Retrospectivos , Resultado del Tratamiento
5.
Stroke ; 53(8): 2538-2548, 2022 08.
Artículo en Inglés | MEDLINE | ID: mdl-35418238

RESUMEN

BACKGROUND: Data on long-term outcomes following an acute stroke are sparse. We assessed survival, risk of recurrent stroke and loss in life expectancy following an acute stroke using population-wide data from Australia and New Zealand. METHODS: We included all adults with the first stroke hospitalization during 2008 and 2017 at all public and most private hospitals. Patients were followed up to 10 years after the stroke by linkage to each region's Registry of Deaths and subsequent hospitalizations. Flexible parametric survival modeling was used to estimate all-cause mortality, stroke recurrence, and loss in life expectancy. Competing risk model was used when estimating the risk of stroke recurrence. RESULTS: Three hundred thirteen thousand one hundred sixty-two patients were included (mean age 73.0±14.6 y, 52.0% males) with ischemic stroke (175 547, 56.1%) being the most common, followed by hemorrhagic stroke (77 940, 24.9%) and unspecified stroke (59 675, 19.1%). The overall survival probability was 79.4% at 3 months, 73.0% at 1 year, 52.8% at 5 years, and 36.4% at 10 years. Cumulative incidence of stroke recurrence was 7.8% at 3 months, 11.0% at 1 year, 19.8% at 5 years, and 26.8% at 10 years. Hemorrhagic stroke was associated with greater mortality (hazard ratio, 2.02 [95% CI, 1.99-2.04]) and recurrent stroke (hazard ratio, 1.63 [95% CI, 1.59-1.67]) compared with ischemic stroke. Female sex (hazard ratio, 1.10 [95% CI, 1.09-1.11]) and increasing age (≥85 years versus 18-54 years: hazard ratio, 7.36 [95% CI, 7.15-7.57]) were also associated with increased mortality. Several risk factors including atherosclerotic coronary and noncoronary vascular disease, cardiac arrhythmia, and diabetes were associated with increased risk of mortality and recurrent stroke. Compared with the general population, an acute stroke was associated with a loss of 5.5 years of life expectancy, or 32.7% of the predicted life expectancy, and was pronounced in patients with a hemorrhagic stroke (7.4 years and 38.5% of predicted life expectancy lost). CONCLUSIONS: In this population-wide study, death and recurrence of stroke were common after an acute stroke and an acute stroke was associated with considerable loss in life expectancy. Further improvements in treatment and secondary prevention of stroke are needed to reduce these risks.


Asunto(s)
Accidente Cerebrovascular Hemorrágico , Accidente Cerebrovascular Isquémico , Accidente Cerebrovascular , Adulto , Anciano , Anciano de 80 o más Años , Estudios de Cohortes , Femenino , Humanos , Esperanza de Vida , Masculino , Persona de Mediana Edad , Nueva Zelanda/epidemiología , Recurrencia , Factores de Riesgo , Accidente Cerebrovascular/etiología
6.
J Card Surg ; 37(5): 1233-1239, 2022 May.
Artículo en Inglés | MEDLINE | ID: mdl-35187728

RESUMEN

OBJECTIVE: The study aimed to evaluate the indications and describe the aortic valve reconstruction techniques by Ozaki's procedure in Vietnam and report mid-term outcomes of this technique in Vietnam. METHODS: Between June 2017 and December 2019, 72 patients diagnosed with isolated aortic valve disease, with a mean age of 52.9 (19-79 years old), and a male:female ratio of 3:1 underwent aortic valve reconstruction surgery by Ozaki's technique at Cardiovascular Center, E Hospital, Vietnam. RESULTS: The aortic valve diseases consisted of aortic stenosis (42%), aortic regurgitation (28%), and a combination of both (30%). In addition, the proportion of aortic valves with bicuspid morphology and small annulus (≤21 mm) was 28% and 38.9%, respectively. The mean aortic cross-clamp time was 106 ± 13.8 min, mean cardiopulmonary bypass time was 136.7 ± 18.5 min, and 2.8% of all patients required conversion to prosthetic valve replacement surgery. The mean follow-up time was 26.4 months (12-42 months), the survival rate was 95.8%, the reoperation rate was 2.8%, and rate of postoperative moderate or higher aortic valve regurgitation was 4.2%. Postoperative valvular hemodynamics was favorable, with a peak pressure gradient of 16.1 mmHg and an effective orifice area index of 2.3 cm2 . CONCLUSIONS: This procedure was safe and effective, with favorable valvular hemodynamics and a low rate of valvular degeneration. However, more long-term follow-up data are needed.


