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V(D)J recombination is essential to generate antigen receptor diversity but is also a potent cause of genome instability. Many chromosome alterations that result from aberrant V(D)J recombination involve breaks at single recombination signal sequences (RSSs). A long-standing question, however, is how such breaks occur. Here, we show that the genomic DNA that is excised during recombination, the excised signal circle (ESC), forms a complex with the recombinase proteins to efficiently catalyze breaks at single RSSs both in vitro and in vivo. Following cutting, the RSS is released while the ESC-recombinase complex remains intact to potentially trigger breaks at further RSSs. Consistent with this, chromosome breaks at RSSs increase markedly in the presence of the ESC. Notably, these breaks co-localize with those found in acute lymphoblastic leukemia patients and occur at key cancer driver genes. We have named this reaction "cut-and-run" and suggest that it could be a significant cause of lymphocyte genome instability.
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Inestabilidad Genómica/genética , Leucemia-Linfoma Linfoblástico de Células Precursoras/genética , Translocación Genética/genética , Recombinación V(D)J/genética , Animales , Secuencia de Bases/genética , Células COS , Chlorocebus aethiops , Cromosomas/genética , ADN/genética , Roturas del ADN de Doble Cadena , Células HEK293 , Proteínas de Homeodominio/genética , Humanos , Ratones , Células 3T3 NIH , Leucemia-Linfoma Linfoblástico de Células Precursoras/patología , Recombinasas/genéticaRESUMEN
Transcription enhancers are essential activators of V(D)J recombination that orchestrate non-coding transcription through complementary, unrearranged gene segments. How transcription is coordinately increased at spatially distinct promoters, however, remains poorly understood. Using the murine immunoglobulin lambda (Igλ) locus as model, we find that three enhancer-like elements in the 3' Igλ domain, Eλ3-1, HSCλ1 and HSE-1, show strikingly similar transcription factor binding dynamics and close spatial proximity, suggesting that they form an active enhancer hub. Temporal analyses show coordinate recruitment of complementary V and J gene segments to this hub, with comparable transcription factor binding dynamics to that at enhancers. We find further that E2A, p300, Mediator and Integrator bind to enhancers as early events, whereas YY1 recruitment and eRNA synthesis occur later, corresponding to transcription activation. Remarkably, the interplay between sense and antisense enhancer RNA is central to both active enhancer hub formation and coordinate Igλ transcription: Antisense Eλ3-1 eRNA represses Igλ activation whereas temporal analyses demonstrate that accumulating levels of sense eRNA boost YY1 recruitment to stabilise enhancer hub/promoter interactions and lead to coordinate transcription activation. These studies therefore demonstrate for the first time a critical role for threshold levels of sense versus antisense eRNA in locus activation.
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Cadenas lambda de Inmunoglobulina , Transcripción Genética , Animales , Ratones , Elementos de Facilitación Genéticos , Cadenas lambda de Inmunoglobulina/genética , ARN sin Sentido/genética , Factores de Transcripción/genéticaRESUMEN
Activating variants in the PIK3CA gene cause a heterogeneous spectrum of disorders that involve congenital or early-onset segmental/focal overgrowth, now referred to as PIK3CA-related overgrowth spectrum (PROS). Historically, the clinical diagnoses of patients with PROS included a range of distinct syndromes, including CLOVES syndrome, dysplastic megalencephaly, hemimegalencephaly, focal cortical dysplasia, Klippel-Trenaunay syndrome, CLAPO syndrome, fibroadipose hyperplasia or overgrowth, hemihyperplasia multiple lipomatosis, and megalencephaly capillary malformation-polymicrogyria (MCAP) syndrome. MCAP is a sporadic overgrowth disorder that exhibits core features of progressive megalencephaly, vascular malformations, distal limb malformations, cortical brain malformations, and connective tissue dysplasia. In 2012, our research group contributed to the identification of predominantly mosaic, gain-of-function variants in PIK3CA as an underlying genetic cause of the syndrome. Mosaic variants are technically more difficult to detect and require implementation of more sensitive sequencing technologies and less stringent variant calling algorithms. In this study, we demonstrated the utility of deep sequencing using the Illumina TruSight Oncology 500 (TSO500) sequencing panel in identifying variants with low allele fractions in a series of patients with PROS and suspected mosaicism: pathogenic, mosaic PIK3CA variants were identified in all 13 individuals, including 6 positive controls. This study highlights the importance of screening for low-level mosaic variants in PROS patients. The use of targeted panels with deep sequencing in clinical genetic testing laboratories would improve diagnostic yield and accuracy within this patient population.