Asunto(s)
Insuficiencia de la Válvula Aórtica , Estenosis de la Válvula Aórtica , Implantación de Prótesis de Válvulas Cardíacas , Adulto , Anciano , Válvula Aórtica/cirugía , Insuficiencia de la Válvula Aórtica/cirugía , Estenosis de la Válvula Aórtica/cirugía , Femenino , Estudios de Seguimiento , Humanos , Masculino , Persona de Mediana Edad , Pericardio/trasplante , Resultado del Tratamiento , Vietnam/epidemiología , Adulto Joven
7.
Eur Heart J ; 43(1): 32-40, 2021 12 28.
Artículo en Inglés | MEDLINE | ID: mdl-33624819

RESUMEN

AIMS: Peripheral artery disease (PAD) revascularization can be performed by either endovascular or open surgical approach. Despite increasing use of endovascular revascularization, it is still uncertain which strategy yields better long-term outcomes. METHODS AND RESULTS: This retrospective cohort study evaluated patients hospitalized with PAD in Australia and New Zealand who underwent either endovascular or surgical revascularization between 2008 and 2015, and compared procedures using a propensity score-matched analysis. Hybrid interventions were excluded. The primary endpoint was mortality or major adverse limb events (MALE), defined as a composite endpoint of acute limb ischaemia, urgent surgical or endovascular reintervention, or major amputation, up to 8 years post-hospitalization using time-to-event analyses 75 189 patients fulfilled eligibility (15 239 surgery and 59 950 endovascular), from whom 14 339 matched pairs (mean ± SD age 71 ± 12 years, 73% male) with good covariate balance were identified. Endovascular revascularization was associated with an increase in combined MALE or mortality [hazard ratio (HR) 1.13, 95% confidence interval (CI): 1.09-1.17, P < 0.001]. There was a similar risk of MALE (HR 1.04, 95% CI: 0.99-1.10, P = 0.15), and all-cause urgent rehospitalizations (HR 1.01, 95% CI: 0.98-1.04, P = 0.57), but higher mortality (HR 1.16, 95% CI: 1.11-1.21, P < 0.001) when endovascular repair was compared to surgery. In subgroup analysis, these findings were consistent for both claudication and chronic limb-threatening ischaemia presentations. CONCLUSION: Although the long-term risk of MALE was comparable for both approaches, enduring advantages of surgical revascularization included lower long-term mortality. This is at odds with some prior PAD studies and highlights contention in this space.


Asunto(s)
Procedimientos Endovasculares , Enfermedad Arterial Periférica , Anciano , Anciano de 80 o más Años , Amputación Quirúrgica , Isquemia Crónica que Amenaza las Extremidades , Femenino , Humanos , Isquemia , Recuperación del Miembro , Extremidad Inferior , Masculino , Persona de Mediana Edad , Enfermedad Arterial Periférica/cirugía , Puntaje de Propensión , Estudios Retrospectivos , Factores de Riesgo , Factores de Tiempo , Resultado del Tratamiento
8.
Heart Lung Circ ; 31(7): 944-953, 2022 Jul.
Artículo en Inglés | MEDLINE | ID: mdl-35283016

RESUMEN

AIMS: Atrial fibrillation (AF) is a leading cause of hospitalisations, yet little is known about 30-day readmissions following discharge despite increasing policy focus on reducing readmissions. We assessed the rate, timing, causes and predictors of 30-day unplanned readmission following an acute and elective AF hospitalisation using population-wide data. METHODS: We studied all patients hospitalised for AF from 2010 to 2015 at all public and most private hospitals in Australia and New Zealand. The main outcome measures were unplanned readmissions within 30 days of discharge, primary diagnosis associated with these readmissions, and their predictors as modelled by logistic regression. RESULTS: Among 301,654 patients hospitalised for AF (mean age 69.2±13.6 yrs, 55.6% female, 65.2% acute presentations), 29,750 (9.9%) experienced an unplanned readmission within 30 days with 62.6% occurring by 14 days. Unplanned readmissions occurred more frequently following an acute versus elective AF hospitalisations (12.5% vs 4.9%, p<0.001). The most common diagnoses associated with readmissions were recurrence of AF (n=9,890, 33.2%), and preventable conditions including heart failure (n=2,683, 9.0%), pneumonia (n=724, 2.4%) and acute myocardial infarction (n=510, 1.7%). A higher risk of 30-day readmission was associated with congenital cardiac/circulatory defect (OR 2.18, CI 1.44-3.30), congestive heart failure (OR 1.34, CI 1.30-1.39), and arrhythmia/conduction disorders (OR 1.25, CI 1.21-1.28). CONCLUSION: Almost 1 in 10 AF hospitalisations resulted in unplanned readmission within 30-days, mostly for AF recurrence. Improved clinical management of AF and transitional care planning are required to reduce unplanned readmissions following AF hospitalisations.


Asunto(s)
Fibrilación Atrial , Insuficiencia Cardíaca , Anciano , Anciano de 80 o más Años , Fibrilación Atrial/epidemiología , Fibrilación Atrial/terapia , Femenino , Hospitalización , Humanos , Masculino , Persona de Mediana Edad , Nueva Zelanda/epidemiología , Readmisión del Paciente , Estudios Retrospectivos , Factores de Riesgo
9.
Med J Aust ; 214(11): 519-525, 2021 06.
Artículo en Inglés | MEDLINE | ID: mdl-33997979

RESUMEN

OBJECTIVE: To assess long term survival and patient characteristics associated with survival following acute myocardial infarction (AMI) in Australia and New Zealand. DESIGN: Cohort study. SETTING, PARTICIPANTS: All patients admitted with AMI (ICD-10-AM codes I21.0-I21.4) to all public and most private hospitals in Australia and New Zealand during 2009-2015. MAIN OUTCOME MEASURE: All-cause mortality up to seven years after an AMI. RESULTS: 239 402 initial admissions with AMI were identified; the mean age of the patients was 69.3 years (SD, 14.3 years), 154 287 were men (64.5%), and 64 335 had ST-elevation myocardial infarction (STEMI; 26.9%). 7-year survival after AMI was 62.3% (STEMI, 70.8%; non-ST-elevation myocardial infarction [NSTEMI], 59.2%); survival exceeded 85% for people under 65 years of age, but was 17.4% for those aged 85 years or more. 120 155 patients (50.2%) underwent revascularisation (STEMI, 72.2%; NSTEMI, 42.1%); 7-year survival exceeded 80% for patients in each group who underwent revascularisation, and was lower than 45% for those who did not. Being older (85 years or older v 18-54 years: adjusted hazard ratio [aHR], 10.6; 95% CI, 10.1-11.1) or a woman (aHR, 1.15; 95% CI, 1.13-1.17) were each associated with greater long term mortality during the study period, as was prior heart failure (aHR, 1.79; 95% CI, 1.76-1.83). Several non-cardiac conditions and geriatric syndromes common in these patients were independently associated with lower long term survival, including major and metastatic cancer, cirrhosis and end-stage liver disease, and dementia. CONCLUSION: AMI care in Australia and New Zealand is associated with high rates of long term survival; 7-year rates exceed 80% for patients under 65 years of age and for those who undergo revascularisation. Efforts to further improve survival should target patients with NSTEMI, who are often older and have several comorbid conditions, for whom revascularisation rates are low and survival after AMI poor.


Asunto(s)
Infarto del Miocardio sin Elevación del ST/epidemiología , Infarto del Miocardio con Elevación del ST/epidemiología , Sobrevivientes , Factores de Edad , Anciano , Anciano de 80 o más Años , Australia/epidemiología , Estudios de Cohortes , Femenino , Hospitalización , Humanos , Masculino , Persona de Mediana Edad , Nueva Zelanda/epidemiología , Infarto del Miocardio sin Elevación del ST/mortalidad , Infarto del Miocardio sin Elevación del ST/terapia , Factores de Riesgo , Infarto del Miocardio con Elevación del ST/mortalidad , Infarto del Miocardio con Elevación del ST/terapia , Factores Sexuales , Análisis de Supervivencia
10.
BMC Health Serv Res ; 21(1): 883, 2021 Aug 28.
Artículo en Inglés | MEDLINE | ID: mdl-34454482