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Anomalías Múltiples , Megalencefalia , Anomalías Musculoesqueléticas , Enfermedades Cutáneas Vasculares , Telangiectasia/congénito , Malformaciones Vasculares , Humanos , Mutación , Anomalías Musculoesqueléticas/genética , Fosfatidilinositol 3-Quinasa Clase I/genética , Malformaciones Vasculares/diagnóstico , Malformaciones Vasculares/genética , Secuenciación de Nucleótidos de Alto RendimientoRESUMEN
Broadly neutralizing antibodies have huge potential as novel antiviral therapeutics due to their ability to recognize highly conserved epitopes that are seldom mutated in viral variants. A subset of bovine antibodies possess an ultralong complementarity-determining region (CDR)H3 that is highly adept at recognizing such conserved epitopes, but their reactivity against Sarbecovirus Spike proteins has not been explored previously. Here, we use a SARS-naïve library to isolate a broadly reactive bovine CDRH3 that binds the receptor-binding domain of SARS-CoV, SARS-CoV-2, and all SARS-CoV-2 variants. We show further that it neutralizes viruses pseudo-typed with SARS-CoV Spike, but this is not by competition with angiotensin-converting enzyme 2 (ACE2) binding. Instead, using differential hydrogen-deuterium exchange mass spectrometry, we demonstrate that it recognizes the major site of vulnerability of Sarbecoviruses. This glycan-shielded cryptic epitope becomes available only transiently via interdomain movements of the Spike protein such that antibody binding triggers destruction of the prefusion complex. This proof of principle study demonstrates the power of in vitro expressed bovine antibodies with ultralong CDRH3s for the isolation of novel, broadly reactive tools to combat emerging pathogens and to identify key epitopes for vaccine development.
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Anticuerpos Antivirales , Regiones Determinantes de Complementariedad , Glicoproteína de la Espiga del Coronavirus , Animales , Bovinos , Anticuerpos Neutralizantes , Anticuerpos Antivirales/genética , Regiones Determinantes de Complementariedad/genética , Epítopos/genética , SARS-CoV-2/genética , Coronavirus Relacionado al Síndrome Respiratorio Agudo Severo/genética , Glicoproteína de la Espiga del Coronavirus/genéticaRESUMEN
BACKGROUND: Post-hemorrhagic ventricular dilatation (PHVD) in preterm infants can be assessed with ventricular size indices from cranial ultrasound. We explored inter-observer reliability of these indices for prediction of severe PHVD. METHODS: For all 139 infants with IVH, serial neonatal ultrasound at 3 time points (days 4-7, day 14, 36 weeks PMA) were assessed independently by 3 observers with differing levels of training/experience. Ventricular index (VI), anterior horn width (AHW), and fronto-temporal horn ratio (FTHR) were measured and used to diagnose PHVD. For all, inter-observer reliability and predictive values for receipt of surgical intervention were calculated. RESULTS: Inter-observer reliability for all observers varied from poor to excellent, with higher reliability for VI/AHW (ICC 0.49-0.84/0.51-0.81) than FTHR (0.41-0.82), particularly from the second week. Good-excellent inter-expertise reliability was found between observers with ample experience/training (0.65-0.99), particularly for VI and AHW, while poor-moderate when comparing with an inexperienced observer (0.28-0.88). Slightly higher predictive value for PHVD intervention (n = 12) was found for AHW (AUC 0.86-0.96) than for VI and FTHR (0.80-0.96/0.80-0.95). CONCLUSIONS: AHW and VI are highly reproducible in experienced hands compared to FTHR, with AHW from the second week onwards being the strongest predictor for receiving surgical intervention for severe PHVD. AHW may aid in early PHVD diagnosis and decision-making on intervention. IMPACT: While ventricular size indices from serial cUS are superior to clinical signs of increased intracranial pressure to assess PHVD, questions remained on their inter-observer reproducibility and reliability to predict severity of PHVD. AHW and VI are highly reproducible when performed by experienced clinicians. AHW from the second week of birth is the strongest predictor of PHVD onset and severity. AHW, combined with VI, may aid in early PHVD diagnosis and decision-making on need for surgical intervention. Consistent use of these indices has the potential to improve PHVD management and therewith the long-term outcomes in preterm infants.