RESUMEN

BACKGROUND: Little is known about the utilisation and safety of catheter ablation of atrial fibrillation (AF) among public and private sector hospitals. AIMS: To examine the uptake of AF ablations and compare procedural safety between the sectors. METHOD: Hospitalisation data from all public and private hospitals in four large Australian states (NSW, QLD, VIC and WA) were used to identify patients undergoing AF ablation from 2012 to 17. The primary endpoint was any procedure-related complications up to 30-days post-discharge. Logistic regression was used to evaluate the association between treatment at a public hospital and risk of complications adjusting for covariates. RESULTS: Private hospitals performed most of the 21,654 AF ablations identified (n = 16,992, 78.5 %), on patients who were older (63.5 vs. 59.9y) but had lower rates of heart failure (7.9 % vs. 10.4 %), diabetes (10.2 % vs. 14.1 %), and chronic kidney diseases (2.4 % vs. 5.2 %) (all p < 0.001) than those treated in public hospitals. When compared with private hospitals, public hospitals had a higher crude rate of complications (7.25 % vs. 4.70 %, p < 0.001). This difference remained significant after adjustment (OR 1.74 [95 % CI 1.54-2.04]) and it occurred with both in-hospital (OR 1.83 [1.57-2.14]) and post-discharge (OR 1.39 [1.06-1.83]) complications, with certain complications including acute kidney injury (OR 5.31 [3.02-9.36]), cardiac surgery (OR 5.18 [2.19-12.27]), and pericardial effusion (OR 2.18 [1.50-3.16]). CONCLUSIONS: Private hospitals performed most of AF ablations in Australia with a lower rate of complications when compared with public hospitals. Further investigations are needed to identify the precise mechanisms of this observed difference.


Asunto(s)
Fibrilación Atrial , Ablación por Catéter , Cuidados Posteriores , Fibrilación Atrial/epidemiología , Fibrilación Atrial/cirugía , Australia/epidemiología , Ablación por Catéter/efectos adversos , Hospitales Privados , Humanos , Alta del Paciente , Sector Privado , Resultado del Tratamiento
11.
Semin Cell Dev Biol ; 75: 70-77, 2018 03.
Artículo en Inglés | MEDLINE | ID: mdl-28866329

RESUMEN

Export of protein-coding and non-coding RNA molecules from the nucleus to the cytoplasm is critical for gene expression. This necessitates the continuous transport of RNA species of different size, shape and function through nuclear pore complexes via export receptors and adaptor proteins. Here, we provide an overview of the major RNA export pathways in humans, highlighting the similarities and differences between each. Its importance is underscored by the growing appreciation that deregulation of RNA export pathways is associated with human diseases like cancer.


Asunto(s)
Núcleo Celular/metabolismo , Citoplasma/metabolismo , Isoformas de ARN/metabolismo , ARN/metabolismo , Transporte Activo de Núcleo Celular , Animales , Humanos , Modelos Biológicos , ARN/genética , Isoformas de ARN/genética , Transporte de ARN , Proteínas de Unión al ARN/genética , Proteínas de Unión al ARN/metabolismo
12.
Hum Mutat ; 40(10): 1841-1855, 2019 10.
Artículo en Inglés | MEDLINE | ID: mdl-31112317

RESUMEN

The activities of DNA-binding transcription factors, such as the multi-zinc-finger protein ZBTB18 (also known as RP58, or ZNF238), are essential to coordinate mammalian neurodevelopment, including the birth and radial migration of newborn neurons within the fetal brain. In humans, the majority of disease-associated missense mutations in ZBTB18 lie within the DNA-binding zinc-finger domain and are associated with brain developmental disorder, yet the molecular mechanisms explaining their role in disease remain unclear. To address this, we developed in silico models of ZBTB18, bound to DNA, and discovered that half of the missense variants map to residues (Asn461, Arg464, Glu486) predicted to be essential to sequence-specific DNA contact, whereas others map to residues (Leu434, Tyr447, Arg495) with limited contributions to DNA binding. We studied pathogenic variants to residues with close (N461S) and limited (R495G) DNA contact and found that each bound DNA promiscuously, displayed altered transcriptional regulatory activity in vitro, and influenced the radial migration of newborn neurons in vivo in different ways. Taken together, our results suggest that altered transcriptional regulation could represent an important pathological mechanism for ZBTB18 missense variants in brain developmental disease.