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Hemorragia Cerebral Intraventricular/diagnóstico por imagen , Ventrículos Cerebrales/diagnóstico por imagen , Recien Nacido Extremadamente Prematuro , Ultrasonografía , Femenino , Edad Gestacional , Humanos , Recién Nacido , Masculino , Variaciones Dependientes del Observador , Valor Predictivo de las Pruebas , Reproducibilidad de los Resultados , Estudios RetrospectivosRESUMEN
AIM: To evaluate the impact of outreach education targeting neuroprotection on outcomes of outborn infants with moderate-to-severe hypoxic ischemic encephalopathy (HIE). METHODS: A retrospective cohort study of infants admitted with moderate-to-severe HIE was conducted following the implementation of outreach education in January 2016. Key interventions were early identification and referral of infants with encephalopathy utilizing telemedicine and a centralized communication system, hands-on simulation, and interactive case discussion and dissemination of clinical management guidelines and educational resources. The association between the intervention and a composite outcome of death and/or severe brain injury on brain magnetic resonance imaging (MRI) was tested controlling for the confounding factors. RESULTS: Of 165 neonates, 37 (22.4%) died and/or had a severe brain injury. This outcome decreased from 35% (27/77) to 11% (10/88) following the implementation of outreach education (P<0.001). Eligible infants not undergoing therapeutic hypothermia within 6 hours from birth decreased from 19.5% (15/77) to 4.5% (4/88). The use of inotropes decreased from 49.3% (38/77) to 19.6% (13/88). Any core temperature below 33°C was recorded for 20/53 (38%) before and 16/78 (21%) after, while those within the target range of 33°C to 34°C at admission to a tertiary care facility increased from (15/53) 28% to (51/88) 58%. Outreach education was independently associated with decreased composite outcome of death and/or severe brain injury on MRI (adjusted odds ratio 0.2; 95% confidence interval 0.07 to 0.52). CONCLUSION: Outreach education targeting neuroprotection for infants with moderate-to-severe HIE was associated with a reduction in death and/or severe brain injury.
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OBJECTIVES: Brain injury in preterm neonates may cause clinical deterioration and requires timeous bedside diagnosis. Teaching cranial ultrasound (US) skills using fragile preterm neonates is challenging. The purpose of this study was to test the effectiveness and feasibility of using task-trainer computer-based simulators and US-suitable cranial phantoms in combination with teaching sessions in teaching novices to perform focused cranial US evaluations for identifying substantial intraventricular hemorrhage. METHODS: This was a prospective interventional educational study targeting participants with no prior skills in neonatal cranial US. Participants attended a 2-day training workshop, with didactic and hands-on interactive sessions using computer-based and 3-dimensional printed phantom simulators. Participants then performed a cranial US scan on a healthy neonate to assess the diagnostic quality of the images acquired. Individual precourse and postcourse knowledge tests were compared. To test recall, participants also submitted US images acquired on neonates within 3 and 6 months of attending the course. RESULTS: Forty-five participants completed the training modules. Mean knowledge scores increased significantly (in brain anatomy, brain physiology, intracranial disorders, and US physics domains). Thirty-eight cranial US scans were acquired during the course, 22 within 3 months after completion, and 34 within 6 months after completion. Thirty-two (84%) of the initial 38 case images, 17 (77%) of 22 images submitted within 3 months, and 32 (94%) of 34 images submitted within 6 months after course completion were of diagnostic quality. CONCLUSIONS: A structured training module with didactic and hand-on training sessions using simulators and phantoms is feasible and supports training of clinicians to perform focused cranial US examinations.
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Lesiones Encefálicas/diagnóstico por imagen , Simulación por Computador , Ecoencefalografía/métodos , Fantasmas de Imagen , Ultrasonido/educación , Competencia Clínica , Humanos , Recién Nacido , Nacimiento Prematuro , Estudios ProspectivosRESUMEN
Manganese (Mn) and zinc (Zn) are essential divalent cations used by cells as protein cofactors; various human studies and animal models have demonstrated the importance of Mn and Zn for development. Here we describe an autosomal-recessive disorder in six individuals from the Hutterite community and in an unrelated Egyptian sibpair; the disorder is characterized by intellectual disability, developmental delay, hypotonia, strabismus, cerebellar atrophy, and variable short stature. Exome sequencing in one affected Hutterite individual and the Egyptian family identified the same homozygous variant, c.112G>C (p.Gly38Arg), affecting a conserved residue of SLC39A8. The affected Hutterite and Egyptian individuals did not share an extended common haplotype, suggesting that the mutation arose independently. SLC39A8 is a member of the solute carrier gene family known to import Mn, Zn, and other divalent cations across the plasma membrane. Evaluation of these two metal ions in the affected individuals revealed variably low levels of Mn and Zn in blood and elevated levels in urine, indicating renal wasting. Our findings identify a human Mn and Zn transporter deficiency syndrome linked to SLC39A8, providing insight into the roles of Mn and Zn homeostasis in human health and development.
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Proteínas de Transporte de Catión/genética , Enfermedades Cerebelosas/genética , Enanismo/genética , Genes Recesivos , Discapacidad Intelectual/genética , Manganeso/sangre , Zinc/sangre , Adolescente , Proteínas de Transporte de Catión/metabolismo , Cationes Bivalentes , Enfermedades Cerebelosas/sangre , Enfermedades Cerebelosas/complicaciones , Enfermedades Cerebelosas/etnología , Niño , Enanismo/sangre , Enanismo/complicaciones , Enanismo/etnología , Etnicidad , Exoma , Femenino , Expresión Génica , Secuenciación de Nucleótidos de Alto Rendimiento , Humanos , Discapacidad Intelectual/sangre , Discapacidad Intelectual/complicaciones , Discapacidad Intelectual/etnología , Transporte Iónico , Masculino , Manganeso/orina , Población Blanca , Adulto Joven , Zinc/orinaRESUMEN
Severe longitudinally extensive transverse myelitis (LETM) can cause quadriplegia, marked sensory dysfunction, and respiratory failure. Some patients are unresponsive to conventional immune therapy. We report two cases of severe immune-mediated LETM requiring intensive care admission that failed to respond to high-dose corticosteroids, plasma exchange, intravenous immunoglobulin, and rituximab. Disease cessation and significant recovery was achieved after cyclophosphamide induction. In patients with severe acute immune-mediated LETM who fail to respond to corticosteroids and plasma exchange, cyclophosphamide induction should be considered. This agent and regimen provides a robust immunosuppressive response and can be induced rapidly. Cyclophosphamide effects and supportive evidence are discussed.