Asunto(s)
Corteza Cerebral/embriología , Corteza Cerebral/metabolismo , Mutación Missense , Neuronas/metabolismo , Proteínas Represoras/genética , Dedos de Zinc/genética , Animales , Proteínas de Unión al ADN/química , Proteínas de Unión al ADN/metabolismo , Regulación de la Expresión Génica , Células HEK293 , Células HeLa , Humanos , Ratones , Modelos Moleculares , Unión Proteica , Conformación Proteica , Dominios y Motivos de Interacción de Proteínas , Proteínas Represoras/química , Relación Estructura-Actividad
13.
Pediatr Crit Care Med ; 20(6): 560-567, 2019 06.
Artículo en Inglés | MEDLINE | ID: mdl-31166288

RESUMEN

OBJECTIVES: Our aim was to perform an antimicrobial time-out 48-72 hours after commencing therapy in order to achieve a decrease in days of therapy per 1,000 patient days for vancomycin, meropenem, and piperacillin/tazobactam in all PICU patients during an 8-month period. DESIGN: This is a pre- and postimplementation quality improvement study. SETTINGS: A 30-bed PICU at a tertiary children's hospital. PATIENTS: Patients less than 21 years old admitted to the PICU from July 1, 2015, until March 31, 2016, or from July 1, 2016, until March 31, 2017, who received antibiotics for greater than 48 hours were eligible for inclusion. INTERVENTION: An antimicrobial time-out was performed after 48-72 hours of antimicrobials for all patients in the PICU during postimplementation. MEASUREMENTS AND MAIN RESULTS: The primary outcome measure was days of therapy per 1,000 patient-days for three target antibiotics: vancomycin, meropenem, and piperacillin/tazobactam. Ninety-five patients meeting inclusion criteria were admitted to the PICU during the pre-time-out period and 95 patients during the post-time-out period. The cohort that underwent time-outs had lower days of therapy for vancomycin (81.3 vs 138.1; p = 0.037) and meropenem (34.7 vs 67.1; p = 0.045). Total acquisition cost was 31 % lower for piperacillin/tazobactam and vancomycin and 46% for meropenem post implementation. Time-outs led to antimicrobial duration being defined 63% of the time and deescalation or discontinuation of antimicrobials 29% of the time. CONCLUSIONS: A 48-72-hour time-out process in rounds is associated with a reduction in days of therapy for antibiotics commonly used in the PICU and may lead to more appropriate usage. The time-outs are associated with discontinuation, deescalation, or duration being defined, which are key elements of Centers for Disease Control and Prevention-recommended antimicrobial stewardship programs.


Asunto(s)
Antibacterianos/administración & dosificación , Antiinfecciosos/administración & dosificación , Unidades de Cuidado Intensivo Pediátrico/estadística & datos numéricos , Antibacterianos/economía , Antibacterianos/uso terapéutico , Antiinfecciosos/economía , Antiinfecciosos/uso terapéutico , Niño , Preescolar , Quimioterapia Combinada , Utilización de Medicamentos/economía , Utilización de Medicamentos/estadística & datos numéricos , Duración de la Terapia , Femenino , Humanos , Lactante , Masculino , Meropenem/administración & dosificación , Meropenem/economía , Combinación Piperacilina y Tazobactam/administración & dosificación , Combinación Piperacilina y Tazobactam/economía , Calidad de la Atención de Salud , Estudios Retrospectivos , Centros de Atención Terciaria , Vancomicina/administración & dosificación , Vancomicina/economía
14.
Hum Mol Genet ; 25(21): 4635-4648, 2016 11 01.
Artículo en Inglés | MEDLINE | ID: mdl-28158450