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Ciclofosfamida/uso terapéutico , Inmunosupresores/uso terapéutico , Mielitis Transversa/tratamiento farmacológico , Neuromielitis Óptica/tratamiento farmacológico , Femenino , Humanos , Imagen por Resonancia Magnética/métodos , Mielitis Transversa/diagnóstico , Mielitis Transversa/patología , Neuromielitis Óptica/diagnóstico , Neuromielitis Óptica/patología , Columna Vertebral/patología , Resultado del Tratamiento , Adulto JovenRESUMEN
Objective To compare the new intraventricular hemorrhage (IVH) Abdi score to the Papile grading system of IVH for prediction of composite outcome of death or neurodevelopmental impairment (NDI). Methods In a cohort study, all preterm infants with IVH who were born ≤1,250 g and/or ≤ 28 weeks of gestation at birth were prospectively followed up in our neonatal follow-up clinic. All cranial ultrasounds of the included infants were reviewed by neuroradiologists who were blinded to the clinical data and neurodevelopmental outcomes. Cranial ultrasounds were graded according to the Papile scoring system and by calculation of the Abdi score. Results A total of 183 preterm infants met inclusion and exclusion criteria. Of these, 80 (44%) had the composite primary outcome of death or NDI (51 died, 29 survived with NDI). The area under receiver operating characteristic curve for predicting death or NDI was 0.87 (95% confidence interval [CI]: 0.81-0.93) for Abdi score and 0.85 (95% CI: 0.79-0.91) for Papile grading (p = 0.04). Abdi scores had higher specificity than Papile grade II at Abdi score 5 (63.9 vs. 39.2%; p < 0.001) and Abdi score 6 (73.2 vs. 39.2%; p < 0.001). Conclusion Abdi scores seem to be more specific than Papile grading system in predicting death or NDI by 3 years' corrected age.
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Hemorragia Cerebral Intraventricular/diagnóstico por imagen , Mortalidad , Trastornos del Neurodesarrollo/epidemiología , Adolescente , Adulto , Hemorragia Cerebral Intraventricular/epidemiología , Preescolar , Estudios de Cohortes , Ecoencefalografía , Femenino , Humanos , Recien Nacido con Peso al Nacer Extremadamente Bajo , Recien Nacido Extremadamente Prematuro , Recién Nacido , Recien Nacido Prematuro , Recién Nacido de muy Bajo Peso , Masculino , Embarazo , Estudios Prospectivos , Medición de Riesgo , Índice de Severidad de la Enfermedad , Adulto JovenRESUMEN
TALE (transcription activator-like effector) proteins can be tailored to bind to any DNA sequence of choice and thus are of immense utility for genome editing and the specific delivery of transcription activators. However, to perform these functions, they need to occupy their sites in chromatin. In the present study, we have systematically assessed TALE binding to chromatin substrates and find that in vitro TALEs bind to their target site on nucleosomes at the more accessible entry/exit sites, but not at the nucleosome dyad. We show further that in vivo TALEs bind to transcriptionally repressed chromatin and that transcription increases binding by only 2-fold. These data therefore imply that TALEs are likely to bind to their target in vivo even at inactive loci.
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Cromatina/metabolismo , Transactivadores/metabolismo , Acetilación , Animales , Sitios de Unión , Ratones , Células 3T3 NIH , Unión ProteicaRESUMEN
BACKGROUND: The chronic cerebrospinal venous insufficiency theory proposes that altered cerebral venous hemodynamics play a role in the pathophysiology of multiple sclerosis. We aimed to explore the validity of this hypothesis by assessing the diagnostic criteria for chronic cerebrospinal venous insufficiency in persons with and without multiple sclerosis. METHODS: We compared the proportion of venous outflow abnormalities between patients with multiple sclerosis and healthy controls using extracranial Doppler ultrasonography and gadolinium-enhanced magnetic resonance venography. Interpreting radiologists were blinded to the clinical status of participants. RESULTS: We enrolled 120 patients with multiple sclerosis and 60 healthy controls. High proportions of both patients (67/115 [58%]) and controls (38/60 [63%]) met 1 or more of the proposed ultrasound criteria for diagnosis of chronic cerebrospinal venous insufficiency (p = 0.6). A minority of patients (23/115 [20%]) and controls (6/60 [10%]) fulfilled 2 or more of the proposed criteria (p = 0.1). There were no differences between patients and controls in the prevalence of each individual ultrasound criterion. Similarly, there were no differences in intracranial or extracranial venous patency between groups, as measured by magnetic resonance venography. INTERPRETATION: We detected no differences in the proportion of venous outflow abnormalities between patients with multiple sclerosis and healthy controls. Moreover, our study revealed significant methodologic concerns regarding the proposed diagnostic criteria for chronic cerebrospinal venous insufficiency that challenge their validity.
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Encéfalo/irrigación sanguínea , Venas Yugulares/fisiopatología , Angiografía por Resonancia Magnética , Esclerosis Múltiple/etiología , Médula Espinal/irrigación sanguínea , Ultrasonografía Doppler en Color , Insuficiencia Venosa/diagnóstico , Adulto , Velocidad del Flujo Sanguíneo , Estudios de Casos y Controles , Enfermedad Crónica , Estudios Transversales , Femenino , Humanos , Venas Yugulares/diagnóstico por imagen , Masculino , Persona de Mediana Edad , Estudios Prospectivos , Método Simple Ciego , Insuficiencia Venosa/complicaciones , Insuficiencia Venosa/diagnóstico por imagen , Insuficiencia Venosa/fisiopatologíaRESUMEN
Intraventricular hemorrhage with congenital cytomegalovirus (CMV) infection is rare and has been reported only in extremely premature infants or in association with thrombocytopenia. We report the first case of a full-term male infant with congenital CMV infection and intraventricular hemorrhage with a normal platelet count and coagulation profile. The infant also had a left subependymal cyst and bilateral occipital cysts without any other manifestations of CMV infection.
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Quistes Aracnoideos/diagnóstico , Infecciones por Citomegalovirus/congénito , Infecciones por Citomegalovirus/complicaciones , Citomegalovirus/aislamiento & purificación , Cardiopatías/diagnóstico , Hemorragia/diagnóstico , Adulto , Quistes Aracnoideos/patología , Femenino , Cabeza/diagnóstico por imagen , Cardiopatías/patología , Hemorragia/patología , Humanos , Recién Nacido , Imagen por Resonancia Magnética , Masculino , RadiografíaRESUMEN
Hypoxic-ischemic encephalopathy (HIE) and associated multiorgan injury are significant causes of morbidity and mortality in term and near-term neonates. Therapeutic hypothermia (TH) is the current standard of care for neuroprotection in neonates with HIE. In our experience, the majority of babies born with HIE were found in nontertiary care facilities in our region, where effective methods of cooling during transport to tertiary care centers are desirable. Most centers initiate passive TH at referral hospitals, while active cooling is typically initiated during transport. The objective of this study was to evaluate the effectiveness of three methods of cooling during transport of neonates with HIE in southern Alberta. In this prospective cohort study, 186 neonates with HIE were transported between January 2013 and December 2021. Among the 186 neonates, 47 were passively cooled, 36 actively cooled with gel packs, and 103 cooled with a servo-controlled cooling device. The clinical characteristics were comparable for the three groups, with no difference in adverse events. Fifteen neonates (8%) died and 54 neonates (29%) suffered radiologically determined brain injury. Servo-controlled cooling was found to be superior to other methods in maintaining a target temperature without significant fluctuation during transport and with temperature in the target range on arrival at tertiary care facilities. The rate of overcooling was also lower in the servo-controlled group compared with other groups. There were no statistically significant differences between the groups in relation to mortality and brain MRI changes associated with HIE. Adjusting for GA, 10-minute Apgar score, base excess, HIE stage, and need for intubation during transport, passive cooling increased the odds of temperature fluctuation outside the range by 12-fold and gel pack cooling by 13-fold compared with servo-controlled cooling. The use of servo-controlled TH devices should be the preferred practice wherever feasible. (REB17-1334_REN3).