RESUMEN

Mutation in a growing spectrum of genes is known to either cause or contribute to primary or secondary microcephaly. In primary microcephaly the genetic determinants frequently involve mutations that contribute to or modulate the microtubule cytoskeleton by causing perturbations of neuronal proliferation and migration. Here we describe four patients from two unrelated families each with an infantile neurodegenerative disorder characterized by loss of developmental milestones at 9­24 months of age followed by seizures, dystonia and acquired microcephaly. The patients harboured homozygous missense mutations (A475T and A586V) in TBCD, a gene encoding one of five tubulin-specific chaperones (termed TBCA-E) that function in concert as a nanomachine required for the de novo assembly of the α/ß tubulin heterodimer. The latter is the subunit from which microtubule polymers are assembled. We found a reduced intracellular abundance of TBCD in patient fibroblasts to about 10% (in the case of A475T) or 40% (in the case of A586V) compared to age-matched wild type controls. Functional analyses of the mutant proteins revealed a partially compromised ability to participate in the heterodimer assembly pathway. We show via in utero shRNA-mediated suppression that a balanced supply of tbcd is critical for cortical cell proliferation and radial migration in the developing mouse brain. We conclude that TBCD is a novel functional contributor to the mammalian cerebral cortex development, and that the pathological mechanism resulting from the mutations we describe is likely to involve compromised interactions with one or more TBCD-interacting effectors that influence the dynamics and behaviour of the neuronal cytoskeleton.


Asunto(s)
Trastornos Heredodegenerativos del Sistema Nervioso/genética , Microcefalia/genética , Proteínas Asociadas a Microtúbulos/genética , Animales , Encéfalo/metabolismo , Citoesqueleto/metabolismo , Fibroblastos/metabolismo , Trastornos Heredodegenerativos del Sistema Nervioso/metabolismo , Humanos , Lactante , Recién Nacido , Ratones , Ratones Endogámicos C57BL/embriología , Proteínas Asociadas a Microtúbulos/metabolismo , Microtúbulos/genética , Microtúbulos/fisiología , Tubulina (Proteína)/genética , Tubulina (Proteína)/metabolismo , Secuenciación del Exoma/métodos
15.
Angew Chem Int Ed Engl ; 57(11): 2929-2933, 2018 03 05.
Artículo en Inglés | MEDLINE | ID: mdl-29349857

RESUMEN

A chemoenzymatic synthon was designed to expand the scope of the chemoenzymatic synthesis of carbohydrates. The synthon was enzymatically converted into carbohydrate analogues, which were readily derivatized chemically to produce the desired targets. The strategy is demonstrated for the synthesis of glycosides containing 7,9-di-N-acetyllegionaminic acid (Leg5,7Ac2 ), a bacterial nonulosonic acid (NulO) analogue of sialic acid. A versatile library of α2-3/6-linked Leg5,7Ac2 -glycosides was built by using chemically synthesized 2,4-diazido-2,4,6-trideoxymannose as a chemoenzymatic synthon for highly efficient one-pot multienzyme (OPME) sialylation followed by downstream chemical conversion of the azido groups into acetamido groups. The syntheses required 10 steps from commercially available d-fucose and had an overall yield of 34-52 %, thus representing a significant improvement over previous methods. Free Leg5,7Ac2 monosaccharide was also synthesized by a sialic acid aldolase-catalyzed reaction.


Asunto(s)
Azidas/química , Glicósidos/síntesis química , Manosa/análogos & derivados , Ácidos Siálicos/síntesis química , Acetilación , Azidas/síntesis química , Bacterias/enzimología , Técnicas de Química Sintética , Glicósidos/química , Manosa/síntesis química , Ácidos Siálicos/química
16.
Hum Mol Genet ; 23(19): 5147-58, 2014 Oct 01.
Artículo en Inglés | MEDLINE | ID: mdl-24833723

RESUMEN

The microtubule cytoskeleton is critical for the generation and maturation of neurons in the developing mammalian nervous system. We have previously shown that mutations in the ß-tubulin gene TUBB5 cause microcephaly with structural brain abnormalities in humans. While it is known that TUBB5 is necessary for the proper generation and migration of neurons, little is understood of the role it plays in neuronal differentiation and connectivity. Here, we report that perturbations to TUBB5 disrupt the morphology of cortical neurons, their neuronal complexity, axonal outgrowth, as well as the density and shape of dendritic spines in the postnatal murine cortex. The features we describe are consistent with defects in synaptic signaling. Cellular-based assays have revealed that TUBB5 substitutions have the capacity to alter the dynamic properties and polymerization rates of the microtubule cytoskeleton. Together, our studies show that TUBB5 is essential for neuronal differentiation and dendritic spine formation in vivo, providing insight into the underlying cellular pathology associated with TUBB5 disease states.