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Hipotermia Inducida , Hipoxia-Isquemia Encefálica , Humanos , Recién Nacido , Hipotermia Inducida/métodos , Hipoxia-Isquemia Encefálica/terapia , Hipoxia-Isquemia Encefálica/etiología , Estudios Prospectivos , Estudios Retrospectivos , Temperatura CorporalRESUMEN
Crossed cerebellar diaschisis and bright pulvinar are rare in patients with status epilepticus. We present a case of a 53-year-old man who was found confused, incontinent, and nonverbal. The EEG findings were consistent with non-convulsive status epilepticus. The brain MR images showed findings consistent with crossed cerebellar diaschisis and bright pulvinar. We report and discuss this case to increase the awareness of these MRI signs in confused and obtunded patients.
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Cerebelo/patología , Imagen por Resonancia Magnética , Pulvinar/patología , Estado Epiléptico/patología , Electroencefalografía , Humanos , Masculino , Persona de Mediana EdadRESUMEN
OBJECTIVE: To study the impact of an evidence-based neuroprotection care (NPC) bundle on long-term neurodevelopmental impairment (NDI) in infants born extremely premature. STUDY DESIGN: An NPC bundle targeting predefined risk factors for acute brain injury in extremely preterm infants was implemented. We compared the incidence of composite outcome of death or severe neurodevelopmental impairment (sNDI) at 21 months adjusted age pre and post bundle implementation. RESULTS: Adjusting for confounding factors, NPC bundle implementation associated with a significant reduction in death or sNDI (aOR, 0.34; 95% CI 0.17-0.68; P = 0.002), mortality (aOR, 0.31; 95% CI (0.12-0.79); P = 0.015), sNDI (aOR, 0.37; 95% CI: 0.12-0.94; P = 0.039), any motor, language, or cognitive composite score <70 (aOR, 0.48; 95% CI: 0.26-0.90; P = 0.021). CONCLUSION: Implementation of NPC bundle targeting predefined risk factors is associated with a reduction in mortality or sNDI in extremely preterm infants.
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Trastornos del Neurodesarrollo , Paquetes de Atención al Paciente , Nacimiento Prematuro , Femenino , Humanos , Incidencia , Lactante , Recien Nacido Extremadamente Prematuro , Recién Nacido , Trastornos del Neurodesarrollo/epidemiología , Trastornos del Neurodesarrollo/etiología , Trastornos del Neurodesarrollo/prevención & control , NeuroprotecciónRESUMEN
BACKGROUND: We evaluated the effect of the quality improvement (QI) bundle on the rate of inotrope use and associated morbidities. METHODS: We included inborn preterm neonates born at < 29 weeks admitted to level III NICU. We implemented a QI bundle focusing on the first 72 h from birth which included delayed cord clamping, avoidance of routine echocardiography, the addition of clinical criteria to the definition of hypotension, factoring iatrogenic causes of hypotension, and standardization of respiratory management. The rate of inotropes use was compared before and after implementing the care bundle. Incidence of cystic periventricular leukomalacia (cPVL) was used as a balancing measure. RESULTS: QI bundle implementation was associated with significant reduction in overall use of inotropes (24 vs 7%, p < 0.001), dopamine (18 vs 5%, p < 0.001), and dobutamine (17 vs 4%, p < 0.001). Rate of acute brain injury decreased significantly: acute brain injury of any grade (34 vs 20%, p < 0.001) and severe brain injury (15 vs 6%, p < 0.001). There was no difference in the incidence of cPVL (0.8 vs 1.4%, p = 0.66). Associations remained significant after adjusting for confounding factors. CONCLUSIONS: A quality improvement bundled approach resulted in a reduction in inotropes use and associated brain morbidities in premature babies.
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Lesiones Encefálicas , Hipotensión , Hemodinámica , Humanos , Recién Nacido , Recien Nacido Prematuro , Mejoramiento de la CalidadRESUMEN
OBJECTIVE: To evaluate impact of a quality improvement (QI) outreach education on incidence of acute brain injury in transported premature neonates. STUDY DESIGN: Neonates born at <33 weeks gestation outside the tertiary center were included. The QI intervention was a combination of neuroprotection care bundle, in-person visits, and communication system improvement. Descriptive and regression (adjusting for Gestational Age, Birth Weight, Gender, and antenatal steroids, Mode of delivery, Apgars at 5 minutes, Prophylactic indomethacin, PDA, and Inotropes use) analyses were performed. The primary outcome was a composite of death and/or severe brain injury on cranial ultrasound using a validated classification. RESULTS: 181 neonates studied (93 before and 88 after). The rate and adjusted odds of death and/or severe brain injury reduced significantly post intervention (30% vs 15%) and (AOR 0.36, 95%CI, 0.15-0.85, P = 0.02) respectively. CONCLUSION: Implementation of outreach education targeting neuroprotection can reduce acute brain injury in transported premature neonates.
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Lesiones Encefálicas , Nacimiento Prematuro , Lesiones Encefálicas/epidemiología , Lesiones Encefálicas/prevención & control , Femenino , Edad Gestacional , Humanos , Incidencia , Indometacina , Recién Nacido , Embarazo , Mejoramiento de la Calidad , Estudios Retrospectivos , EsteroidesRESUMEN
Acquired brain injury remains common in very preterm infants and is associated with significant risks for short- and long-term morbidities. Cranial ultrasound has been widely adopted as the first-line neuroimaging modality to study the neonatal brain. It can reliably detect clinically significant abnormalities that include germinal matrix and intraventricular hemorrhage, periventricular hemorrhagic infarction, post-hemorrhagic ventricular dilatation, cerebellar hemorrhage, and white matter injury. The purpose of this article is to provide a consensus approach for detecting and classifying preterm brain injury to reduce variability in diagnosis and classification between neonatologists and radiologists. Our overarching goal with this work was to achieve homogeneity between different neonatal intensive care units across a large country (Canada) with regards to classification, timing of brain injury screening and frequency of follow up imaging. We propose an algorithmic approach that can help stratify different grades of germinal matrix-intraventricular hemorrhage, white matter injury, and ventricular dilatation in very preterm infants.
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Background: Perinatal hypoxia is a recognized cause of hypocalcemia in neonates in the first 3 days of life. Therapeutic hypothermia (TH) promotes neuroprotection by decreasing calcium influx into the cells during the reperfusion phase thereby increase serum calcium levels. This study examines the trends of serum calcium levels in neonates with hypoxic ischemic encephalopathy (HIE) and the effect of TH.Material and methods: A retrospective cohort study of neonates with moderate to severe HIE admitted to level III neonatal intensive care units (NICU's) in Calgary between September 2011 and October 2015. HIE was staged using modified Sarnat scoring system. Ionized calcium levels were followed in the first 3 days of age.Results: One hundred thirteen neonates admitted with the diagnosis of moderate to severe HIE were included; 89 (79%) underwent TH. Hypercalcemia was significantly higher with TH 57 (64%) compared to 8 (33%) in noncooled group (p = .007). Hypocalcemia was less in TH group; 11 (12%) compared to 5 (21%) in non TH group. Hypo/hypercarbia did not alter the serum calcium levels. Furthermore; there was no increase in the incidence of intracranial hemorrhage, clinical or electrographic seizures, antiepileptic drug use, or hypoxic/ischemic MRI changes with calcium derangements.Conclusion: The incidence of hypocalcemia was reduced by almost half and hypercalcemia was significantly increased with TH in the first 3 days of life. The reduction in hypocalcemia and the increase in hypercalcemia may be attributed to the neuroprotective effect of TH.