Asunto(s)
Diferenciación Celular/genética , Corteza Cerebral/metabolismo , Espinas Dendríticas/metabolismo , Mutación , Neuronas/citología , Neuronas/metabolismo , Tubulina (Proteína)/genética , Animales , Axones/metabolismo , Corteza Cerebral/embriología , Femenino , Expresión Génica , Técnicas de Silenciamiento del Gen , Genes Reporteros , Ratones , Microtúbulos/química , Microtúbulos/metabolismo , Neuronas/patología , Multimerización de Proteína , Interferencia de ARN
17.
Artículo en Inglés | MEDLINE | ID: mdl-27190496

RESUMEN

BACKGROUND: Severe dysphagia may occur in the immune mediated necrotizing myopathies (IMNM). Neck swelling and severe dysphagia as the initial symptoms upon presentation has not been previously described. CASE PRESENTATION: A 55-year-old male with a 4 week history of neck swelling, fatigue, dysphagia, myalgias, night sweats, and cough was admitted for an elevated CK. He underwent extensive infectious and inflammatory evaluation including neck imaging and muscle biopsy. Neck CT and MRI showed inflammation throughout his strap muscles, retropharyngeal soft tissues and deltoids. Infectious work up was negative. Deltoid muscle biopsy demonstrated evidence of IMNM. Lab tests revealed anti-3-hydroxy-3-methylglutaryl-coenzyme A reductase (HMGCR) antibodies confirming the diagnosis of HMGCR IMNM. CONCLUSIONS: HMGCR IMNM is a rare and incompletely understood disease process. Awareness of HMGCR IMNM could potentially lead to earlier diagnosis, treatment and improved clinical outcomes as disease progression can be rapid and severe.

19.
Hum Mutat ; 41(12): 2217, 2020 Dec.
Artículo en Inglés | MEDLINE | ID: mdl-33244835
20.
J Plast Reconstr Aesthet Surg ; 91: 105-110, 2024 Apr.
Artículo en Inglés | MEDLINE | ID: mdl-38412600

RESUMEN

BACKGROUND: Single-stage microtia auricular reconstruction is becoming more relevant. The determining factor is a temporoparietal fascia flap (TPF) with both branches of the superficial temporal artery (STA). There are not many studies regarding vascular branching in people with microtia. METHODS: We conducted an anatomical study on the TPF flap harvested during single-stage endoscopic-assisted microtia auricular reconstruction from May 2018 to July 2021. We observed the flaps under endoscopic and surgical microscopes to determine several variables (vascular size, number of frontal/parietal branches, distance from the branching location to the estimated external ear canal, distance from the frontal artery to projected course of facial nerve's frontal branch, etc.). RESULTS: The study included 55 flaps from 54 patients. Of the 55 flaps, 50 (90.9%) had a parietal branch, and all 55 (100%) had a frontal branch with a mean diameter of 0.98 and 0.91 mm, respectively. Regarding the frontal artery, 1.8%, 25.5%, 50.9%, 16.35% and 5.45% had 0-4 traverse frontal branch(es), respectively. The mean distance from the frontal artery to the estimated course of the frontal nerve was 10.56 mm. Parietal artery absence is more likely in patients with severe hemifacial microsomia or STA trunk go under the auricular cartilage remnants (p < 0.05). Either frontal or parietal artery absence or small diameter can cause necrosis. Frontal arteries travelling near the frontal nerve may result in post-operative nerve palsy. CONCLUSIONS: Microtia auricular reconstructive surgery is always a big challenge for plastic surgeons. Anatomical variants are common. A detailed anatomical description of the STA, with the help of microsurgery and endoscopy, allows arterial-based flap designing and harvest, which tremendously improves surgical success rate by diminishing flap necrosis and nerve damage. CLINICAL QUESTION/LEVEL OF EVIDENCE: Therapeutic, IV.


Asunto(s)
Microtia Congénita , Humanos , Microtia Congénita/cirugía , Arterias Temporales/cirugía , Colgajos Quirúrgicos/irrigación sanguínea , Fascia/trasplante , Necrosis
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